MSC Covid

Inflammopharmacology (2023) 31:171–206
https://doi.org/10.1007/s10787-022-01132-6 Inflammopharmacology
REVIEW
Critical roles of cytokine storm and bacterial infection in patients

with COVID‑19: therapeutic potential of mesenchymal stem cells
Babak Arjmand1,2 · Sepideh Alavi‑Moghadam1 · Masoumeh Sarvari2 · Mostafa Rezaei‑Tavirani3 ·
Ahmad Rezazadeh‑ Mafi4 · Rasta Arjmand1 · Mohsen Nikandish5 · Ensieh Nasli‐Esfahani6 · Bagher Larijani7
Received: 21 December 2022 / Accepted: 28 December 2022 / Published online: 4 January 2023
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2023
Abstract
The severe acute respiratory syndrome coronavirus 2 has been a shocking disaster for healthcare systems worldwide since
December 2019. This virus can affect all systems of the body and its symptoms vary from a simple upper respiratory infection
to fatal complications including end-organ damage. On the other hand, the normal immune system plays a pivotal role in the
recovery of infectious diseases such as COVID-19. However, occasionally, exaggerated immune system inflammation and
an excessive synthesis of cytokines, known as a "cytokine storm," can deteriorate the patient's clinical condition. Secondary
bacterial co-infection is another problem in COVID-19 which affects the prognosis of patients. Although there are a few
studies about this complication, they suggest not using antibiotics commonly, especially broad-spectrum ones. During this
pandemic, various approaches and therapeutics were introduced for treating COVID-19 patients. However, available treat-
ments are not helpful enough, especially for complicated cases. Hence, in this era, cell therapy and regenerative medicine
will create new opportunities. Therefore, the therapeutic benefits of mesenchymal stem cells, especially their antimicrobial
activity, will help us understand how to treat COVID-19. Herein, mesenchymal stem cells may stop the immune system from
becoming overactive in COVID-19 patients. On the other side, the stem cells' capacity for repair could encourage natural
healing processes.
Keywords Bacterial Infections · COVID-19 · Cytokine storm · Mesenchymal stem cells · Cell therapy
1
* Babak Arjmand Cell Therapy and Regenerative Medicine Research Center,
barjmand@sina.tums.ac.ir Endocrinology and Metabolism Molecular‑Cellular Sciences
Institute, Tehran University of Medical Sciences, Tehran,
Sepideh Alavi‑Moghadam
Iran
sepidalavi@gmail.com
2
Iranian Cancer Control Center (MACSA), Tehran, Iran
Masoumeh Sarvari
3
maasoomehsarvari@yahoo.com Proteomics Research Center, Shahid Beheshti University
of Medical Sciences, Tehran, Iran
Mostafa Rezaei‑Tavirani
4
Tavirany@yahoo.com Department of Radiation Oncology, Imam Hossein Hospital,
Shaheed Beheshti Medical University, Tehran, Iran
Ahmad Rezazadeh‑ Mafi
5
ahmadrmafi@yahoo.com AJA Cancer Epidemiology Research and Treatment Center
(AJA-CERTC), AJA University of Medical Sciences, Tehran,
Rasta Arjmand
Iran
rastaarjmand52@gmail.com
6
Diabetes Research Center, Endocrinology and Metabolism
Mohsen Nikandish
Clinical Sciences Institute, Tehran University of Medical
Mohsen.nik93@yahoo.com
Sciences, Tehran, Islamic Republic of Iran
Ensieh Nasli‐Esfahani 7
Endocrinology and Metabolism Research Center,
n.nasli@yahoo.com
Endocrinology and Metabolism Clinical Sciences Institute,
Bagher Larijani Tehran University of Medical Sciences, Tehran, Iran
emrc@tums.ac.ir
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Vol.:(0123456789)
172 B. Arjmand et al.
Abbreviations SOD Superoxide Dismutase

ACE2 Angiotensin-Converting Enzyme 2 TCZ Tocilizumab
ARDS Acute Respiratory Distress Syndrome TNF Tumor Necrosis Factor
CAT Catalase TGF-β Transforming Growth Factor-β
CCL5 C‑C motif Chemokine Ligand 5 TIMP Tissue Inhibitors of Matrix
COPD Chronic Obstructive Pulmonary Disease metalloproteinases
COVID-19 Coronavirus Disease 2019 TLRs Toll like Receptors
CRS Cytokine Release Storm TMPRSS2 Transmembrane protease serine 2
CXCL C-X-C motif Chemokine Ligand TTSPs Type-II Transmembrane Serine Proteases
DAMPs Damage Associated Molecular Patterns Tyk2 Tyrosine kinase 2
DCs Dendritic Cells VAP Ventilator-Associated Pneumonia
EGF Epidermal Growth Factor VEGF Vascular Endothelial Growth Factor
ERK Extracellular signal Regulated Kinase
EVs Extracellular Vesicles
FDA Food and Drug Administration Introduction
FGF Fibroblast Growth Factor
GH Growth Hormone Severe acute respiratory syndrome coronavirus 2 (SARS-
GM-CSF Granulocyte Macrophage Colony Stimu- CoV-2) first was identified in China in 2019, which spreads
lating Factor all over the world and causes the coronavirus pandemic. Cor-
GPx Glutathione Peroxidases onavirus disease- 2019 (COVID-19) can have a wide range
GSH Glutathione of symptoms ranging from asymptomatic cases to patients
HGF Hepatocyte Growth Factor with severe forms of COVID-19. Accordingly, while some
HSP70 Heat shock protein 70 cases are asymptomatic and some patients develop a viral
IDO Indoleamine 2, 3-dioxygenase upper respiratory infection, other individuals face life-threat-
IFN Interferon ening symptoms such pneumonia, respiratory failure, shock,
IGF-1 Insulin-like Growth Factor-1 and multi-organ dysfunction (Arjmand et al. 2020a; Azodi
IL Interleukin et al. 2020; Batu and Özen 2020; Aghili et al. 2021; Azodi
JAK-STAT Janus Kinase -Signal Transducer and Acti- et al. 2021). Additionally, cytokine storm or cytokine release
vator of Transcription syndrome (CRS), overproduction of cytokines, and bacterial
JNK Jun NH (2)-terminal Kinase co-infection or secondary bacterial infection are examples
LCN2 Lipocalin-2 of lethal complications of COVID-19 (Feng et al. 2020;
MAPK Mitogen Activated Protein Kinase Rana 2020, Moezzi et al. 2021). Herein, while COVID-19
MCP-1 Monocyte Chemoattractant Protein-1 is mostly transmitted through the lungs, it has been demon-
MMPs Matrix Metalloproteinases strated to also have gastrointestinal effects, with diarrhea
MSCs Mesenchymal Stem Cells being reported in roughly one-third of patients. Accord-
NF-κB Nuclear Factor kappa B ingly, bacterial transmission via the gastrointestinal tract
NK Natural Killer has the potential to exacerbate severe COVID-19 infection
NLRP3 Nucleotide-binding oligomerization and hyper inflammation (Wang et al. 2020; Sahu et al. 2021;
domain-like receptors containing pyrin Ghazanfar et al. 2022). Indeed, hyper inflammation and
domain 3 cytokine storm can worsen the patients’ conditions, espe-
NLRs Nucleotide-binding oligomerization cially in patients with prior immune system problems. In this
domain-like receptors respect, the pieces of literature have been shown that these
PAMPs Pathogen Associated Molecular Patterns severe complications are associated with immune-related
PDGF Platelet Derived Growth Factors and rheumatology diseases including rheumatoid arthri-
PGE2 Prostaglandin E2 tis (RA). Nevertheless, during this pandemic, managing
PTPs Protein Tyrosine Phosphatases COVID-19 and severe concurrent issues in addition to their
RA Rheumatoid Arthritis past immunosuppressive medications becomes a challenge
RAAS Renin Angiotensin Aldosterone System (Rana 2020; Song et al. 2020). Actually, secondary bacterial
RM Regenerative Medicine infections have been seen not only in COVID-19 but also in
SAR Sarilumab other viral respiratory infections such as influenza. Though
SARS-CoV-2 Severe Acute Respiratory Syndrome the overall rate of this complication is low, its proportion
Coronavirus 2 rate among the critical patients is slightly high. Accordingly,
SOCS Suppressor of Cytokine Signaling rapid diagnosis and on-time treatment is a vital to point in
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Critical roles of cytokine storm and bacterial infection in patients with COVID‑19: therapeutic… 173
these cases. Additionally, similar to other infections, con- human organs. ACE 2 as a part of Renin Angiotensin Aldos-
tacts, environmental exposures, airborne and droplets from terone System (RAAS) has an important role in controlling
other patients, as well as healthcare professionals, could human’s blood pressure. Indeed, ACE 2 activates a cascade
spread opportunistic organisms to highly sensitive patients of hormonal reactions in RAAS by converting angiotensin
and result in secondary infection in these patients. Thus, I to angiotensin II. On the other hand, SARS-CoV-2 enter
environmental exposures during the home or health-care host cells through ACE 2 and spread to various organs by
center isolation, hospital admission, and even convalescence free infected cells (Horiuchi et al. 1999; Wrapp et al. 2020).
time are highly affect the secondary infections rate (Hamel Additionally, studies have shown that SARS-CoV-2 down-
et al. 2010; Rice et al. 2012, Langford et al. 2020, Rawson regulates the ACE 2 receptor on cell membranes which leads
et al. 2020). Herein, although routine therapeutics includ- to imbalance of various parts of RAAS and finally organ
ing corticosteroids and antibiotics are used to manage these damage (Kuba et al. 2005). During SARS-CoV-2 infection,
problems, they cannot cure these patients (Fu et al. 2020; innate immune response activation leads to antiviral interfer-
Vaillancourt and Jorth 2020). Accordingly, new treatments ons and different chemokines production and attracts more
and techniques such as regenerative medicine (RM) and cell innate cells including polymorphonuclear leukocytes, mono-
therapy are required to improve the management of these cytes, natural killer (NK) cells, and dendritic cells (DCs) to
patients (Saeedi et al. 2019; Arjmand et al. 2021). In light the infective sites. Additionally, these mechanisms help to
of the information provided, this review will explore the recruit more lymphocytes and provide potent help to antivi-
immunopathology and pathophysiological mechanisms of ral activities of the innate response (Dandekar and Perlman
COVD-19, comorbidities such as secondary and co-bacterial 2005; Chen and Subbarao 2007). Also, adaptive response
infection, and potential novel therapeutic methods. assists the innate system to eliminate the virus through neu-
tralizing antibody production by B cells and the cytolytic
effect of CD8 T cells. Additionally, CD4 T cells contribute
COVID‑19: immunopathology to an adaptive response by various mechanisms including
and pathophysiological mechanisms other lymphoid cell recruitment, helping B cells to provide
high-affinity antibodies, CD8 T cell priming and etc. (Fig. 1;
Actually, immune system activates against the SARS-CoV-2 Sant and McMichael 2012; García 2020). As well, evidence
and its antiviral responses limit viral infection in human has shown the immune response is considerably different
body. However, SARS-CoV-2 by various mechanisms can in various clinical manifestations of COVID-19. For exam-
damage the normal immune response which causes the criti- ple, although in mild forms of COVID-19 innate NK-cells
cal morbidities. Accordingly, it will be possible to develop and transient short-lived Ig A, M, G antibodies play a piv-
novel medicines, improved management techniques, and otal role against the viral infection, in severe forms large
efficient vaccinations as a result of new insights into the amounts of monocytes and long-lived Ig A, G antibodies are
immunopathology and pathophysiological mechanisms of important (Carsetti et al. 2020). Interestingly, NK cells as a
this disease. Subsequently, the authors are summarized the frontline in the immune response against COVID-19 are a
opposing and protective functions of immunity in COVID- bridge between innate and adaptive immune responses. In
19(Alrubayyi 2020). this regard, a subset of NK cells called NKG2C + cells carry
out their cytotoxic effect and pro-inflammatory effector
Innate and adaptive immune responses molecules released by enhancing the activity of the CD94/
to SARS‑CoV‑2 infection NKG2C receptor and its HLA-E ligand (Vietzen et al. 2020).
Unfortunately, sometimes NK-cell cytolytic effect is dam-
SARS-CoV-2 is a new strain of the Coronaviridae fam- aged by virus interaction and cytokine storm effect. Hence,
ily of viruses that causes the various types of COVID-19 researchers suggest cytolytic NK-cell transferring as a poten-
from asymptomatic to severe and lethal forms. Accordingly, tial therapeutic method in COVID-19 (Ghasemzadeh et al.
the immune system through different mechanisms combat 2021). Collectively, a better understanding of the immune
SARS-CoV-2 infection. Some references has shown that in response against SARS-Cov-2 will promote the treatments
an early phase of infection, SARS-CoV-2 multiplies rapidly and vaccines.
in the body by suppressing the innate immune system. How-
ever, in late phases body’s immune system striking responses
can lead to severe complications including cytokine storm
and acute respiratory distress syndrome (ARDS) (Chowd-
hury et al. 2020; García 2020; Huang et al. 2020; Soleima-
nian and Yaghobi 2020). Angiotensin-converting enzyme 2
(ACE2) can be found in the membrane of different cells of
13
Lysis of infected
cells, GM-CSF
Innate immune cells e.g.

