Stem Cell Therapy for COVID-19

Is It a Promising Treatment ?
Artrien Adhiputri

Pulmonology and Respiratory Disease Department

Medical Faculty Universitas Sebelas Maret / RSUD Dr. Moewardi
2022
COVID-19
 Backgrounds
Caused by SARS‐CoV-2, proliferating quickly worldwide
Pandemic on March, 2020.

✔ Most clinical manifestations pneumonia even ARDS, ↑

✔ The management antiviral, vitamin, symptomatic,
supportif, antibiotic, immune based therapy, comorbid
therapy.
n ti o n&
eve
PrIFN‐β1, c ti o ns
convalescent plasma, stem cells, IL-6
n fe
o n t r ol i
inhibitor, IL-1 inhibitor, human Ig, steroid, etc.
c
3
 Pathophysiological Progression of COVID-19

Mary Kathryn, et al. Pathophysiology of COVID-19: Mechanisms Underlying Disease Severity and Progression. 2020. J. Physiol. 4
 Stages of COVID-19

Zhongwen Li, et al. Stem cell therapy for COVID-19, ARDS and pulmonary fibrosis. 2020. Cell Proliferation. 5
Stem Cells
Backgrounds

• Unspecialized cells of the human body that able to

differentiate into any cell of an organism & have the
ability of self-renewal through cell division.
• There are different kinds of stem cells which depend on
their originality and/or their differentiation potency
(which is reduced by each step).
• Become a magnificent game changer for medicine
regenerative medicine and tissue repairment.

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Classifications

Barky AR, Ali EM, Mohamed TM. Stem cells, classifications and their clinical applications. Am J Pharmacol Ther. 2017. 8
 According to the differentiation potency
Totipotent stem cells
Highest differentiation potential Have the capacity to divide &
differentiate into all cell types in an organism (zygotes)

Pluripotent stem cells

Form cells of all germ layers but not extraembryonic structures [Embryonic
stem cell (ESCs) & induced pluripotent stem cells (iPSCs)]

Multipotent stem cells

They can specialize in discrete cells of specific cell lineages.

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 Derivation of stem cells

Jesse K. Biehl, et al. Introduction to Stem Cell Therapy. J Cardiovasc Nurs. 2009 ; 24(2): 98–105. 10
 According to the differentiation potency

Oligopotent stem cells

Can differentiate into only a few cell types. A myeloid stem cell can
divide into white blood cells but not red blood cells.

Unipotent stem cells

The narrowest differentiation capabilities (only able to form 1 cell type) and
a special property of dividing repeatedly promising candidate for
therapeutic use in regenerative medicine.

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 According to the origins
Embryonic stem cells
Pluripotent, from the very early stages of embryo development after 4-5
days after fertilization can differentiate into endoderm, mesoderm &
ectoderm embryonic germ layers, also any type of somatic cells great
capacity in tissue regeneration therapy.

Fetal stem cells

Primal cell types found in the organs of the fetuses able to differentiate
into 2 types of stem cells: pluripotent & hematopoietic stem cells. Human
fetal stem cells have been used by many people that are suffering from many
devastating diseases.
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 According to the origins
Umbilical cord stem cells
Umbilical cord blood contains prevalent stem cells which differ from those
of bone marrow & adult peripheral blood Multipotent

Wharton’s jelly
Umbilical cord matrix source of mesenchymal stem cells. These cells
express typical stem cell markers, can be propagated for long times and can
be induced to differentiate in vitro.

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 According to the origins
Mesenchymal stem cells
Different population of cells with the potential to differentiate into
various somatic lineages. Can be isolated from the bone marrow and readily
discreted from the hematopoietic stem cells due to their plastic adherence.
Used in tissue engineering & regenerative medicine. Can be
long-storaged without major loss of their potency.

Hematopoietic stem cells

Self-renewing potential & differentiated cells of all hematopoietic
lineages.

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 According to the origins
Neural stem cells
Self-replication cells, they are established in specialized molecular
microenvironments in the adult mammalian brain.

Gastrointestinal stem cells

The stem cells of the gastrointestinal tract reside in a “niche” in the intestinal
crypts and gastric glands.

