190 Current Stem Cell Research & Therapy, 2010, 5, 190-194

Adipose Tissue Derived Stem Cells for Regeneration and Differentiation into Insulin-
Producing Cells

Song Cheol Kim*,1,2, Duck Jong Han1 and Ji Yeon Lee2

1
Department of Surgery, University of Ulsan College of Medicine & Asan Medical Center, Korea; 2Laboratory of Cell Therapy, Asan
Institute for Life Science, Seoul, Korea

Abstract: Stem cells are considered an ideal tool for the supply of insulin-producing cells or repairing damaged pancreatic tissues to treat
diabetes mellitus, with the possibility of unlimited sources. This cell population includes embryonic, adult bone marrow, pancreatic stem
cells, extra pancreatic (such as hepatic cells) and adipose-derived stem cells. Multipotent adipose tissue-derived stem cells (ADSCs) are
abundant in the human body, and thus are an ideal donor source for autologous transplantation to generate insulin-producing cells.
Moreover these cells are better sources than bone marrow stem cells (BMSCs) for clinical applications, owing to minimal invasive pro-
cedures, high proliferation and multi-differentiation potential. Human adipose tissue-derived stem cells (hADSCs) may thus provide an
alternative stem cell source, replacing BM-MSCs or embryonic stem cells (ESCs) for future clinical use in diabetes mellitus treatment.

Keywords: Stem cell, adipose tissue derived stem cells, insulin-producing cells, diabetes, regeneration, cell therapy.

INTRODUCTION and transdifferentiate into pancreatic beta-cells in vivo [10-14].

Curative treatment of insulin-deficient diabetes mellitus with
minute-to-minute control can be achieved by: i) restoring the en-
dogenous insulin source and ii) transplanting an insulin-producing
pancreatic or non pancreatic source of cells. To accomplish this
goal, several clinical trials investigating stem cell potential in hu-
man or non-human subjects, such as regeneration of residual islet
cells in the diseased pancreas or reprogramming of the regenerative
power by precursor or stem cells [1], and islet-cell transplantation
[2] are underway. Among these strategies, transplantation of islets
from cadaveric donors is a promising cell-based therapy for diabe-
tes mellitus. However, limited availability of donor cells and im-
mune suppression are major obstacles in islet transplantation.
Therefore, considerable effort has been devoted to identifying alter-
native stem cell sources for generating transplantable pancreatic
beta-cells. Here, we review the use of stem cells for pancreatic re-
generation and differentiation into insulin-producing cells, and
adipose-derived stem cell strategies for clinical use in the genera-
tion of insulin-producing cells.
STEM CELL STRATEGY FOR PANCREATIC REGEN-
ERATION AND DIFFERENTIATION INTO INSULIN-
PRODUCING CELLS
Stem cells are an ideal tool for supplying cells producing spe-
cific hormones or proteins or repairing damaged tissues. A major
advantage of the stem cell approach is the supply of an unlimited
number of cells that have the potential to become a functional or-
gan. Adult stem cells have the advantage of differentiating into
different tissue-specific cell types, along with no significant ethical
concerns. Different sources of stem cells are proposed for the pro-
duction of beta cells essential to control hyperglycemia in the hu-
man body. Embryonic stem cells are pluripotent, and differentiate