monocytes, macrophages,
neutrophils CD8
Effector
T cell
Naive Acvated
INF I, Interleukins, T cell T cell
NK cell Memory
chemokines T cell
Memory
B cell
B cell
Anbodies
Plasma cell
Fig. 1 Innate and adaptive immune response against SARS-CoV-2. Furthermore, innate immune cells, NK cells, INF I, and various inter-
SARS-CoV-2 enters host cells via ACE 2 receptors. Then virus leukins together help to induce humoral and cellular responses (León-
begins to replicates in the living cell which induces the inflammation. Rodríguez et al. 2020)
Hyper inflammation and cytokine storm; promote shedding of membrane receptors and boost endog-
signaling pathways enous shedding mechanisms can play a role in the develop-
ment of CRS (Földvári-Nagy et al. 2021).
Generally, cellular signaling networks are required for
replication, translation, nuclear membrane transport, cap- JAK/STAT signaling cascade
sid assembly, and dispersion, as well as the reactivation
of virus latency to produce infectious virus (Chi and Liu According to investigations, the Janus tyrosine kinase
2013). On the other hand, the immune system is equipped (JAK)—signal transducers and activators of transcription
with a sophisticated mechanism that can respond to a vari- (STAT) signaling pathway could be involved in the down-
ety of infections (Klimpel 1996; Chaplin 2010). Herein, the stream effects of ACE2 hyperactivation (Hu et al. 2021; Luo
immune system’s inflammatory pathways will be activated et al. 2021). On the other hand, the JAK-STAT pathway has
to produce a normal antiviral response (Fig. 2). Excessive a role in immune system coordination, especially cytokine
inflammatory response to the SARS-CoV-2 virus is fol- receptors, and can regulate T helper cell polarization. JAKs
lowed by the releasing a large number of pro-inflammatory (e.g., Jak1, Jak2, Jak3, and tyrosine kinase 2 (Tyk2)) bind to
cytokines. The mention life-threatening condition is known the cytoplasmic domains of type I and II cytokine receptors
as CRS. During days 8 to 12 of the infection, some people (Seif et al. 2017; Luo et al. 2021). When cytokine receptors
with COVID-19 pneumonia suffer from CRS. According to phosphorylate JAKs, subsequently STATs (STAT1-6) are
clinical definitions, they require oxygen therapy and have a phosphorylated and trafficked into the nucleus to translate
fever, exhaustion, anorexia, headaches, diarrhea, dyspnea, inflammatory mediators. Suppressors of cytokine signaling
coughing, and cyanosis (Marc et al. 2022). Indeed. The (SOCS), protein inhibitors of activated STATs (PIAS), and
CRS has been recognized as a significant cause of death protein tyrosine phosphatases (PTPs) are among the regula-
in COVID-19 individuals (Ragab et al. 2020; Sinha et al. tor proteins that control the beginning, length, and termi-
2020; Yang et al. 2021). In this respect, according to some nation of mentioned signaling cascades(Xu and Qu 2008;
evidence, when cytokine levels in the plasma of COVID- Krämer and Heinzel 2010; Seif et al. 2017). IL2-7 and
19 reported cases were compared to healthy individuals, IL-12, GM-CSF, growth hormone (GH), epidermal growth
higher levels of cytokines such as interleukin (IL)-6, IL-7, factor (EGF), platelet-derived growth factors (PDGF), and
IL-10, granulocyte–macrophage colony-stimulating factor IFNs are only a few of the cytokines and growth factors that
(GM-CSF), interferon(IFN-), tumor necrosis factor(TNF-), send signals through the JAK-STAT pathway(Bousoik and
and etc. were found (Han et al. 2020; Arjmand et al. 2021). Montazeri Aliabadi 2018; Hu et al. 2021; Yin et al. 2021).
Moreover, there is a theory that microorganisms that Accordingly, there is some evidence that inhibiting the JAK
13
Fig. 2 Signaling Pathways and COVID-19. TMPRSS2 is one of STAT)).When ACE2 is depleted, Ang II is overproduced, and its
the type-II transmembrane serine proteases (TTSPs) that cleaves attachment to AT1R activates the ADAM17 protease. ADAM17 can
the viral spike protein to reveal the fusion peptide for cell entrance. cleave membrane-anchored proteins and immunological cytokines
These TTSPs play a crucial role in the virus lifecycle. The binding e.g.,interlukin-6 (IL-6), tumor necrosis factor alpha (TNF- α), and
of the spike glycoprotein of the severe acute respiratory syndrome EGFR ligands, to initiate pro-inflammatory pathways. In addition,
coronavirus 2 (SARS-CoV-2) to angiotensin-converting enzyme 2 ADAM17 cleaves the Notch-ligand complex, and the -secretase
(ACE2) which is shedding by ADAM17 (A disintegrin and metal- complex cleaves the Notch intracellular domain, resulting in Notch
loprotease 17) can cause a dysregulation of the renin–angiotensin release and transport to the nucleus, as well as transcriptional activa-
system (RAS), favoring the ACE–angiotensin II (Ang II)–angioten- tion of Notch target genes such as inflammatory cytokines and furin.
sin II type I transmitter (AT1R) axis. The ACE2 enzyme transforms In the lungs, Des-arg9 bradykinin (DABK) is a biological substrate
Ang II into a heptapeptide (Ang 1–7) 7(When it binds to a specific of ACE2, and ACE2 deficiency resulted in DABK activation of the
receptor in the body, it has positive effects such as vasodilation, anti- bradykinin receptor (B1R) and the release of pro-inflammatory
thrombotic, anti-fibrotic, and anti-inflammatory) and Ang I into a chemokines. Furthermore, B1R activation can result in AT1R overex-
nonapeptide (Ang 1–9) as a master regulator of the RAS signaling pression, while ADAM17 stimulation can result in EGFR transactiva-
pathway. AT1R, G protein-coupled receptor (GPCR) family member, tion. The expression of B1R can be considerably increased by Ang II
regulates the harmful effects of Ang II by activating several down- stimulation, implying probable cross-talk between AT1R and B1R in
stream signaling pathways, for instance MAP kinases (p38MAPK), SARS-CoV-2 infection (de Queiroz et al. 2020; Furuhashi et al. 2020;
receptor tyrosine kinases (Epidermal growth factor receptor (EGFR)), Zipeto et al. 2020, Farahani et al. 2022). BioRender was used to cre-
and non-receptor tyrosine kinases (Janus tyrosine kinase (JAK)— ate this image
signal transducers and activators of transcription (STAT) (JAK/
-STAT pathway can be a therapeutic option for COVID-19 NF‑κB signaling cascade
treatment. In this context, multiple clinical trials are under
planned to investigate the possible use of JAK -STAT path- The nuclear factor kappa-light-chain enhancer of activated
way inhibitors in treating patients with COVID-19-associ- B cells (NF-kappaB) (NF-κB) family of transcription fac-
ated CRS (Alijotas-Reig et al. 2020; Satarker et al. 2021). tors is involved in immunity, inflammation, and cellular
13
development. The Rel-like domain-containing proteins be considered a plausible therapeutic target because of its
p65/RelA, RelB, c-Rel, NF-κB 1, and NF-κB 2 belong to involvement in the viral infection (Kumar et al. 2018; Yue
the NF-κB family (Oeckinghaus and Ghosh 2009; Gelmann and López 2020).
et al. 2013). NF-κB is an upstream regulator of IL-1, IL-2,
IL-6, IL-12, TNF-, LT-, GM-CSF, and other chemokines Notch signaling cascade
production in different cells e.g., macrophages in the central
nervous, cardiovascular, and gastrointestinal system, lungs, Notch signaling, a major regulator of the cardiovascular sys-
liver, and kidney (Hariharan and Hakeem 2021). AS the tem, has been linked to a range of viral infection-related bio-
other crucial point, the NF-κB has long been recognized as logical processes. Indeed, Notch pathway regulates a variety
a disease-causing factor and it is involved in inflammation. of proliferative and differentiation processes in cells, so it's
Herein, during SARS-CoV-2 prevalence, virus proteins trig- no wonder that viruses that rely on the cell cycle machinery
gered enhanced NF-κB activation, resulting in high disease find it appealing (Rizzo et al. 2020; Breikaa and Lilly 2021;
severity and death. Therefore, NF-κB pathway could be a Trivedi et al. 2021). FURIN is a Notch activator that belongs
target for therapeutic interventions (Li et al. 2021). to the protein convertases family. It has been discovered that
a variety of viruses, including measles, yellow fever, ebola,
NLRP3 signaling cascade and avian influenza, employ its enzymatic activity to boost
their pathogenicity and spread. In the case of COVID-19,
Nucleotide-binding oligomerization domain-like recep- SARS-CoV-2 S protein has two purposes: it binds the recep-
tors (NLRs) are intracellular pattern recognition proteins. tor and mediates the viral particle's integration into the cell
They can recognize pathogen-associated molecular patterns membrane. FURIN as a protease, cleaves Protein S, expos-
(PAMPs), damage-associated molecular patterns (DAMPs), ing the fusion sequences and allowing them to enter the
or other signals in the cytosol (Franchi et al. 2006). Since cell (Braun and Sauter 2019, Racaniello et al. 2020; Dayer
this is necessary for immune responses to invading patho- 2021). Generally, researchers believe Notch could be uti-
gens, inflammasome activation of the NLRs (containing lized to combat heart and lung disease induced directly by
pyrin domain 3 (NLRP3)) stimulates the release of cytokines SARS-CoV-2 infection and the cytokine storm that occurs
as a response to viral infection. Herein, the formation of a in response to the virus (Breikaa and Lilly 2021).
cytokine storm in severe COVID-19 individuals reveals that
the NLRP3 inflammasome is involved in COVID-19 (Batiha
et al. 2021; Zhao et al. 2021). Generally, viroporins, ion Bacterial infections in COVID‑19 patients
flux, and other complicated molecular processes activate the
NLRP3 inflammasome in response to SARS-CoV-2 infec- Several cell types, including lung epithelial cells and entero-
tion. Moreover, NLRP3 inflammation is linked to the onset cytes (in the ileum and colon), can express the ACE2 recep-
of respiratory, cardiovascular, and neurological symptoms tor. Enterocytes serve as columnar cells that make up the
in COVID-19. Accordingly, inhibitors that target the NLRP3 majority of the gastrointestinal intestine's epithelium. On
inflammasome and its downstream pathways are among the the other hand, bacteria can transmit via the gastrointestinal
novel attractive therapeutic intervention for COVID-19 tract; therefore, they have the potential to exacerbate severe
(Maes et al. 2021; Zhao et al. 2021). COVID-19 infection by occurring bacterial infection. Ser-
ratia marcescens, Staphylococcus aureus, Pseudomonas
MAP kinase signaling cascade aeruginosa, Listeria monocytogenes and etc. are some of
the bacteria that typically cause bacterial infections dur-
The mitogen-activated protein kinase (MAPK) as a family ing viral pneumonia (Fattorini et al. 2020; Földvári-Nagy
of highly conserved serine-threonine protein kinases (e.g., et al. 2021). Long-standing research has shown that bac-
extracellular signal-regulated kinase (ERK), p38, and c-Jun terial infections can exacerbate the consequences of viral
NH (2)-terminal kinase (JNK)) connects cell surface recep- respiratory symptoms. In this respect, co-infections, sec-
tors to the transcription machine and converts extracellular ondary infections, and/or superinfections may play differ-
inputs, such as viral infections, to the nucleus of the cell, and ent roles in patients with COVID-19 infection, although it
then to a variety of outputs that could help the host respond- is yet unknown exactly how they do so. Generally, studies
ing to viral infections(Roux and Blenis 2004; Cuenda 2019). indicated that, the major number of co-infected individuals
Moreover, in virus-infected cells, the MAPK pathway is also who died were infected with gram-negative bacteria. They
involved in controlling the immune reaction and apoptosis. can either directly promote membrane receptor shedding
On the other hand, MAPK signaling can act as a positive or or boost natural shedding mechanisms (Mahmoudi 2020).
negative modulator of viral replication. In this context, based
on some investigations, the MAPK signaling pathway can
13
Fig. 3 Bacterial Infections in COVID-19 Patients. First, SARS- trointestinal organs, the virus can enter the bloodstream and induce
CoV-2 infects type 2 pneumocytes in the lungs. Then, causing pneu- viremia. Pathogenic bacteria from the gut lumen can translocate into
monia and (in progressive stage) acute respiratory distress syndrome the circulation due to changes in the intestinal microenvironment
(ARDS) as well as increasing vulnerability to bacterial infection by (Sirivongrangson et al. 2020). BioRender was used to create this
weakening the pulmonary immune response. In organs with high image
levels of angiotensin-converting enzyme 2 (ACE2), such as the gas-
Bacterial co-infections, due to their effects on morbidity and studies have estimated the bacterial infection rate ranging
mortality of COVID-19 patients, have become a hot topic from 5.9 to 8.1% among all and critically ill patients (Lang-
during this pandemic. Indeed, the mechanisms and associa- ford et al. 2020). On the other hand, the rate of co-infections
tions of this event are not clear, but impaired respiratory are higher in severely ill patients and critically ill patients
epithelial integrity, the decline in mucociliary clearance, and are more susceptible to secondary bacterial infections (Fat-
increasing bacterial colonization in the respiratory tract are torini et al. 2020; Feldman and Anderson 2021; Pourajam
some of the possible explanations (Chertow and Memoli et al. 2022). Hence, patient’s condition can be considered an
2013; Goncalves Mendes Neto et al. 2021). Furthermore, it important risk factor in co-infections occurrence. However, a
is discovered that endotoxin, a component of gram-negative body of literature with regard to less burden of co-infections
bacteria's cell walls which has been widely studied and iden- in this pandemic suggests that applying prophylactic antibi-
tified as one of the principal causes of fatal shock during otics in patients seems unreasonable. Also, super-infection
severe sepsis, is also one of the main causes of the cytokine by nosocomial antibiotic-resistant bacteria is an alarm for
storm (Fig. 3). However, extra studies are required to clarify preventing from routine use of broad-spectrum antibiotics
the exact mechanisms and risk factors of bacterial infections. in these settings (Fattorini et al. 2020; Isaacs and Burmester
2020; Lansbury et al. 2020; Vaillancourt and Jorth 2020;
Risk factors for bacterial infections Zhu et al. 2020; Farrell et al. 2021). Furthermore, some
articles have found that co-infections inhibit the immune
With respect to the previous experiences in flu outbreaks, system which deteriorates the patients’ condition. As well
co-infections are one of major problems during such pan- as, special groups with weak immune systems and previ-
demics. The prevalence of secondary bacterial infections is ous underlying lung problems including chronic obstructive
not high, albeit they increase the mortality and morbidity pulmonary disease (COPD) have higher risk of experiencing
rate of COVID-19 cases. Also, co-infections pose a chal- co-infections. For example, when severe underlying condi-
lenge to the creation of a regimen with least side effects and tions in elderly people are accompanied with prolonged
antibacterial resistance and improving the prognosis of these hospitalization make these patients more prone to such
patients. Accordingly, during COVID-19 pandemic we face co-infections (Fattorini et al. 2020; Sharifipour et al. 2020;
with various co-infections especially with bacterial ones, Westblade et al. 2021). Additionally, such as other infec-
but the number of patients with co-infections are less than tions, contact is one of important ways of transmission of
previous pandemics (Fattorini et al. 2020). In this regard, infections. For instance, direct contact with a person who is
13
infected or colonized with opportunistic microorganisms, and effective antibiotic regimen seems to be necessary in
indirect contact with contaminated tools such as intubation possible co-infection cases (Chaudhry et al. 2021). Addition-
instruments and dressings, droplets from infected patients ally, the great number of antibiotic-resistant bacterial infec-
during sneezing, coughing, suctioning and intubation pro- tions are another challenge during this pandemic that anti-
cess stand accused of causing secondary infection in hos- biotic stewardship may solve this problem to some extent.
pitalized patients (Hamel et al. 2010; Esposito et al. 2020). Oral complications are another issue in COVID-19 patients
Moreover, concerning to rate of ventilator-associated bacte- which can become a life-long or even a dangerous prob-
rial pneumonia (VAP), mechanical ventilation though to its lem. According to epidemiological results, perioral pres-
supportive care in COVID-19 patients with ARDS it predis- sure ulcers, followed by oral candidiasis are more common.
poses these patients to the development of VAP (Póvoa et al. Such problems are more prevalent in ICU-as patients due to
2020). Also, mentioned factors can cause secondary bacte- some risk factors including long prone position and ventila-
rial infections not only during the illness period but also tion devices around and in their mouth and nose (Hocková
in convalescence time. Accordingly, avoiding close contact et al. 2021; Orilisi et al. 2021). Hence, an accurate care
and proper self-quarantine is recommended for suspected or with attention to possible secondary infections manifesta-
diagnosed with COVID-19 patients. Shoukat and colleagues tions and multidisciplinary management of these patients are
have studied the benefits of self-isolation during this pan- required to eliminate the possible risk factors and improve
demic. Their results have demonstrated that self-isolation their prognosis.
could delay the outbreaks peaks, ICU admission, and burden
on health-care facilities (Shoukat et al. 2020). As well as, it
seems self-isolation not only prevent the spreading disease to Therapeutic interventions
other people, but also it reduces the possible transmission of
other opportunistic infections. Since, COVID-19 affect vari- During the recent pandemic, various therapeutic interven-
ous organs of body which make them susceptible to second- tions with antiviral and immunomodulatory properties are
ary infections during and after their disease period. Recently, recommended for COVID-19. Actually, the food and drug
routine immunosuppressive treatments unlike to their effec- administration (FDA) fully approves only some of them,
tiveness in severe COVID-19 are introduced as an risk factor however, some others do not have FDA approval. Indeed,
for secondary infections (Hocková et al. 2021). Hereupon, during this public health emergency different therapeutics
further studies are required to determine more possible risk are suggested to apply with considerations by health authori-
factors to better control and prevention of co-infections. ties. Anyway, more studies are required to shed light on this
field (Sanders et al. 2020; Niknam et al. 2022).
The most common bacterial infections
Drugs
Previously, the common possible mechanisms and risk
factors of co-infections are discussed. Commonly, SARS- Since this outbreak, various protocols and treatments are
CoV-2 infects the respiratory and lung cells. Therefore, like announced to treat and manage the COVID-19 cases.
other viruses it can cause viral and secondary bacterial pneu- Although they have assisted to treat the patients, they cannot
monia and other respiratory complications (Vaillancourt and cure all patients and improve all of their COVID-19 related
Jorth 2020). Different factors make the patient prone to co- complications. With regards to the association of inflamma-
infection with different pathogens. In a study by Zhu et al., tion with complications of SARS-CoV-2, immunomodula-
respiratory pathogens as co-infections in COVID-19 cases tory and immunosuppressive therapies are promising drugs.
are described by RT-PCR. Their investigation has shown Accordingly, remdesivir, nucleotide prodrug of an adenosine
that bacterial infections are more common than viral and analog, is approved by FDA for the treatment of COVID-
fungal ones. Overall, among various bacterial infections 19. This drug inhibits viral replication via binding to the
Staphylococcus aureus and Streptococcus pneumonia are viral RNA-dependent RNA polymerase. However, due to
more frequent than Klebsiella pneumoniae and Haemophilus its adverse effects on the liver and kidney, monitoring of
influenza infections (Zhu et al. 2020; Chaudhry et al. 2021). their function is required in patients (Williamson et al. 2020;
In addition to typical pathogens, atypical bacteria includ- Ghandour et al. 2021). Studies about the CRS have shown
ing Mycoplasma pneumoniae, Chlamydia pneumoniae, and that among the overproduction of various interleukins, the
Legionella pneumophila can cause co-infections whit simi- rising level of IL-6 is more associated with the mortality
lar clinical and imaging manifestations. Since the patients rate. Hence, FDA-approved anti-IL-6 receptor monoclo-
with atypical bacterial co-infections are more susceptible to nal antibodies including tocilizumab (TCZ) and sarilumab
develop ARDS, require for mechanical ventilator, and pro- (SAR) through halting IL-6 action may improve patients’
longed hospital and ICU admission, on time recognizing condition. In this regard, TCZ and SAR are examples of
13
monoclonal therapies which block the signaling cascade the risk of the patient reverting to pre-antibiotic status and
of IL-6 (Giamarellos-Bourboulis et al. 2020; Hojyo et al. developing antibiotic resistance. In general, the majority of
2020). As well, corticosteroids with anti-inflammatory drug treatments for COVID-19 target the signaling pathways
effects are widely used in severely ill patients, especially involved in these diseases (Table 1). Additionally, studies in
with acute respiratory distress syndrome (ARDS) (Rezk and RM and cell therapy have recommended some possible treat-
Ibrahim 2013). In this regard, combination therapy of corti- ments. (Golchin et al. 2020). In addition to various therapeu-
costeroids with other antiviral drugs including tocilizumab tics, vaccine as a primary prevention was a hot topic. At this
and remdesivir is recommended for severe patients. On the time, different types of vaccines with various mechanisms
other hand, the goals of antimicrobial stewardship should are available globally. Finally, both novel therapeutics agents
be incorporated into COVID-19 patient care pathways. and vaccines are required to effectively manage patients
Herein, individuals with COVID-19 and a life—threatening and counteract the consequence of uncontrolled immune
co-bacterial respiratory infection should start a five-day anti- responses like cytokine storm.
biotic treatment until their signs, symptoms, and systemic
inflammation improve. Excessive use of antibiotics increases Regenerative medicine therapeutics
RM involves the application of various FDA-approved thera-