Epidermal stem cells

Rapidly rejuvenating tissue, consists of 3 types differentiation potential:
epidermal, Transiently Amplified (TA) & terminally differentiated cells
maintaining homeostasis & cellular regeneration of normal skin.
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 According to the origins

Hepatic stem cells

Strong regenerative capacity Mature liver cells can propagate to replace
the damaged tissue permit the recovery of the parenchymal function.

Pancreatic stem cells

Insulin-producing cells previously generated from pluripotent stem cells.
Provide a novel cell source for drug discovery & cell transplantation therapy in
diabetes.

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Stem Cells on
COVID-19
 Backgrounds
Khoury et al (2020)
Systemic administration of MSCs treat respiratory virus‐related lung
injury.

Zhao et al and Liang et al (2020)

Stem cell 1st initiated on COVID-19 patients

• Critically ill young patients
• Critically ill older patients in lung function after
• Patients who are at risk of stem cell administration
infection due to comorbidities

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 Possible Stem Cell Sources & Types
✔ Multipotent, found in various autologous & allogenic
sources (cord blood, cord tissue, placenta, bone marrow,
adipose tissue, dental pulp, peripheral blood).

MSCs
✔ No ethical issues.
✔ proliferative potential & multi-lineage differentiation capacity.
✔ The immunomodulatory & regenerative potential help in
modulation of proliferation, activation & function of various
immune cells.

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 Potential Mechanisms of Stem Cell Therapy in
COVID-19
✔ Have properties of self-renewal and multi-lineage
differentiation potential.
✔ Becoming one of the emerging treatment strategies for
several refractory diseases with no known treatments,
including viral infections, such as COVID-19 pandemic
especially MSCs.
✔ Regenerate and repair damaged tissues by trans
differentiation or secretion of various bioactive molecules to
stimulate resident cells.
✔ Well known for its promising anti‐inflammatory properties. 20
 Potential Mechanisms of Stem Cell Therapy in
COVID-19
COVID-19 • Causes T-cell imbalance Lymphopenia
• CD4+ & CD8+ T cells in the peripheral blood significantly
• Overall immune system is abnormally activated & dysregulated
by the cytokine storm.

Organ failure followed by edema,

secondary infection, cardiac damage,
& ARDS.
MSCs
▪ Powerful anti‐inflammatory & immunomodulatory
▪ ≠ overactivation of the immune system
▪ endogenous repair of injured tissues 21
 Cytokine storm modulation by mesenchymal stem cells.
Mahmood S. Choudhery, David T. Harris. Stem cell therapy for COVID‐19: Possibilities and challenges. Cell Biol Int. 2020;1–10. 22
MSCs
✔ Express levels of HLA class I molecules
✔ HLA class II molecules
✔ Co-stimulatory molecules such as CD40, CD40L, CD80 & CD86

Allows MSCs to escape the cytotoxic effects of lymphocytic T cells, B

cells & NK cells, were thus termed 'immune-privileged' cells.
✔ Activate innate & adaptive immune regulatory responses by
interact with host immune cells through cytokines secretion.
✔ Detect microenvironmental injury signals to direct
pro-regenerative signalling processes.

Immunomodulatory & anti-inflammatory effects, extensive tissue damage

repair, as is the case with COVID-19.
MSCs
✔ Inhibit excessive proliferation of T cells & suppress the activity
of cytotoxic CD8+ T lymphocytes.
✔ the secretion of IFN-γ & TNF-α, the secretion of IL-4 from
a pro-inflammatory to an anti-inflammatory state.
✔ Inhibit abnormal activated Th1, restore the Th1/Th2 balance.

✔ Promote the proliferation of mature DCs & drive it into a novel

regulatory DC population to escape apoptosis.
✔ regulate macrophage polarization (M1 M2) to suppress
chronic inflammation and promote tissue healing after injury (by
secreting IL-10 to inhibit NF-κB signalling).

