Diabetes Research and Clinical Practice - Volume 120 - Supplement 1 - October 2016

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Xenogeneic islet transplantation can be a viable option
for unstable type 1 diabetes, and the next research target
should be curing type 1 diabetes with xenogeneic islet
transplantation.
S16-3
Clinical islet autotransplantation: Beyond simple replacement
of islet cell mass
Kwang-Won KIM1. 1Gachon University Gil Medical Center, Incheon,
Korea
Islet autotransplantation (IAT) is performed when the
pancreas is removed for treatment of benign pancreatic
diseases. In chronic pancreatitis with intractable abdominal
pain, IAT after total pancreatectomy has been proven to
reduce abdominal pain by total pancreatectomy while avoid-
ing brittle diabetes. In contrast to the islet allotransplantation,
IAT is not vulnerable to immune rejection, recurrent auto-
immunity, or beta-cell toxicity of immunosuppressants.
For this reason, IAT represents the maximum functional
potential of transplanted islets, with some reported cases of
unexpected insulin independence in low-dose autologous islet
transplants.
Besides the proven efficacy of IAT in intractable chronic
pancreatitis, we have examined the efficacy of IAT after
partial pancreatectomy for treatment of benign tumor. We
reported the outcome of the 20 patients who underwent
IAT after 50% to 60% partial pancreatectomy in this clinical
setting. Although the 7-year diabetes-free survival rate was
not different between control and IAT groups, prolonged
diabetes-free survival was observed in patients who under-
went IAT when a high islet yield (>5,154 islet equivalents
per gram of pancreas) during the islet isolation was achieved.
The islet yield and islet function in this clinical setting
was superior to those of allogeneic islet transplantation. In
addition, we have shown that transplanted islets can promote
the regeneration of endogenous beta-cells and differentiation
of adult stem cells into beta-cells in experimental models of
IAT after partial pancreatectomy.
In conclusion, IAT after partial pancreatectomy for benign
tumors could be a promising indication of IAT. IAT in this
setting may improve the metabolic milieu after the pancreatic
resection, and is a unique opportunity for understanding the
biologic effect of intraportal islet transplantation beyond the
simple replacement of islet cell mass.
Stem Cell Therapy
S22-1
Expandable human pancreatic progenitor cells – a novel
inroad toward the production of β cells
Ray DUNN 1. 1A*STAR Institute of Medical Biology, Singapore
Type 1 diabetes (T1D) results from the autoimmune destruc-
tion of pancreatic β cells that secrete insulin. One potential
cell-based therapy for this chronic disease is the production of
functional β cells from the directed differentiation of human
pluripotent stem cells. Such in vitro derived β cells would
then be transplanted into T1D patients to liberate them from
lifelong insulin dependency. To this end, several reports
emerged over the last year that detail more efficient differen-
tiation protocols that yield ∼35% insulin-containing β cells
after at least four weeks of in vitro differentiation. Importantly,
these β-like cells were able to restore normoglycemia in
rodent models of T1D. Although an improvement over
previous methods, undesirable polyhormonal cells ( ∼15%)
and hormone-negative cells (∼50%) were consistently pro-
duced alongside β-like cells. Furthermore, differentiation
output varied considerably depending on the human
embryonic stem cell (hESC) or human induced pluripotent
stem cell (hiPSC) line used. We reason that one way to address
both the limits of efficiency and reproducibility from line-to-
line is to develop tools to capture and stably expand stage-
specific, multipotent β-cell progenitors. Pure populations of
these self-renewing progenitors would then allow for further,
and we propose, more homogeneous differentiation toward
the insulin-secreting β cell. This strategy eliminates the need
(and significant cost) of sequentially differentiating hESC or
hiPSC from pluripotent cell type, to mesendoderm, to defini-
tive endoderm, to gut endoderm and finally to pancreatic
endoderm. We have thus developed conditions for culturing
hPSC-derived multipotent pancreatic progenitors, which are
capable of long-term expansion and are much closer develop-
mentally to β cells. These “ ePP” cells express markers
characteristic of endogenous human pancreatic progenitors,
including the key transcription factors PDX1 and SOX9.
Exposure to differentiation cues induces upregulation of
markers of the exocrine, endocrine and ductal pancreatic
lineages indicating multi lineage potency. Their ability to
further differentiate into β cells is currently being evaluated in
vitro and in vivo in immunodeficient mice.
S22-2
Generation of insulin-producing β-like cells from human iPS
cells
Shoen KUME1. 1School of Life Science and Technology, Tokyo
Institute of Technology, Tokyo, Japan
ES cells and iPS cells are considered to be potential alternative
cell sources for the transplantation therapy as well as cell
models for biological studies. Up to date, studies to generate
the pancreatic beta cells from pluripotent stem cells have
achieved remarkable progresses. However, it still remain
elusive whether the derived pancreatic beta cells resemble
the human beta cells and could be used in clinical settings.
We have been trying to establish culture systems to generate
insulin-producing beta cells using mouse and human ES/iPS
cells. In an attempt to search for novel molecules that promote
differentiation and/or proliferation of pancreatic beta-cells,
we established a screening system, and screened a chemical
library consisting of low molecular bioactive chemical
compounds of which the pharmaceutical actions are already
known. Through studies on revealing the targets of the
chemical compounds, we identified molecules that function
in regulating pancreatic beta cell differentiation. We also
extend the chemical screening using mouse mature islets,
to identify molecules that regulate beta cell mass.
Besides chemical screening, we also analyzed the importance
of amino acids in the media. We found that methionine
metabolism is crucial for the maintenance of pluripotency in
human pluripotent cells. Deprival of methionine rendered the
cells at a poised state for differentiation, and thus increased
the efficiency for differentiation. The details will be discussed
at the meeting.
S22-3
Autologous hematopoietic stem cell transplantation in type 1
diabetes
Dalong ZHU1, L. LI1, Shanmei SHEN1, Y. BI1, W. GU 2. 1Division of
Endocrinology, the Affiliated Drum Tower Hospital of Nanjing
University, Nanjing, 2Department of Endocrinology and Metabolism,
Ruijin Hospital, Shanghai Jiao Tong University School of Medicine,
Shanghai, PR China
Type 1 diabetes (T1DM) is an autoimmune disease resulted
from T cell-mediated destruction of insulin-producing pan-
creatic β-cells. Therapies aiming at block of T cell autoimmun-
ity and preservation of the remaining β-cell function are of
great significance in managing T1DM. Hematopoietic stem
cells (HSCs) are multipotent stem cells residing in the bone
marrow. Voltarelli JC et al. were the first in the world to apply
Speech Abstracts / Diabetes Research and Clinical Practice 120S1 (2016) S1–S39 S17