Table 1 Drug-based treatments for COVID-19 targeting signaling peutics i.e., autologous or allogeneic stem cells, NK cells,
pathways (Zhou et al. 2021; Farahani et al. 2022)
extracellular vesicles (EVs), and tissue products, as well as
Name of drug Mechanism of action different combinations of these, to effectively replace miss-
ing tissue, both structurally and functionally, or to aid tissue
Silluximab Inhibiting IL-6
regeneration (Mao and Mooney 2015; Golchin and Farahany
Clazakizumab Inhibiting IL-6
2019; Goodarzi et al. 2019b; Arjmand et al. 2020b). Mes-
Sirukumab Inhibiting IL-6
enchymal stem cells (MSCs) are currently one of the most
Olokizuma Inhibiting IL-6
studied therapeutic cellular products in RM (Larijani et al.
Emapalumab Inhibiting IFN‐γ
2014; Goodarzi et al. 2018; Arjmand et al. 2019). Previ-
Infliximab Inhibiting TNF-α
ous studies have demonstrated that MSCs are effective in
Adalimuab Inhibiting TNF-α
treating a range of diseases. For instance, MSCs have the
Risankizumab Inhibiting IL-12/IL-23
ideal characteristics for cardiovascular repair and can pro-
Ustekinumab Inhibiting IL-12/IL-23
tect the myocardium in the cardiovascular system by lower-
Guselkumab Inhibiting IL-12/IL-23
ing inflammation, fostering myocardial cell differentiation
Secukinumab Inhibiting IL-17A
around infarct areas and angiogenesis, increasing apoptosis
Ixekizumab Inhibiting IL-17A
resistance, and inhibiting fibrosis. On the other hand, MSCs
Lenzilumab Inhibiting GM-CSF
Gimsilumab Inhibiting GM-CSF
are promising candidates for the therapy of a number of
Otilimab Inhibiting GM-CSF
digestive system diseases due to their potent immunomodu-
Tjoo3234 Inhibiting GM-CSF
latory and regenerative characteristics. Moreover, for people
Tocilizumab Inhibiting IL-6R/gp130
with end-stage liver disease, MCS therapy has been seen as
Sarilumab Inhibiting IL-6R/gp130
a possible alternative treatment option. Also, MSCs are par-
Levlilimab Inhibiting IL-6R/gp130
ticularly relevant as stem cell therapeutics in the treatment
Anakinra Inhibiting IL-1R
of cancer due to their capacity for immunomodulation and
Etanercept Inhibiting TNFR
tumor-homing. However, limited progress has been made
Marilimunab Inhibiting GM-CSFR
in translational medicine due to ignorance of the conten-
Dexamethasone Inhibiting NF-κB
tious roles that MSC play in the interaction with malignan-
Hydroxy Choloroquine Inhibiting NF-κB
cies. Specifically, recent evidence suggests that MSC may
Dapansutrile Inhibiting NLRP3
play a therapeutic function in lung disorders and infections
ZYIL1 Inhibiting NLRP3
(Huang 2015; White et al. 2016; Cruz and Rocco 2020; Shi
Baricitinib Inhibiting JAK/STAT
et al. 2020; Lan et al. 2021; Hoang et al. 2022). Accord-
Ruxolitrnib Inhibiting JAK/STAT
ingly, transplantation of MSCs and MSC-derived EVs are
Tofacitinib Inhibiting JAK/STAT
the main RM-based auxiliary treatments for COVID-19 that
have been accepted by physicians or in clinical trials. Moreo-
Interleukin (IL-), Interferon gamma (IFN-γ), Tumour necrosis fac- ver, infusion of convalescent plasma is another RM -based
tor α (TNFα), Granulocyte–macrophage colony-stimulating factor treatment for COVID-19 (Parhizkar Roudsari et al. 2020;
(GM-CSF), Nuclear factor kappa-light-chain-enhancer of activated B
cells (NF-κB), Receptor (R), Glycoprotein 130 (gp130), Janus kinase Arjmand et al. 2021; Gilany et al. 2021).
(JAK)-signal transducer and activator of transcription (STAT)
13
Effects of mesenchymal stem cells aggregate in the lungs, where they can reduce or prevent
lung fibrosis by having anti-inflammatory effects, improving
Within hours of starting an inflammatory response, toll- the lung microenvironment, and possibly restoring vascular
like receptors (TLRs) on innate effector cells recognize barrier integrity, as well as promoting endogenous repair
pathogen-produced compounds. TLR ligation may activate and regeneration mechanisms (Ellison-Hughes et al. 2020).
phagocytic cells as well as stromal cells (such as MSCs) Furthermore, the antimicrobial capabilities of MSCs have
resulting in an inflammatory response (Auletta et al. 2012; been demonstrated. Hereupon, based on their predomi-
Rahmani-Kukia et al. 2020). Herein, MSCs polarize into two nantly immunosuppressive characteristics, MSCs' impact
effective phenotypes (MSC1 or pro-inflammatory phenotype on host defense against a live bacterial infection has been
and MSC2 or immune-suppressive phenotype), each with questioned. They can improve survival and reduce bacte-
its own immune modulatory actions and secretome. In this rial numbers in the blood. In this context, MSCs' ability
respect, many studies are concentrating on the use of MSCs to upregulate antimicrobial peptides (Lipocalin 2) produc-
in cell therapy. In other words, MSCs are currently being tion in response to inflammatory stimuli such as LPS and
tested in clinical trials for the treatment of a wide range TNFα contributes to the bacterial clearance effect observed
of incurable diseases and they show extremely promising with MSC therapeutic interventions. Generally, scientists
results due to their rapid proliferation, immunomodulation found that systemic treatment with MSC activation could
effects, high differentiation capacity, and secretion of use- be a promising new strategy for treating multidrug-resistant
ful growth factors, ability to migrate into the site of dam- bacterium infections (Krasnodembskaya et al. 2010; Gupta
age, and free of ethical and social issues (Waterman et al. et al. 2012; Johnson et al. 2017; Mishra et al. 2020; Yagi
2010; Rivera-Cruz et al. 2017; Goodarzi et al. 2019a; Gilany et al. 2020). Figure 4 shows the different effects of MSCs
et al. 2021). They have the ability to self-renew and differ- that contribute to their therapeutic function. Generally, the
entiate into a variety of mesenchymal lineages, including safety and potential effectiveness of any novel therapeu-
bones, cartilages, adipose tissues, and tendons. Further- tic intervention are both heavily dependent on preclinical
more, they can be isolated from a wide range of fetal and research. Accordingly, an early assessment of MSCs' pre-
adult tissues (Larijani et al. 2015; Goodarzi et al. 2019a; clinical performance is necessary before using them in the
Abedi et al. 2020; Aghayan et al. 2020, Ghezelayagh et al. COVID-19 clinical phase. Nevertheless, due to the rapid
2021; Islam et al. 2021; Madani et al. 2021; Xaki et al. 2021; spread of the COVID-19 pandemic, studies have centered
Aghayan et al. 2022). Nowadays, this fact has been discov- more on clinical rather than preclinical studies. But, some
ered that MSC therapy may inhibit the active immune sys- preclinical experiments in animal models of ARDS and lung
tem from triggering a cytokine storm in COVID-19 cases, injury have shown that MSCs intervention may be advan-
and the stem cells' reparative powers may support endog- tageous and a number of animal models that resemble the
enous repair (Ellison-Hughes et al. 2020; Parhizkar Roud- pathophysiology of COVID-19 have been identified (e.g.,
sari et al. 2020; Rajarshi et al. 2020; Arjmand et al. 2021, hamsters, Mice, Ferret, mink, cats, dogs and non-human
Gilany et al. 2021). MSCs become activated and adopt an primates) and others are still being developed. Indeed,
immune-suppressive phenotype in the presence of an inflam- since SARS-CoV-2 is a recently discovered virus, it has to
matory environment (high levels of TNF- and IFN-), by be more studied (El-Metwaly et al. 2019, Jung et al. 2019;
secreting high levels of soluble factors such as indoleamine Rahmati et al. 2020; Saleh and Ghazzawi 2021; Shou et al.
2, 3-dioxygenase (IDO), prostaglandin E2 (PGE2), nitric 2021). Therefore, majority of investigations in the field of
oxide (NO), transforming growth factor (TGF-β), hepato- Covid-19 have been in the clinical stage. Herein Table 2
cyte growth factor (HGF), and hemoxygenase (HO), which shows clinical trials based on MSCs in COVID-19.
suppress T cell proliferation. Moreover, the development of
regulatory T cells (Tregs) is promoted by MSCs' constant Mesenchymal stem cells‑based vs. cell‑free strategies
production of TGF-β (Zheng et al. 2015; Contreras et al. (limitations and advantages)
2016; Ellison-Hughes et al. 2020). However, MSCs may
develop a pro-inflammatory phenotype and boost T cell According to previous paragraphs, the therapeutic poten-
responses by secreting chemokines that attract lymphocytes tial of MSCs as a subgroup of stem cells is considerably
to sites of inflammation (i.e., MIP-, RANTES, C-X-C Motif investigated. Also, unlike other types of stem cells, the
Chemokine Ligand (CXCL)9, and CXCL10) in the absence source of MSCs is from various tissues which dedicate this
of an inflammatory environment (low levels of TNF- and subtype a wide availability. Additionally, many studies and
IFN-). The difficult balancing act between these opposing clinical trials have investigated MSCs' therapeutic role in
routes might strengthen the host defense while also encour- COVID-19. In this regard, one of the main pathogenesis
aging regeneration (Meiliana et al. 2016; Ellison-Hughes in severe COVID patients is hyper inflammation which is
et al. 2020; Mishra et al. 2020). On the other hand, MSCs hypothesized that MSC and its derivatives may suppress it
13
Fig. 4 Therapeutic effects of mesenchymal stem cells. Mesenchy- ferentiation, cell–cell contact, or paracrine actions (Sadeghi et al.
mal stem cells can play a fundamental role in COVID-19 treatment 2020; Fernández-Francos et al. 2021). BioRender was used to create
via realizing several angiogenic, mitogenic, anti-apoptotic, anti- this image. Indoleamine 2, 3-dioxygenase (IDO), Interferon gamma
inflammatory, and anti-oxidative factors. They are implicated in the (IFN-γ), Prostaglandin E2 (PGE2), Tumor necrosis factor α (TNFα),
down-regulation of acute-phase response, such as the suppression of Interleukins (IL), Transforming growth factor beta (TGF-β), C–X–C
inappropriately activated T lymphocytes, and macrophages, and the motif chemokine (CXCL), Induced protein 10 (IP-10), C‑C motif
release of pro-inflammatory cytokines, which could minimize the chemokine ligand 5 (CCL5), Lipocalin-2 (LCN2), Fibroblast growth
occurrence of cytokine storms (immunomodulatory effects. Further- factor (FGF), Insulin-like growth factor 1 (IGF-1), Granulocyte–mac-
more, they have the ability to suppress cell apoptosis (anti-apoptotic rophage colony-stimulating factor (GM-CSF), Hepatocyte growth
effects), enhance endogenous tissue repair (regenerative effects), and factor (HGF), Tissue inhibitors of matrix metalloproteinases (TIMP),
release antimicrobial compounds (antimicrobial effects). Direct scav- Vascular endothelial growth factor (VEGF), Platelet-derived growth
enging of free radicals, promoting endogenous antioxidant defenses, factor (PDGF), Epidermal growth factor (EGF), Angiopoietin (Ang),
immunomodulation via reactive oxygen species (ROS) suppression, Monocyte chemoattractant protein-1 (MCP-1), Matrix metallopro-
altering mitochondrial bioenergetics, and donating functional mito- teinases (MMPs), Superoxide dismutase (SOD), Catalase (CAT),
chondria to damaged cells are some of the mechanisms by which Glutathione peroxidases (GPXs), Glutathione (GSH), Heat shock pro-
mesenchymal stem cells have antioxidant effects. Moreover, mes- tein 70 (Hsp70)
enchymal stem cells can enhance angiogenesis through direct dif-
through their anti-inflammatory and immunomodulatory tissues through secreting EVs, cytokines, chemokine, solu-
properties (Leng et al. 2020). Additionally, studies have ble proteins, and many other paracrine factors. These fac-
shown that MSCs through ceasing the maturation process tors and EVs have the privilege of altering their contents
of several types of immune cells and promoting regulatory and even determining their target by editing their receptors.
T-cells suppress the immune system (Sarvar et al. 2016). Also, EVs play a pivotal role in intra- and inter-cellular
Moreover, MSCs mediate their regenerative, immunomodu- interactions. Hence, EVs could be administered as vehicles
latory, anti-tumor, and other effects on the other cells and to transfer drugs and special substances including genes to
13
Table 2 A review of in progress, active, and completed clinical trials conducted using MSCs in COVID-19(https://clinicaltrials.gov/)
182
Official title Status/phase Number trial ID Source of MSCs Number of patients Doses and route of admin- Primary outcomes/results
istration
13
Effectiveness and safety pro- Completed/phase 3 NCT05122234 MSC secretome- derived 40 (20/20) MSC secretome was given Assessment of inflamation
file of mesenchymal stem from the fifth passage of once at a dose of 15 mL marker levels (IL-6, IL-10,
cell secretome as a treat- the umbilical cord MSCs per administration dis- LIF, VEGF, and Ferritin),
ment for severe cases of solved in 100 mL of IL-6 and IL-6/ IL-10 ratio
COVID-19: a randomized normal saline, IV increase in control group on
controlled trial the 14th day after interven-
tion/ high levels of IL-6 and
ferritin in placebo group
on the seventh day after the
intervention, no significant
differences in inflammatory
marker levels on the seventh
day and 14th day after
intervention between both
groups, no adverse event
reported
Mesenchymal Stem Cell Completed/not applicable NCT04713878 Human umbilical cord 21 (7/7/7) 1 million cell/kg, IV, in 3 Change of clinical symptoms
Therapy with COVID-19 dosage as respiratory distress or
Pneumonia: Prospective, need for oxygen support,
Randomized Clinical Change of cytokine storm
Research parameters and pulmo-
nary functions and clinical
symptoms
Prospective, Randomized Unknown/phase 2 NCT04444271 Bone marrow harvested cells 20 (10/ 10 2 × 106 cells/kg, 2 times Overall survival
Phase 2 Clinical Trial
of Mesenchymal Stem
Cells(MSCs) for the
Treatment of Coronavirus
Disease 2019(COVID-19)
Safety and Efficacy of Mes- Unknown/phase 2 NCT04429763 Human umbilical cord N = 30 1 × 1 06 cells/Kg, single dose Clinical deterioration or death,
enchymal Stem Cells in Change in two or more
the Management of Severe degrees in the NEWS scale
COVID-19
B. Arjmand et al.
Table 2 (continued)
istration
A Proof of Concept Study Completed/not applicable NCT04898088 30 (15/15) MSC Transplantation Expression of PARP1 gene as
for the DNA Repair Driven indicator of base excision
by the Mesenchymal Stem repair, Expression of genes
Cells in Critical COVID- ATM, RAD51, RAD52
19 Patients and WRN as indicator of
Recombinational repair,
Expression of genes
RAD23B and ERCC1as
indicator of Nucleotide
excision repair, Expression
of genes MLH1, MSH2
and MSH6 as indicator of
Mismatch repair
Exploratory Clinical Study Unknown/phase 2 NCT04315987 90 (45/45) 2 × 10^7 cells, IV, 4 times Disappear time of ground-
to Assess the Efficacy of glass shadow in the lungs
NestaCell® Mesenchymal
Stem Cell to Treat Patients
With Severe COVID-19
Pneumonia
Mesenchymal Stem Cells for Unknown/phase 2 NCT04416139 Umbilical cord allogenic 5 1 million x Kg, single dose Functional Respiratory
the Treatment of Severe changes: PaO2 / FiO2 ratio,
Acute Respiratory Distress Clinical cardiac changes:
Syndrome Due to COVID- Heart rate per minute, Clini-
19. Pilot Study cal Respiratory Changes:
Respiratory rate per minute,
Critical roles of cytokine storm and bacterial infection in patients with COVID‑19: therapeutic…
Changes in body tem-