Improve the immune status

MSCs

✔ IV injection of BMSCs the production of neutrophils by 32%,

thereby their NLR levels & improving their clinical oxygenation
index.
✔ Inhibit excessive proliferation of B cells, prevent their
differentiation into plasma cells and excessive levels of IG
secretion.
✔ overactivated NK cells

✔ Secreting hepatocyte growth factor (HGF), VEGF, keratinocyte

growth factor (KGF) & FGF.

apoptosis of the alveolar epithelial cells & endothelial, promote

lung tissue repair, reduce the levels of pro-fibrotic. 25
Immunity- and matrix-regulatory cells (IMRCs)
✔ New type of human embryonic stem cells (hESC)-derived
MSC-like cells that resemble MSCs in self-renewal & tri-lineage
mesenchymal differentiation potentials.
✔ immunomodulatory & anti-fibrotic functions (inhibition of TGF-
β1), & significantly extended lifespans in vitro for consistent
quality in production.

A recent report IV delivered IMRCs could home into the lungs and
inhibit both pulmonary inflammation & fibrosis after
bleomycin-induced acute lung injury in mouse models in vivo.
A pilot study showed that they could ameliorate the ARDS in 2
severely ill COVID-19 patients.
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 The potential mechanisms of MSCs therapy for COVID-19.
Zhongwen Li, et al. Stem cell therapy for COVID-19, ARDS and pulmonary fibrosis. 2020. Cell Proliferation. 27
 Putative mechanisms of action
of MSCs against lung
inflammation caused by
COVID-19.

Felipe Saldanha-Araujo, et al. Mesenchymal

Stem Cells: A New Piece in the Puzzle of
COVID-19 Treatment. Frontiers in
immunology. 2020.
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 Clinical Trials of Stem Cell Therapy in
COVID-19

✔ Most studies patients with severe/critical pneumonia COVID-19.

✔ Most common source of MSCs umbilical cord/Wharton's jelly.
✔ Most routes Infusion (IV) dosage ranged 0.5 -1 x106 cells/kg 3
rounds.

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 Clinical Trials of Stem Cell Therapy in
COVID-19
Leng et al., 2020

• 7 COVID‐19 (critically severe 1, severe 4, common type 2).

• Single dose of MSCs (106 cells/kg BW) & patients were followed
for 14 days.
• No adverse events in terms of allergic reactions or secondary
infections.
• Pulmonary function and symptoms were significantly improved
in all patients 2 days after MSCs injection.

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 Chest CT images of the critically
severe COVID-19 patient.
Jan 23, no pneumonia
Jan 30, GGO & pneumonia
infiltration in multi-lobes of the
double sides.
Jan 31, Cell transplantation
Feb 2, pneumonia invaded all
through the whole lung.
Feb 9, the pneumonia infiltration
faded away largely.
Feb 15, only little GGO was
residual locally

Zikuan Leng, et al. Transplantation of ACE2- Mesenchymal Stem Cells

Improves the Outcome of Patients with COVID-19 Pneumonia. Aging and
Disease. Vol 11. April 2020. 31
 Clinical Trials of Stem Cell Therapy in
COVID-19
Liang et al., 2020

• A 65 years old female COVID‐19 confirmed. Although the

patient was treated with the standard regimens, later was
critically ill and transferred to ICU.
• UC‐MSCs were infused three times of 5x107 UC‐MSCs 3 days
apart.
• The patient responded to the MSC administration and within a
week pneumonia was greatly relieved (CT-scan).

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Bing Liang, BS. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord
mesenchymal stem cells. Clinical case report Medicine. 2020. 33
Bing Liang, BS. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord
mesenchymal stem cells. Clinical case report Medicine. 2020. 34
 Clinical Trials of Stem Cell Therapy in
COVID-19
Dilogo et al., 2020

• 40 critically ill COVID‐19 patients (controls : 20)

• Single dose of UC-MSCs (1x106 cells/kg BW)
• No life-threatening complications or acute allergic reactions.
• The survival rate in the MSCs group was 2.5 times higher than
that in the control group.
• The majority of those with >2 comorbidities who recovered came
from the MSCs group, with a 4:1 ratio to the control group.