into almost all cell types. A number of studies have demonstrated
insulin-producing pancreatic differentiation of ESCs [3-9]. How-
ever, the ethical issues and risk of teratoma formation remain to be
resolved. MSCs from bone marrow are the most extensively inves-
tigated adult stem cells to date, and several research groups report
that BM-MSCs differentiate into insulin-producing cells in vitro
*Address correspondence to this author at the Department of Surgery, Uni-
versity of Ulsan College of Medicine and Asan Medical Center, 388-1
Pungnap-dong, Songpa-gu, Seoul 138-736, Korea; Tel: 82-2-3010-3936;
Fax: 82-2-474-9027; E-mail: drksc@amc.seoul.kr
However, the in vivo transdifferentiation of BM-MSCs remains a
controversial issue [15-17]. The highly invasive procedure, limited
quantity of bone marrow obtainable from a single donor and low
cell numbers are significant obstacles in the production of sufficient
BM-MSCs for clinical applications. Stem cells in adult tissues, such
as liver [18], pancreas duct [19], umbilical cord blood [20] and
placenta [21], differentiate into pancreatic beta-cells. A recent re-
port indicates that human adipose tissue contains multipotent stem
cells that have the potential to differentiate into adipogenic, chon-
drogenic, myogenic, and osteogenic lineages [22]. Pancreatic dif-
ferentiation from human adipose tissue-derived stem cells (hASCs)
has additionally been reported by Timper et al. [23] and Lee et al.
[24]. Here, we discuss the various stem cell types that are able to
differentiate into insulin-producing cells.
1. Embryonic Stem Cells
Embryonic stem cells can differentiate into almost all cell types.
The application of these pluripotent cells in the field of regenerative
medicine is currently under investigation [25]. Murine and human
ESCs generate embryoid bodies that contain cells with a beta-cell-
like phenotype in vitro, and differentiated ESCs lower blood glu-
cose levels in rodents [26-27]. Segev and colleagues [4] reported
enhanced expression of beta-cell-specific genes in ESCs after ma-
nipulation of culture medium, while Soria et al. [28] observed that
insulin expression also occurs spontaneously during culture of un-
differentiated ES cells.
Lumelsky and co-workers [29] initially reported that a nestin-
positive pancreatic islet cell-like structure can be selected, ex-
panded, and differentiated from ES cells. These cells displayed 50-
fold lower intracellular insulin content than normal pancreatic islet
cells, but were not able to reverse the diabetic status of streptozoto-
cin-induced diabetic mice. As an alternative trial to enhance the
phenotype of insulin-producing cells, treatment with enhancers
(such as inhibitors of phosphoinositide 3 kinase) and overexpres-
sion of transcription factors, such as PAX4, PDX1, and NKX6.1,
was investigated, but with minimal success. While the potential
application of ESCs for producing beta cells has brought idealism
into the field of diabetic research, a significant drawback requires
some considerations. It is suggested that beta cells derived from
ESCs represent aberrant products from uncontrolled differentiation
programs. An earlier study shows that animals develop tumors
when transplanted with ESC-derived insulin-producing cells [30].
Thus, it is crucial to assess the efficacy of ESCs in detail before