perature/ R: The infusion of
ahUCMSC in patients with
severe ARDS caused by
COVID-19, was safe, and
demonstrated its anti-inflam-
matory capacity in the lungs,
by improving the respiratory
function expressed by PaO2
/ FiO2, which allowed the
survival of 3 patients, with
extubation at 9 days
13
183
Table 2 (continued)
184
istration
13
Treatment of COVID-19 Unknown/phase 1 NCT04313322 Cord tissue of newborns 1 × 106/kg, 3 doses Clinical outcome (Improve-
Patients Using Wharton's ment of clinical symptoms
Jelly-Mesenchymal Stem including duration of fever,
Cells respiratory destress, pneu-
monia, cough, sneezing,
diarrhea), CT Scan (Side
effects measured by Chest
Readiograph), RT-PCR
results (Results of Real-Time
Polymerase Chain Reac-
tion of Viral RNA, Turing
negative)
Safety and Efficiency of Unknown/phase 1 NCT04252118 20 (10/10) 3.0 × 107 MSCs, IV, 3 times Size of lesion area by chest
Mesenchymal Stem Cell radiograph or CT (Evalua-
in Treating Pneumonia tion of Pneumonia Improve-
Patients Infected With ment), Side effects in the
COVID-19 MSCs treatment group
(Number of participants
with treatment-related
adverse events as assessed
by CTCAE v4.0)
A Seamless Phase I/IIa Active/phase I/IIa NCT05501418 Allogeneic umbilical cord 75 Two Co-Primary Efficacy
Clinical Study to Evaluate MSCs Endpoints (Proportion of
the Safety and Efficacy of patients alive with sus-
Allogeneic Umbilical Cord tained improvement within
Mesenchymal Stem Cells the 21 days of the treat-
in Patients With Severe ment period (Proportion
and Critical COVID-19 Analysis), which indicates
Condition the capability of UMSC01
to save more lives), Two Co-
Primary Efficacy Endpoints
(Time (days) to reach sus-
tained improvement within
the 21 days of the treatment
period (Time-to-Event
Analysis), which indicates
the capability of UMSC01 to
enable patients to less suffer
from the disease condition)
B. Arjmand et al.
Table 2 (continued)
istration
Adjuvant Therapy With Recruiting/phase 1 NCT04611256 Aadipose tissue derived- 20 1 × 1 06/kg, IV, 2 doses Change form baseline in
Mesenchymal Stem Cells MSCs Arterial oxygen saturation
in Patients Diagnosed With (Pulmonary lesion area will
COVID-19 in Critical be taken by a chest x-ray or
Condition computed axial tomogra-
phy), Change form baseline
in Arterial oxygen saturation
(Aretrial oxygen satura-
tion will be taken by an
oximeter), Days to clinical
improvement (Number of
days of patient discharge)
Bone Marrow Mesenchymal Not yet recruiting/phase 2 NCT05125562 Bone marrow MSC-derived 30 Three infusions: (1) Normal Change in SARS-CoV-2 log
Stem Cell Derived Extra- extracellular vesicles Saline 100 mL, (2) Normal viral load from baseline to
cellular Vesicles Infusion saline 90 mL and ExoFlo Day = 7 (Change in SARS-
Treatment for Mild-to- 10 mL, which is 7 × 10^11 CoV-2 log viral load from
Moderate COVID-19: A EVs, and (3) Normal saline baseline to Day = 7)
Phase II Clinical Trial 85 mL and ExoFlo 15 mL,
which is 10.5 × 10^11 EVs
Safety and Efficacy Study of Recruiting/phase I/II NCT04336254 Allogeneic human dental 20 3.0 × 107 cells solution Time to Clinical Improvement
Allogeneic Human Dental pulp stem cells (30 ml), IV, 3 doses
Pulp Mesenchymal Stem
Cells to Treat Severe Pneu-
monia of COVID-19: a
Single-center, Prospective,
Randomized Clinical Trial