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Dilogo, et al. Umbilical cord mesenchymal stromal cells as critical COVID-19 adjuvant therapy: A randomized
controlled trial. Stem cells translational medicine. 2021. 36
 Clinical Trials of Stem Cell Therapy in
COVID-19
Multicentre, 2021

• 42 severe of COVID‐19 patients (controls : 21)

• 3 times of UC-MSCs (1x106 cells/kg BW)
• No life-threatening complications or acute allergic reactions.
• Significantly improving oxygenation index
• Decreasing Brixia Score (chest x-ray)

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 Side Effects of Stem Cells Therapy

Transient facial flushing & fever immediately after UC-MSCs

infusion that resolved spontaneously within 4 hours.
Fever of 38°C after 2 hours of UC-MSC infusion which recovered
within 24 hours.
Hypoxaemia within 12 hours of UC-MSC administration &
recovered within 36 hours of receiving nasal cannula O2 therapy.
Hypoxemia is thought to be caused by the progression of

These findings suggest that MSCs treatment for

patients with COVID-19 is safe & tolerable 38
Durand, et al. Insights into the use of mesenchymal stem cell in COVID-19 mediated acute respiratory failure. npj
Regenerative Medicine. 2020. 39
 Complications of Stem Cells Therapy

The risks associated with tumor-genesis after stem cell

transplantation need to be considered because of their ability
to proliferate over a long period of time, viability, & resistance
to apoptosis.
The risk of thromboembolic complications can be assumed to be
when injecting clotted cells compared to single cell
suspensions (The patient's underlying medical condition should
also be taken into account)

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 Conclusions

A cytokine storm in COVID-19 might lead to ARDS & death, there is no

specific therapy for the management until now.

MSCs are multipotent stromal cells that have immunomodulatory &

endogenous repair potential capacities especially in the treatment of
COVID-19.

More researches are needed for understanding the mechanism of various

kind of stem cells particularly MSCs for treating COVID-19 patients.

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 References
• Zakrzewski, et al. Stem cells: past, present, and future. Stem Cell Research
& Therapy. BMC. 2019.
• Barky AR, et al. Stem cells, classifications and their clinical applications. Am
J Pharmacol Ther. 2017.
• Eljarrah A, et al. Therapeutic potential of mesenchymal stem cells in
immune-mediated diseases. In: Ratajczak MZ, editor. Stem cells therapeutic
applications. 1st ed. Cham: Springer; 2019. p. 93-103.
• Mary Kathryn, et al. Pathophysiology of COVID-19: Mechanisms Underlying
Disease Severity and Progression. 2020. J. Physiol.
• Zhongwen Li, et al. Stem cell therapy for COVID-19, ARDS and pulmonary
fibrosis. 2020. Cell Proliferation.
• Mahmood S. Choudhery, David T. Harris. Stem cell therapy for COVID‐19:
Possibilities and challenges. Cell Biol Int. 2020;1–10.
• Meng F, et al. Human umbilical cord-derived mesenchymal stem cell therapy
in patients with COVID-19: a phase 1 clinical trial. Signal Transduct Target
43
Ther. 2020.
 References
• Jesse K. Biehl, et al. Introduction to Stem Cell Therapy. J Cardiovasc Nurs.
2009 ; 24(2): 98–105.
• Felipe Saldanha-Araujo, et al. Mesenchymal Stem Cells: A New Piece in the
Puzzle of COVID-19 Treatment. Frontiers in immunology. 2020.
• Bing Liang, et al. Clinical remission of a critically ill COVID-19 patient treated
by human umbilical cord mesenchymal stem cells. Clinical case report
Medicine. 2020.
• Zikuan Leng, et al. Transplantation of ACE2- Mesenchymal Stem Cells
Improves the Outcome of Patients with COVID-19 Pneumonia. Aging and
Disease. Vol 11. April 2020.
• Dilogo, et al. Umbilical cord mesenchymal stromal cells as critical COVID-19
adjuvant therapy: A randomized controlled trial. Stem cells translational
medicine. 2021.
• Durand, et al. Insights into the use of mesenchymal stem cell in COVID-19
mediated acute respiratory failure. npj Regenerative Medicine. 2020. 44