1574-888X/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.

Adipose Tissue-Derived Stem Cells Generate Insulin-Producing Cells
recommending these cells as a suitable source of insulin-producing
cells in diabetes treatment.
2. BM-Derived Stem Cells
Bone marrow-derived stem cells (BMSCs) are multipotent, ca-
pable of self-renewal, and a well known source of stem cells for
blood cells. These cells have the ability to generate other cells or
tissue types, due to their ability to differentiate into all embryonic
lineages [31], migrate towards the site of damage, and differentiate
under the influence of factors from the microenvironment [32].
Ianus and colleagues showed that adult bone marrow stem cells
differentiate into insulin-producing cells after engrafting to recipi-
ent pancreas parenchyma, express beta cell markers, and produce
insulin after the glucose challenge test. They showed that this phe-
nomenon was the result of donor cell differentiation with the CRE-
LoxP cell tracking system [33]. BMSCs cultured in vitro can pro-
duce de novo insulin and express insulin upon challenge with high
glucose [10]. Overall, current research suggests that BMSCs do not
differentiate into beta cells in vivo. However, BMSCs support pan-
creatic growth in vivo, and can be manipulated in vitro to differenti-
ate into beta cells.
3. Human Umbilical Cord Blood Cells
Human umbilical cord blood (UCB) cells can differentiate into
insulin-producing cells with the advantages of generating sufficient
autologous stem cells to overcome the immune reaction, as shown
by a number of researchers. Yoshida et al. [34] intravenously trans-
planted human CB–derived cells into non-obese diabetic/severe
combined immunodeficient/
2-microglobulin null mice. After
transplantation of T cell-depleted mononuclear cells, human CB-
derived cells generated insulin-producing cells at a frequency of
0.65 ± 0.64% in xenogeneic hosts. Kang et al. [20] isolated a popu-
lation of stem cells from human cord blood (UCB) expressing the
embryonic stage-specific maker, SSEA-4, and the multipotential
stem cell marker, Oct4. These cells were induced to differentiate
into insulin-producing islet-like structures co-expressing insulin and
C-peptide. Chao and colleagues [35] transplanted human umbilical
cord mesenchymal cells into the livers of streptozotocin-induced
diabetic rats. These islet-like cell clusters contain the human C-
peptide and release human insulin in response to glucose. Real-time
RT-PCR was employed to detect the expression of insulin and other
pancreatic beta cell-related genes (Pdx1, Hlxb9, Nkx2.2, Nkx6.1,
and Glut-2). Hyperglycemia in streptozotocin-induced diabetic rats
was significantly alleviated after xenotransplantation of islet-like
cell clusters without immunosuppressants.
4. Pancreatic Stem Cells
Specific populations of cells located in the adult pancreas are
capable of differentiating into islet cells after partial pancreatec-
tomy., Islet cell production from these stem cells may be a useful
tool to correct islet cell deficiency in the clinical setting [36]. Pan-
creatic stem cells constitute different populations, including those
of endocrine origin (islet-derived population) as well as non endo-
crine-derived stem cells (ductal epithelial and acinar cells). Non-
endocrine stem cells are mainly pancreatic ductal epithelial cells
expressing the ductal markers, CK-19 and PDX1, which possess the
ability to expand and differentiate into endocrine cells. Early pan-
creatic development from the endoderm bud progresses to cy-
tokeratin-expressing ductal structures, followed by eventual loss of
cytokeratin and expression of the endocrine or exocrine phenotype
[37]. Recently Hao and colleagues reported beta cell differentiation
from non endocrine cells procured after human islet isolation to
adult pancreatic stem cells. They cultured the mixture fractions with
G 418 to eliminate mesenchymal cells, leaving highly purified
nonendocrine pancreatic epithelial cells (NEPECs). NEPECs were
capable of endocrine differentiation upon cotransplantation with
fetal pancreatic cells [38].
Current Stem Cell Research & Therapy, 2010, Vol. 5, No. 2 191
Nestin-positive cells represent a well-known endocrine-derived
stem cell type. Nestin is detected in various adult CNS lineages.
These cells have been identified in murine and human pancreas
[39]. Nestin-positive cells represent a population of islet-derived
stem cells, and these progenitor cells are able to differentiate in
vitro into cells with liver, pancreatic exocrine and/or ductal and
endocrine phenotypes. After differentiation, cells produce insulin,
glucagon, glucagon-like peptide-1 (GLP-1), and the transcription
factor PDX1 [40]. However, nestin is regarded as a functional pro-
tein expressed in beta cell precursors due to heterogeneous expres-
sion in pancreas and other tissues. The issue of whether nestin-
positive cells function as b-cell precursors remains a subject of