Safety and Effectiveness Active, not recruiting/early NCT04371601 Umbilical cord 60 106 / Kg body weight / time, Changes of oxygenation index
of Mesenchymal Stem Phase 1 IV,4 doses (PaO2/FiO2),blood gas test
Cells in the Treatment of (Improvement of pulmonary
Pneumonia of Coronavirus function)
Disease 2019
Safety and Efficacy of Unknown/phase I/II NCT04346368 BM 20 1 × 106 /kg body weight, IV Changes of oxygenation index
Intravenous Infusion of (PaO2/FiO2) (Evaluation
Bone Marrow-Derived of pneumonia improve-
Mesenchymal Stem Cells ment), Side effects in the
in Severe Patients With BM-MSCs treatment group
Coronavirus Disease 2019 (Proportion of participants
(COVID-19): A Phase 1/2 with treatment-related
Randomized Controlled adverse events)
Trial
13
185
Table 2 (continued)
186
istration
13
Effectiveness of Mesenchy- Recruiting NCT05240430 Human umbilical cord 1 1 × 106 cells per kilogram, Change in acute phase
mal Stem Cell in Patients IV, single dose reactants (C-reactive
With COVID-19 Associ- protein (CRP) after MSC
ated SARS-CoV-2, Ret- administration in group I, II,
rospective Clinical Study: III, Change in acute phase
When to Apply to Which reactants (procalcitonin)
Patient? after MSC administration
in group I, II, III, Change in
acute phase reactants ( white
blood cell count) after MSC
administration in group I, II,
III, Changes in respiratory
support after MSC admin-
istration in Groups I, II, III,
Changes in arterial blood
gas analysis
A Study of Mesenchymal Active, not recruiting/early NCT04456361 Wharton Jelly of Umbilical 9 1 X 10^8 cells, IV, single Oxygen saturation (Number of
Stem Cells as a Treat- Phase 1 cords dose patients with changes in per-
ment in Patients With centage of resting Oxygen
Acute Respiratory Distress saturation (%O2))
Syndrome Caused by
COVID-19
A Phase II, Multicenter, Completed/phase 2 NCT04288102 Human Umbilical Cord 100 4.0*10^7 cells per time, IV, Change in lesion proportion
Randomized, Double- 3 doses (%) of full lung volume
blind, Placebo-controlled from baseline to day 28
Trial to Evaluate the Effi- (Evaluation of Pneumonia
cacy and Safety of Human Improvement)
Umbilical Cord-derived
Mesenchymal Stem Cells
in the Treatment of Severe
COVID-19 Patients
A Phase II, Open Label, Completed/phase II NCT04349631 Autologous adipose tissue 56 5 IV infusions Incidence of hospitalization
Single-Center, Clinical for COVID-19 (Number of
Trial to Assess Efficacy of subjects that require hospi-
HB-adMSCs to Provide talization for COVID-19),
Immune Support Against Incidence of symptoms for
Coronavirus Disease COVID-19 (Number of sub-
jects that develop symptoms
associated with COVID-19,
such as fever, shortness of
breath/difficulty breathing,
cough)
B. Arjmand et al.
Table 2 (continued)
istration
Treatment of COVID-19-In- Recruiting/phase 2 NCT04905836 Allogeneic culture-expanded 60 30 million cells, IV, 3 doses All-cause mortality rate at
duced Acute Respiratory adipose tissue Day 28, Incidence of all
Distress: A Phase 2 Study AEs (safety), Incidence
of Intravenous Admin- of treatment-emergent
istration of Allogeneic adverse events (safety),
Adipose-Derived Mesen- Incidence of severe adverse
chymal Stem Cells events (safety), Incidence
of infusion-related adverse
events (safety)
A Randomized, Double- Completed/phase 2 NCT04348435 Allogeneic adipose tissue 55 200 million cells/dose, IV, Incidence of hospitalization
Blind, Single Center, Effi- 5 doses for COVID-19, Incidence of
cacy and Safety Study of symptoms associated with
Allogeneic HB-adMSCs to COVID-19
Provide Immune Support
Against COVID-19
Efficacy of Infusions of Completed/phase 2 NCT04625738 Ex vivo expanded Wharton's 30 106 MSC/kg, IV, 3 doses PaO2 / FiO2 ratio (The
Mesenchymal Stem Cells Jelly primary endpoint is the
From Wharton Jelly in the percentage of patients with
Moderate to Severe SARS- a PaO2/FiO2 ratio > 200 at
Cov-2 Related Acute Res- D10 of treatment with MSC-
piratory Distress Syndrome GW or placebo)
(COVID-19): A Phase IIa
Double-blind Randomized
Controlled Trial
A Phase 2A Randomized, Not yet recruiting/phase 2 NCT04992247 Allogeneic Adipose tissue 60 Approximately 15 million Change in 6-Minute Walk
Placebo-Controlled Study cells/vial, IV, 3 doses Distance (6MWD) at Day 60

of Intravenous Alloge-
neic Adipose-Derived
to Treat Post COVID-19
"Long Haul" Pulmonary
Compromise
Clinical Study for Sub- Not yet recruiting/ phase 2 NCT05017298 Allogeneic adipose tissue 30 200 million cells/ time, IV, Incidence of treatment-related
jects With Coronavirus 3 doses adverse events and severe
2019 (COVID-19) Using adverse events during the
Multiple Dose Intravenous study period, Safety for
Infusions of Allogeneic AdMSCs based upon inci-
Adipose Tissue-Derived dence of all AEs (adverse
Mesenchymal Stem Cells events), Compare the mor-
(AdMSCs) tality rate
13
187
Table 2 (continued)
188
istration
13
The Effect of Secretome of Recruiting/phase 2 NCT04753476 Secretome of hypoxia-mes- 48 1 cc/ time, IM, 3 doses Change in patients clinical
Hypoxia-Mesenchymal enchymal stem cells manifestation, Need for a
Stem Cells in Improving ventilator, Duration of using
Survival of Severe Covid- a ventilator, Length of stay,
19 Patients Routine blood profile, CRP,
D-dimer, Blood Gas Anali-
sis, Photo thorax
Bone Marrow Mesenchy- Available/phase 2 NCT04657458 Allogeneic Bone Mar- 24 15 mL, IV, single dose R: owing to safety profile,
mal Stem Cell Derived row MSC (bmMSC) capacity to restore oxygena-
Extracellular Vesicles Infu- Derived Extracellular tion, downregulate cytokine
sion Treatment: A Global Vesicle Product ( ExoFlo) storm, and reconstitute
Expanded Access Protocol immunity, ExoFlo is a prom-
for Patients With COVID- ising therapeutic candidate
19 Associated ARDS Who for severe COVID-19
Do Not Qualify for Phase
II Randomized Control
Trial
A Phase I/IIa Trial to Not yet recruiting/ Phase I/ NCT04527224 Allogenic adipose tissue 10 Number of subjects with
Explore the Safety IIa treatment-related adverse
and Efficacy of Allo- events as assessed by
genic Adipose Tissue- analysis of adverse events
derived Mesenchymal including symptoms, abnor-
Stem Cell (AstroStem- mal findings on physical
V) Therapy in Patients examination, vital signs,
With COVID-19 Pneu- ECG, and standard labora-
monia tory examination
Clinical Research of Unknown/phase I/II NCT04339660 Human umbilical cord 30 1*10^6 UC-MSCs /kg The immune function (TNF-α
Human Mesenchymal body weight suspended 、IL-1β、IL-6、TGF-
Stem Cells in the Treat- in 100 mL saline, IV, 1 β、IL-8、PCT、CRP)
ment of COVID-19 Pneu- time (depending on the (Improvement and recovery
monia condition of the need to be time of inflammatory and
given again at an interval immune factors), Blood oxy-
of 1 week) gen saturation (Evaluation of
Pneumonia change)
B. Arjmand et al.
Table 2 (continued)
istration
Clinical Study for the Not yet recruiting/phase 2 NCT04428801 Autologous 200 200 million cells, IV, 3 doses Tolerability and acute safety
Prophylactic Efficacy Adipose Tissue of AdMSC infusion by
of Autologous Adipose assessment of the total
Tissue-Derived Mesenchy- number of AEs/SAEs
mal Stem Cells (AdMSCs) (adverse events/severe
Against Coronavirus 2019 adverse events) related and
(COVID-19) non-related with the medica-
tion, The overall proportion
of subjects who develop any
AEs/SAEs related and non-
related with the AdMSC
infusions as compared to the
control group, COVID-19
incidence rates in both the
study and control groups
Clinical Study of Human Unknown/not applicable NCT04273646 Human Umbilical Cord 48 (24/24) 5.0 × 106 cells/kg, IV, 4 Pneumonia severity index,
Umbilical Cord Mesen- times Oxygenation index (PaO2/
chymal Stem Cells in FiO2)
the Treatment of
Severe COVID-19
Efficacy and Safety of Nor- Recruiting/phase II/III NCT05132972 Allogenic umbilical cord 42 1 × 106 cells MSC/kg body Duration of hospital stay
moxic Allogenic Umbili- weight, IV, 3 times
cal Cord Mesenchymal
Stem Cells Administered
as Adjuntive Treatment
to Standard Treat-
ment in Severe Patients
With COVID-19
A Pilot Phase Study Completed/phase I NCT04573270 Human umbilical cord 40 IV, 1 time Survival Rate in COVID-19
Evaluating the Effects of infected patients admitted
a Single Mesenchymal to hospital for complica-
Stem Cell Injection in tions, Contraction Rate
Patients With Suspected of COVID-19 in healthy
or Confirmed COVID- healthcare workers following
19 Infection and Health- patients admitted to hospital
care Providers Exposed to for complications due to
Coronavirus Patients COVID-19
13
189
Table 2 (continued)
190
istration
13
IV Infusion of Autologous Not yet recruiting/phase I NCT04352803 Autologous adipose tissue 20 500,000/kg, IV Safety, efficiency (Changes
Adipose Derived Mesen- in progression or rate of
chymal Cells for Abate- subjects progressing to
ment of Respiratory Com- mechanical ventilation,
promise in SARS-CoV-2 Changes in time subjects
Pandemic (COVID-19) remain on mechanical
ventilation, Changes in
length of time subjects wean
off of mechanical ventila-
tion, Length of Hospital
Stay, Mortality rate from all
causes)
Clinical Study of Novel Unknown/ Early Phase 1 NCT04302519 Dental pulp 24 1.0×106 cells /kg, IV, 3 Disppear time of ground-
Coronavirus Induced times glass shadow in the lungs
Severe Pneumonia Treated (Kaplan–meier method was
by Dental Pulp Mesenchy- used to calculate the median
mal Stem Cells glassy shadow time in all
subjects)
Bone Marrow Mesenchymal Not yet recruiting/phase I/II NCT05116761 Bone Marrow MSC Derived 60 10.5 × 10^8 EV, IV Increased distance on Six
Stem Cell Derived Extra- Extracellular Vesicles Minute Walk Test (6MWT),
cellular Vesicles Infusion Incidence of SAEs
Treatment for Post-Acute
and Chronic Post-
COVID-19 Syndrome: A
Phase I/II Clinical Trial
Bone Marrow Mesenchymal Recruiting/phase 3 NCT05354141 Bone marrow MSC-derived 400 1.2 trillion EVs, IV, one or The primary efficacy endpoint
Stem Cell Derived Extra- extracellular vesicles 2 times is overall 60-day mortality
cellular Vesicles as Early (EVs) (ExoFlo) (due to any cause)
Goal Directed Therapy
for COVID-19 Moderate-
to-Severe Acute Res-
piratory Distress Syndrome
(ARDS):
Treatment of Covid-19 Completed/phase I/II NCT04382547 Allogenic pooled olfactory 32 IV Number of patients cured,
Associated Pneumonia mucosa assessed by PCR in addition
With Allogenic Pooled to chest CT scan
Olfactory Mucosa-derived
B. Arjmand et al.
Table 2 (continued)
istration
Application of Umbilical Unknown/phase I NCT04457609 Umbilical Cord 40 1 × 106 unit, IV Clinical improvement: Pres-
Cord Mesenchymal Stem ence of dyspnea, presence
Cells as Adjuvant Therapy of sputum, fever, ventilation
for Critically-Ill COVID- status, blood pressure, heart
19 Patients rate, respiratory rate, oxygen
saturation
Umbilical Cord-derived Completed/phase I/II NCT04355728 Human umbilical cord 24 100 × 106 cells/infusion, IV Safety as defined by the num-
Mesenchymal Stem Cells ber of pre-specified infusion
for COVID-19 Patients associated adverse events,
With Acute Respira- Serious Adverse Events by
tory Distress Syndrome 31 Days after first infusion
(ARDS) and through Study Day
90, Number and Subjects
of AEs and SAEs and by
severity and by Relatedness
to Treatment, Subjects With
Adverse Events by Related-
ness to Treatment
Treatment of Coronavi- Unknown/ phase I/II NCT04461925 Cryopreserved Placenta- 30 1 million cells/kg body Changes of oxygenation
rus COVID-19 Pneumonia Derived Multipotent MSCs weight/ time, IV, 3 times index PaO2/FiO2, Changes
(Pathogen SARS-CoV-2) in length of hospital stay,
With Cryopreserved Allo- Changes in mortality rate
geneic Multipotent Mes-
enchymal Stem Cells of
the Placenta and Umbilical
Cord
An Phase2 Study of ADR- Recruiting/ phase 2 NCT04888949 Adipose tissue 20 1*10^8 cells, IV, 4 times Ventilator Free Days which
001 in Patients With appear in subjects with
Severe Pneumonia Caused ADR-001 treatment are
by SARS-CoV-2 Infection evaluated
Safety and Effectiveness Recruiting/ phase 1 NCT05387278 EV-Pure™ and WJ-Pure™ 20 (10/10) IV To Assess the safety and
of Placental Derived efficacy of EV-Pure™ and
Exosomes and Umbili- WJ-Pure™ administra-
cal Cord Mesenchymal tion in patients exhibiting
Stem Cells in Moderate moderate-to-severe ARDS
to Severe Acute Res- associated with COVID-19,
piratory Distress Syndrome compared to placebo
(ARDS) Associated With
the Novel Corona Virus
Infection (COVID-19)
13
191
Table 2 (continued)
192
istration
13
Mesenchymal Stem Cell Unknown/phase II/III NCT04366063 Cell therapy protocol 1 60 (20/20/20) 2 doses of MSCs 100 × 10e6 Number of participants with
Therapy for Acute Respira- and 2 (± 10%)/ or 2 doses of TRAEs, Blood oxygen
tory Distress Syndrome in MSCs 100 × 10e6 (± 10%) saturation (Evaluation of
Coronavirus Infection: A plus 2 doses of extracellu- Pneumonia Improvement)
Phase 2–3 Clinical Trial lar vesicles (EVs), IV
Efficacy and Safety of Recruiting/phase II/III NCT05216562 60 IV, 2 times Time to clinical improvement
EXOSOME-MSC (Mesen- (days)
chymal Stem Cell-Derived
Exosomes) Therapy to
Reduce Hyper-inflamma-
tion In Moderate COVID-
19 (2019- New Corona
Virus Disease) Patients
Therapeutic Study to Evalu- Completed/phase 1 NCT04535856 Allogeneic MSCs 9 Low dose group: Incidence of Treatment-
ate the Safety and Efficacy 5 × 107cells, high dose Emergent Adverse Event in
of DW-MSC in COVID-19 group: 1 × 10^8 cells Treatment group
Patients: Randomized,
Double-blind, and Placebo-
controlled
Study of Cord Blood Recruiting/ phase I/II NCT04565665 Cord Blood 70 IV Serious adverse events with
Derived Mesenchymal be comprised of grade 3 or 4
Stem Cells for Treatment graft versus host disease or
Acute Respiratory Distress death and will be estimated
Syndrome and reported overall and
by group, along with 95%
confidence intervals(phase
I), Patients alive without
grade 3, 4 infusional toxicity
(Phase II), Patients alive
with grade 3 or 4 infusional
toxicity (Phase II), Patients
not alive (Phase II)
Treatment of COVID-19-In- Recruiting/ phase II NCT04903327 Allogeneic Adipose tissue 100 30 million cells, IV, 3 times All-cause mortality rate at
duced Acute Respiratory Day 28
Distress: A Phase 2 Study
of Intravenous Admin-
istration of Allogeneic
Adipose-Derived Mesen-
chymal Stem Cells
B. Arjmand et al.
Table 2 (continued)
istration
Multicenter Phase I/IIa Recruiting/ Placebo I/IIa NCT05433298 Umbilical cord 60 1.000.000 cells per kilo, IV, The primary expected
Study of Mesenchymal single dose outcome is the safety
Stromal Cells for the and tolerability of using
Treatment of Patients With intravenously infused UTC-
SARS-CoV-2 Pneumonia MSC suspension in patients
with pneumonia caused by
SARS-CoV-2. This outcome
will be evaluated by record-
ing adverse events that must
be reported throughout the
study period
Phase I / II Clinical Trial, Completed/ phase I/II NCT04366323 ALLOGENEIC AND 26 80 million cells, IV, 2 doses Safety of the administration
Multicenter, Randomized EXPANDED ADIPOSE of allogeneic mesenchymal
and Controlled, to Assess TISSUE stem cells derived from
the Safety and Efficacy of adipose tissue assessed by
Intravenous Administra- Adverse Event Rate,Efficacy
tion of Allogeneic Adult of the administration of allo-
Mesenchymal Stem Cells geneic mesenchymal stem
of Expanded Adipose cells derived from adipose
Tissue in Patients With tissue assessed by Survival
Severe Pneumonia Due to Rate
COVID-19
Bone Marrow Mesenchymal Completed/ phase II NCT04493242 Bone marrow derived 120 Group 1: 800 Billion EVs, 7 Day Change in Partial Pres-
Stem Cell Derived Extra- EVs(ExoFlo) group 2: 1.2 Trillion EVs, sure of Arterial Oxygen to
cellular Vesicles Infusion IV Fraction of Inspired Oxygen
Treatment for COVID-19 Ratio