controversy. Other possible islet-related cells include “small cells”
within the pancreatic islet expressing four types of endocrine hor-
mones, specifically, PDX-1, synaptophysin, Bcl-2, and insulin [41].
Guz and colleagues showed that the islet contains these cells, and
that islets in streptozotocin-damaged pancreas contain cells express-
ing insulin and somatostatin, thereby validating a role of this cell
population in beta cell differentiation [42].
5. Other Sources of Non-Pancreatic Organ-Derived Stem Cells
The main advantage of extrapancreatic sources is that these tis-
sues (such as adipose tissue) can be obtained easily. Extrapancreatic
organ-derived stem cells, including those from hepatocytes [43],
human adipose-tissue derived mesenchymal stem cells [23,24], and
splenocytes [44], can differentiate into islet cells. Kojima et al. [45]
reported islet neogenesis in the portal triad area by delivery of a
combination of NeuroD and betacellulin. Delivery of the transcrip-
tion factor, PDX1, or a combination of BETA2 and betacellulin to
the medium [45, 46] can be successfully applied to promote differ-
entiation into a beta cell phenotype.
6. Adipose Tissue-Derived Stem Cells Generate Insulin-
Producing Cells
Human adipose tissue is available in large quantities as a waste
product of cosmetic liposuction, which involves a less invasive
procedure than obtaining human bone marrow. Human adipose
tissue contains multipotent stem cells that have the potential to
differentiate into adipogenic, chondrogenic, osteogenic, myogenic,
neurogenic [22], endothelial [47], hepatic [43], and pancreatic line-
ages [23]. Lack of HLA-DR expression and immunosuppressive
properties of hASCs have been reported by Puissant et al. [48].
Fang and colleagues published preliminary data showing that se-
vere refractory acute graft-versus-host disease (GVHD) could be
treated with human adipose tissue-derived mesenchymal cells from
HLA-mismatched donors [49]. Zhu and co-workers further pro-
posed that ADSCs are a better cell source than BMSCs [50]. They
investigated the proliferation and multi-differentiation potential of
ADSCs via cell phenotype analysis. ADSCs can be continuously
cultured in vitro for up to 1 month without passage, and undergo
several logarithmic growth phases during the culture period.
Moreover, ADSCs express high levels of stem cell-related antigens,
but not hematopoiesis-related antigens or the human leukocyte
antigen, HLA-DR. The stem cell-related transcription factors,
Nanog, Oct-4, Sox-2, and Rex-1, are positively expressed in
ADSCs.
Only four reports on the possibility of ADSC conversion to in-
sulin-producing cells are currently documented in the English lit-
erature, including our study. An earlier investigation by Timper et
al. [23] showed that human adipose tissue-derived MSCs from four
healthy donors differentiated into insulin, somatostatin, and gluca-
gon-expressing cells. During the proliferation period, cells ex-
pressed the stem cell markers nestin, ABCG2, SCF and Thy-1, as
well as the pancreatic endocrine transcription factor, Isl-1. Cells
were induced to differentiate into a pancreatic endocrine phenotype
within 3 days by culturing in defined conditions. Quantitative PCR
revealed downregulation of ABCG2 and upregulation of the pan-
192 Current Stem Cell Research & Therapy, 2010, Vol. 5, No. 2
creatic developmental transcription factors, Isl-1, Ipf-1, and Ngn3,
together with induction of the islet hormones, insulin, glucagon,
and somatostatin.
We subcultured ADSCs every 14 days instead of the normal 5
days [24]. ADSCs maintained strong proliferation ability, pheno-
type, and displayed stronger multi-differentiation potential after 25
passages. Pancreatic regeneration is reported in partially pancre-
atectomized rats, and treatment of the extract from the remnant
pancreas after partial pancreatectomy initiates islet neogenesis and
normoglycemia in streptozotocin (STZ)-induced diabetic mice [51].
To determine whether hADSCs differentiate into pancreatic linea-
ges by regenerating the pancreatic extract (RPE), hADSCs were
treated with RPE. After differentiation, increased expression levels
of transcription factors (FoxA2, Hlxb9, NeuroD, and Nkx2.2) re-
lated to beta cell development were observed in cultures. The levels
of Sox17, a definitive endoderm marker, and IPF-1, which is not
only expressed in pancreatic beta-cells but also involved in early
endocrine development, were examined in differentiated cultures.
Somatostatin was expressed in both control and RPE-treated cul-
tures. Undifferentiated cells expressed Pax6 and Isl-1, and levels of
these genes were slightly increased in RPE-treated cultures. These
genes are not only expressed in early pancreatic cells, but are also
active in the developing and mature central nervous system. This
finding supports the proposal that hADSCs have the potential to
differentiate into neuronal lineages. To confirm that insulin mRNA
in differentiated cells was newly transcribed, we performed immu-