Associated Acute Res-
(ARDS): A Phase II Clini-
cal Trial
A Phase 1 Double-blinded, Recruiting/ Phase 1 NCT04629105 Longeveron MSCs (LMSCs) 70 100 million LMSCs, IV, 3 Incidence of treatment-
Randomized, Placebo- doses emergent serious adverse
controlled Study for events within 4 weeks after
COVID-19 and Influenza treatment
Virus-Elicited Acute Res-
(ARDS) Using Lomecel-B
Immune Modulation Recruiting NCT05191381 Exosomes derived MSCs 40 Cytokine profile in super-
by Stem Cell Derived natants (Quantification of
Exosomes in Critically Ill pro- and anti-inflammatory
COVID-19 biomarkers after 24 h of
whole blood culture)
13
193
Table 2 (continued)
194
istration
13
Phase 1/2a Study of Umbili- Recruiting/ phase I/II NCT04494386 Umbilical cord tissue 60 100 million cells per dose, Incidence of Dose Limiting
cal Cord Lining Stem Cells IV Toxicity (DLT), Incidence
(ULSC) in Patients With of Dose Limiting Toxicity
ARDS Due to COVID-19 (DLT), suspected adverse
reaction (SAR), or SAE,
TEAE and SAE up to 1 and
12 month follow-up
A Phase 1/2a Study of the Not yet recruiting/ Phase NCT04452097 Human umbilical cord 39 Low-dose Group: 0.5 mil- Safety will be defined by the
Safety and Efficacy of 1/2a lion cells/kg, Middle-dose incidence of infusion-related
BX-U001 for the Treat- Group: 1 million cells/kg, adverse events, treatment-
ment of Severe COVID-19 High-dose Group: 1.5 mil- emergent adverse events,
Pneumonia With Moderate lion cells/kg and treatment emergent
to Severe Acute Res- serious adverse events as
piratory Distress Syndrome assessed by the treating
(ARDS) physician
A Phase II, Double-blind, Recruiting/ phase 2 NCT04780685 Allogeneic bone marrow 40 IV Number of patients alive at
Placebo-controlled Study day 14 post treatment
to Assess the Safety, Toler-
ability, and Preliminary
Efficacy of Intravenous
Allogeneic Mesenchymal
Stem Cells in Patients With
Moderate to Severe ARDS
Due to COVID-19
Prospective Phase II Study: Not yet recruiting/phase 2 NCT04377334 Allogeneic bone marrow 40 IV improvement of lung injury
MSCs in Inflammation- score (LIS), 0–16 points,
Resolution Programs of severity increasing with
SARS-CoV-2 Induced higher points
ARDS
Safety and Efficacy of Recruiting/phase I/II NCT04390152 Wharton's jelly 40 50 × 106 cells, IV, 2 doses Intergroup mortality differ-
Intravenous Infusion of ence with treatment
Wharton's Jelly Derived
Mesenchymal Stem Cell
Plus Standard Therapy for
the Treatment of Patients
With Acute Respiratory
Distress Syndrome Diag-
nosis Due to COVID 19:
A Randomized Controlled
Trial
B. Arjmand et al.
Table 2 (continued)
istration
Role of Investigational Completed/not Applicable NCT04492501 Bone marrow 600 2 × 106 cells/kg Survival
Therapies Alone or in
Combination to Treat
Moderate, Severe and
Critical COVID-19
Single Donor Banked Bone Recruiting/phase I/II NCT04345601 Bone marrow 66 1 × 108 cells, IV, 2 times Treatment-related serious
Marrow Mesenchymal adverse events
Stromal Cells for the
Treatment of COVID-19
Induced ARDS: A Non-
Blinded Randomized,
Controlled Study
An Exploratory Study of Completed/phase I NCT04522986 Adipose tissue 6 1×108 cells, IV, 4 times Safety: Adverse Event
ADR-001 in Patients With
Severe Pneumonia Caused
by SARS-CoV-2 Infection
A Prospective, Double-blind, Active, not recruiting/ phase NCT04390139 Wharton-Jelly 30 1E6cells/Kg, IV, 2 doses All-cause mortality at day 28
Randomized, Parallel, I/II
Placebo-controlled Pilot
Clinical Trial for the Eval-
uation of the Efficacy and
Safety of Two Doses of
WJ-MSC in Patients With
Acute Respiratory Distress
Syndrome Secondary to
Infection by COVID-19
Phase 1b Randomized, Active, not recruiting/ NCT04397796 Allogenic bone marrow 45 IV Incidence of AEs, mortality,
Double-Blind, Placebo- phase I death, Number of ventilator-
Controlled Study Of The free days
Safety Of Therapeutic
Treatment With Immu-
nomodulatory Mesenchy-
mal Stem Cells In Adults
With COVID-19 Infection
Requiring Mechanical
Ventilation
13
195
Table 2 (continued)
196
istration
13
A Randomized, Double- Recruiting/ phase II NCT05126563 Allogeneic adipose tissue 80 200 million cells, IV, 3 times Changes in Visual Analog
blinded, Single-center, Scale of Neurological Symp-
Phase 2 Efficacy, and toms.—Extreme fatigue,
Safety Study of Alloge- Brain fog, Headache, Sleep
neic HB-adMSCs for the disturbances, Loss of taste,
Treatment of Patients With Loss of smell/ Incidence of
Chronic Post-COVID-19 TEAEs, treatment-emergent
Syndrome SAEs/ AEs of special
interest (serious or non-
serious)—thromboembolic
events, thromboembolism
of the extremities, infec-
tions, hypersensitivities/
Changes in Laboratory
values. – CBC, CMP values,
Coagulation Panel, Respira-
tory Rate, Heart Rate, Body
Temperature, Blood Pressure
(mmHg), Changes in Weight
in lb, Changes in Physical
examination results.—Gen-
eral
What is the Effect of Mesen- Completed/phase I/II NCT04392778 Umbilical cord 30 (10/10/10) 3 million cells/kg, IV, 3 Improvement of clinical symp-
chymal Stem Cell Therapy times toms related to Covid-19
on Seriously Ill Patients infection (fever, pneumonia,
With Covid 19 in Intensive shortness of breath)
Care? (Prospective Double
Controlled Study)
Mesenchymal Stem Cell Not yet recruiting/ phase I/II NCT04798716 MSC-derived exosomes 40 Group 1: 2 X 1 09, 4 X 1 09, Quantify safety and effi-
Exosomes for the Treat- 8 X 109/mL, group 2: 8 X cacy of ARDOXSO™, an
ment of COVID-19 109, 4 X 1 09, 8 X 1 09 mL, interventional exosome
Positive Patients With group 3 and 4: 8 X 1 09, 8 therapy in COVID-19 in
Acute Respiratory Distress X 109, 8 X 1 09 mL, IV participants confirmed with
Syndrome and/or Novel SARS-CoV-2 infection who
Coronavirus Pneumonia receive ARDOXSO™ as an
intervention,
B. Arjmand et al.
Table 2 (continued)
istration
Phase I/IIa Study to Assess Not yet recruiting/ phase I/ NCT05491681 Allogeneic bone marrow 9 (3/3/3) Low dose: 20 M cells Number of product related
AllogeneiC Expanded IIa Medium dose: 100 M cells adverse events through the
Human Mesenchymal High dose: 200 M cells duration of the study
Stem Cell Therapy in IV
Patients Recovering From
COVID-19 Acute Respira-
tory Distress Trial (ACE
CARD TRIAL)
Safety and Feasibility of Unknown/phase I NCT04467047 Allogeneic bone marrow 10 1*10E6 MSCs/kg body Assessment of Overall
Allogenic Mesenchymal weight, IV survival at 30 days post
Stromal Cells in the Treat- intervention
ment of COVID-19
A Phase 1/2 Randomized, Unknown/phase I/II NCT04398303 Allogenic human umbilical 70 1 million cells / kg body Mortality at day 30
Placebo-Controlled Trial weight, IV
of ACT-20 in Patients
With Severe COVID-19
Pneumonia
Double Blind, Placebo- Completed/phase II NCT04361942 Allogenic MSCs 24 1 million cells/kg, IV Proportion of patients who
controlled, Phase II Trial have achieved withdrawal of
to Evaluate Safety and invasive mechanical ventila-
Efficacy of Allogenic tion, Rate of mortality
Mesenchymal Stromal
Cells MSV_allo for Treat-
ment of Acute Respiratory
Failure in Patients With
COVID-19 Pneumonia
(COVID_MSV)
Efficacy of Intravenous Infu- Unknown/phase II NCT04437823 Human umbilical cord 20 (15/5) 5 × 10^5 (per Kg body Safety and efficacy assess-
sions of Stem Cells in the weight), IV, 3 times ment of infusion associated
Treatment of COVID-19 adverse events, Assessment
Patients of Pneumonia improve-
ment as a result of stem cell
infusions
A Pilot, Open-label, Rand- Recruiting/phase I/II NCT04537351 induced pluripotent stem 24 2 million MSCs/kg of body Trend in trajectory of PaO2/
omized Controlled Clinical cell (iPSC) and mesenchy- weight (up to a maximum FiO2 ratio (P/F ratio)
Trial to Investigate Early moangioblast (MCA) of 200 million cells per between groups (Assessment
Efficacy of CYP-001 in infusion), IV, 2 times of respiratory dysfunction)
Adults Admitted to Inten-
sive Care With Respiratory
Failure
13
197
Table 2 (continued)
198
istration
13
The Extended Protocol of Enrolling by invitation/ NCT04602442 Exosome 90 3 ml special solution Safety assessment such as
Evaluation of Safety and phase II contained 0.5–2 × 1010, adverse events will be reg-
Efficiency of Method of inhalation istered. Adverse events will
Exosome Inhalation in be monitored during all trial,
COVID-19 Associated Safety assessments such as
Two-Sided Pneumonia adverse events during the
inhalation procedures will
be registered
Is Fetal Hemoglobin a Not yet recruiting/not NCT05092724 Fetal blood transfusion 20 To evaluate the effect of
Key for Improvement of Applicable increasing fetal hemoglobin
Hypoxia and Saving Last protocol on the outcome
Breath in COVID-19 in patients with fulminant
Patient?. A Pilot Study COVID-19
Safety and Efficacy Study of Completed/phase I&II NCT05019287 Allogeneic Human Men- 5 ml, IV, 5 times Adverse reactions incidence,
Allogeneic Human Men- strual Blood Stem Cells Time to clinical improve-
strual Blood Stem Cells Secretome ment
Secretome to Treat Severe
Covid-19 Patients, Clinical
Trial Phase I&II
The Protocol of Evaluation Completed/phase I/II NCT04491240 MSC-derived exosomes 30 (10/10/10) 3 ml special solution con- Number of Participants With
of Safety and Efficiency tained 0.5–2 × 10^10 of Non-serious and Serious
of Method of Exosome nanoparticles (exosomes), Adverse Events During
Inhalation in SARS-CoV-2 inhalation, Twice a day Trial and During Inhalation
Associated Two-Sided during 10 days Procedure
Pneumonia
Clinical Research Regarding Unknown/phase II NCT04269525 Umbilical cord 16 3.3 * 10^7 cell number / partial arterial oxygen
the Availability and Safety 50 ml / bag, 3 bags each pressure (PaO2) / oxygen
of UC-MSCs Treatment time, IV, 4 times concentration (FiO2)
for Serious Pneumonia
and Critical Pneumonia
Caused by the 2019-nCOV
Infection
Phase I/IIA Study of Recruiting/phase I/IIA NCT04524962 MSCs RNA-engineered to 30 o assess the safety of
Descartes-30 in Acute Res- secrete a combination of Descartes-30 in patients
piratory Distress Syndrome DNases with moderate-to-severe
ARDS
B. Arjmand et al.
Table 2 (continued)
istration
Clinical Application of Stem Not yet recruiting/phase II NCT04299152 Stem Cell Educator (SCE)- 20 Determine the number of
Cell Educator Therapy Treated Mononuclear Cells Covid-19 patients who were
for the Treatment of Viral Apheresis unable to complete SCE
Inflammation Caused by Therapy
Severe Acute Respiratory
Syndrome Coronavirus 2
(SARS-CoV-2)
Multi-center, Randomized, Active, not recruiting/ phase NCT04466098 9 300 × 106 cells, IV Incidence of grade 3–5
Placebo Controlled, II infusional toxicities and
Interventional Phase 2A predefined hemodynamic or
Clinical Trial Evaluating respiratory adverse events
the Safety and Potential related to the infusion of
Efficacy of Multiple Dos- MSC
ing of Mesenchymal Stro-
mal Cells in Patients With
Severe Acute Respiratory
Syndrome Coronavirus 2
(SARS-Cov-2)
A Multi-center, Rand- Active, not recruiting/ phase NCT04445220 Allogeneic human MSCs 22 SBI-101 device containing Safety and tolerability as
omized, Case Controlled, I/II 250 million cells measured by incidence of
Double-blind, Ascending- IP-related serious adverse
dose Study of Extracorpor- events
eal Mesenchymal Stromal
Cell Therapy (SBI-101
Therapy) in COVID-19
Subjects With Acute Kid-