nocytochemistry analysis for the C-peptide. Notably, C-peptide-
positive cells were observed in differentiated cultures. However, we
were unable to confirm detectable levels of C-peptide in differenti-
ated cultures, possibly due to the insufficient number of differenti-
ated cells induced.
Recently Trivedi and colleagues showed that hADSCs com-
bined with human bone marrow hematopoietic cells synthesize
insulin [52]. Five insulinopenic DM patients were intraportally
administered xenogeneic-free h-ADMSC (mean dose, 1.5 mL; cell
counts, 2.1 x 103/μL). The CD45-/90+/73+ cells (29.8/16.8%) con-
tained 3.08 ng/mL c-peptide and 1578μIU/mL insulin. Aliquots
were supplemented with bone marrow hematopoietic cells contain-
ing 0.93% CD45-/34+. All patients were successfully infused with
h-ADMSC containing bone marrow hematopoietic cells with no
side-effects, and showed 30% to 50% decrease in insulin require-
ment and 4- to 26-fold increased serum c-peptide levels, at a mean
follow-up of 2.9 months.
Kang and colleagues [53] demonstrated that differentiated
HEACs (human eyelid adipose cells) directly regulate blood glu-
cose levels in diabetic mice by releasing human insulin. Stem cells
from HEACs displayed characteristics of neural crest cells, and
HEACs were differentiated into insulin-secreting cells using two-
step culture conditions combined with nicotinamide, activin, and/or
GLP-1. They verified the in vivo effects of differentiated cells via
transplantation experiments. They observed normalization of hy-
perglycemia in 10 of 20 recipients until sacrifice after two months
in streptozotocin-treated immunocompetent diabetic mice without
immunosuppression. Diminished or null expression of some im-
mune-related genes was additionally observed. Interestingly, Kang
and colleagues maintained that HEACs are markedly different from
MSCs isolated from other adipose tissues. They showed that undif-
ferentiated HEACs spontaneously express several neural cell-
related mRNAs and a variety of neural proteins, including GABA,
GalC, serotonin, tubulin III, and GFAP, most of which are also
identified in human neural crest and neuroblastoma cells, while
MSCs from the trunk adipose tissues do not display most of these
neural cell-like characteristics unless cultured under neurogenic
conditions comprising particular chemicals, growth factors, and
neural tissues.
Chandra et al. [54] successfully generated pancreatic hormone-
expressing islet-like cell aggregates from ASCs cultured from
Kim et al.
epididymal fat pads of Swiss albino mice. They used a 10-day dif-
ferentiation protocol involving progressive changes in the differen-
tiation cocktail on days 1, 3 and 5. These cell populations contained
pancreatic endoderm-expressing and hormone-expressing cells.
Calcium-alginate encapsulated day10 ICAs, when transplanted
intraperitoneally into STZ-induced diabetic mice, restored normo-
glycemia within 2 weeks.
During the preparation of this review, an interesting article was
published online by Lin et al. [55]. They reported the derivation of
insulin-producing cells from human or rat ADSCs by transduction
with the pancreatic duodenal homeobox 1 (Pdx1) gene. RT-PCR
analyses revealed that native ADSCs expressed insulin, glucagon,
and NeuroD genes, which were upregulated following Pdx1-
transduction. ELISA analyses showed that transduced cells secreted
higher amounts of insulin in response to increasing concentrations
of glucose. Transplantation of these cells under the renal capsule of
streptozotocin-induced diabetic rats resulted in lower blood glu-
cose, higher glucose tolerance, smoother fur, and less cataracts.
Moreover, histological examination confirmed that the transplanted
cells formed tissue-like structures and expressed insulin. These
results support the suitability of ADSCs for the treatment of diabe-
tes mellitus.
CONCLUSIONS
Stem cell approaches capable of supplying an unlimited number
of cells that have the potential to become a functional organ are
emerging as an effective tool for the curative treatment of insulin-
deficient diabetes mellitus. Among these stem cell populations,
hASCs are a better cell source than BMSCs for clinical applications
owing to minimal invasive procedures, high proliferation rates, and
multi-differentiation potential. Human adipose tissue-derived stem
cells may thus be used as an alternative source, successfully replac-
ing BM-MSCs or ESCs for future clinical use in diabetes mellitus
therapy


ACKNOWLEDGEMENT
This study was supported by a Grant (07-211) from the Asan
Institute for Life Sciences, Seoul, Korea.
Table 1. Benefits of Using ADSCs for the Generation of Insulin-
Producing Cells
1. Less invasive procedure
2.Unlimited numbers of cell sources
3.Possibility of high proliferation and multi-differentiation potential
4.Lower possibility of immunogenicity
5.Better availability
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Received: June 07, 2009 Revised: July 13, 2009 Accepted: August 04, 2009