ney Injury Receiving Renal
Replacement Therapy
Repair of Acute Respira- Recruiting/phase I/II NCT03042143 Human umbilical cord 129 400 million cells, IV Oxygenation index (OI),
tory Distress Syndrome by Incidence of SAEs
Stromal Cell Administra-
tion (REALIST): An Open
Label Dose Escalation
Phase 1 Trial Followed by
a Randomized, Double-
blind, Allocation Con-
cealed, Placebo-controlled
Trial
Cellular Immuno-Therapy Completed/phase I/II NCT04400032 Umbilical cord 15 Group 1: 75 million cells, Number of Participants With
for COVID-19 ARDS group 2: 150 million cells, Treatment-Related Adverse
(CIRCA-19) group 3: 270 million cells, Events
IV
13
199
Table 2 (continued)
200
istration
13
Cell Therapy Using Umbili- Completed/phase I/II NCT04333368 Umbilical cord Wharton's 47 1 Million / kg cells, IV, 3 Respiratory efficacy evaluated
cal Cord-derived Mes- jelly doses by the increase in PaO2/
enchymal Stromal Cells FiO2 ratio from baseline to
in SARS-CoV-2-related day 7 in the experimental
ARDS group compared with the
placebo group
Evaluation of the Safety, Recruiting/phase I/II NCT04684602 Amniotic and umbilical cord 5000 Assessment of quality of life
Tolerability and Efficacy of (QOL), disabilities of arm,
Regenerative Therapy for shoulder, hand, COPD, men-
the Treatment of Various tal state, interstitial cystitis,
Chronic and Acute Condi- back pain, osteoarthritis
tions
Safety and Tolerability of Recruiting/phase I NCT05286255 Allogeneic umbilical cord 10 1.2–1.5 × 106 cells/kg (maxi- Change in oxygen saturation
Allogeneic Umbilical Cord mum dose of 100 × 10^6 or clinical symptoms
Derived Mesenchymal cells), IV, 2 times
Stromal Cells (UC-MSCs)
to Limit COVID Associ-
ated ComplicatioNs: An
Open Label, Phase 1 Study
in Hospitalized Patients
(SAMPSON-1)
A First-In-Human Phase 1b, Not yet recruiting/phase I NCT05348772 MSC (drug name: Amnio- 18 Dose-limiting adverse events/
Open-Label Trial to Evalu- Pul-02) toxicities (DLTs)
ate Safety and Tolerability
of a Novel Somatic Cell
Therapy, AmnioPul-02,in
Subjects With Confirmed
COVID-19
AdMSCs Adipose Tissue-Derived Mesenchymal Stem Cells, AEs Adverse Events, ARDS Acute Respiratory Distress Syndrome, EVs Extracellular Vesicles, MSC Mesenchymal Stem Cell, SAEs
Serious Adverse Events, UCMSC Umbilical Cord-derived Mesenchymal Stem Cell, TEAE treatment-emergent Adverse Event
B. Arjmand et al.
target cells and tissues (Rezakhani et al. 2021). Thus, sup- who could be targeted. Hereupon, therapeutic strategies
plying a conditioned medium including these factors and targeted at simultaneously inhibiting all pro-inflammatory
EVs could dominate many problems of applying MSCs cytokine and chemokine pathways are presented in the con-
per se. In this regard, tumor differentiation, uncontrolled text of COVID-19. Herein, in critical stage research, simul-
migration, transplant rejection and etc. are some of the dis- taneous suppression of numerous cytokines/chemokine is
advantages of cell-based therapies that are not or less seen believed to offer far greater therapeutic potential than single
in cell-free approaches. As well as, EVs have smaller sizes target techniques to prevent the cascade effects of numer-
in proportion to their source cells which reduces the risk of ous elicited cytokines and chemokine in COVID-19 patients.
thrombosis and pulmonary embolization. Totally, cell-free Additionally, more studies are required to develop an effec-
therapeutics are safer with long-lasting storage in compari- tive delivery system that overcomes the limits of therapeu-
son to cell-based tools. Also, due to regulatory restrictions, tic interventions in COVID-19 along with laying the stage
MSCs-based products and cell-free approaches with less or for the eventual creation of instruments that can precisely
no stem cell manipulation shed light on the future of the RM track COVID-19 patient trajectories using information from
era (Sagaradze et al. 2018; Rahmati et al. 2020; Wang et al. metabolic pathways. Generally, in any COVID-19 pandemic
2021; Sharun et al. 2022). However, reaching the standard future scenario, how civilizations react will play a signifi-
protocol to apply MSCs-based products still needs further cant role. Beginning with the extent to which nations can
studies and consideration. efficiently scale and make available new therapies with the
potential to lower the likelihood of progression to severe
disease, some levers are expected to be especially crucial.
Conclusion and future perspectives In this context, faster distribution of booster doses will assist
safeguard the population and finding the ideal mix of public-
Recently, the need for effective therapies in the face of health initiatives will be crucial given public stress and the
COVID-19 and its important consequences such as CRS and lessons of the previous years of getting a disease.
co- bacterial infections has intensified. In this respect, stem
cell therapy and stem cell-based organoid models are gaining
Authors contributions All authors contributed to the study conception
popularity as new treatment and research tools for COVID- and design.SA-M, and MS wrote the first draft. MR-T, AR-M, and RA
19. Especially, MSC-based therapies have lately piqued sci- helped to study and gather information. EN-E extensively edited the
entists' interest due to their potential utility in autologous manuscript. BL participated in a critical review. BA helped supervise
transplantation. Generally, over the years, great progress has the project and gave final approval of the version to be published. All
authors contributed to manuscript revision, read, and approved the
been made in understanding the potential of MSCs and there submitted version.
is a good foundation for future scientific research and thera-
peutic applications. It's also crucial to take into account the Funding The authors declare that no funds, grants, or other support
fact that MSCs produced from various tissue sources have were received during the preparation of this manuscript.
phenotypic heterogeneity, exhibit various potential for dif- Data availability Enquiries about data availability should be directed
ferentiation, and release various physiologically active sub- to the authors.
stances. Therefore, choosing sources of MSCs with certain
biological characteristics will support the development of Declarations
precision medicines in the future. The best source of cells
Conflict of interest The authors have no relevant financial or non-fi-
for really ill elderly COVID-19 patients are allogeneic cells nancial interests to disclose.
and autologous donors can be used, for younger patients.
Generally, to treat COVID-19, a trustworthy source of MSCs
must be identified. Regulations from authorities and clinical
guidelines are required since MSC suppliers have different References
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Inflammopharmacology (2023) 31:171–206

Critical roles of cytokine storm and bacterial infection in patients

Abbreviations SOD Superoxide Dismutase

Innate immune cells e.g.

RM involves the application of various FDA-approved thera-

Changes in body tem-

Randomized Clinical Trial

Placebo-Controlled Study cells/vial, IV, 3 doses Distance (6MWD) at Day 60

Treatment for COVID-19 Ratio

Subjects With Acute Kid-

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MSC Covid

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Copyright

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MSC Covid

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Inflammopharmacology (2023) 31:171–206

Critical roles of cytokine storm and bacterial infection in patients

Abbreviations SOD Superoxide Dismutase

Innate immune cells e.g.

RM involves the application of various FDA-approved thera-

Changes in body tem-

Randomized Clinical Trial

Placebo-Controlled Study cells/vial, IV, 3 doses Distance (6MWD) at Day 60

Treatment for COVID-19 Ratio

Subjects With Acute Kid-

You might also like

Abbreviations SOD Superoxide Dismutase