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Clinical islet autotransplantation: Beyond simple replacement of islet cell mass
Speech Abstracts / Diabetes Research and Clinical Practice 120S1 (2016) S1–S39
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 avoiding brittle diabetes. In contrast to the islet allotransplantation, IAT is not vulnerable to immune rejection, recurrent autoimmunity, 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 underwent 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 DUNN1. 1A*STAR Institute of Medical Biology, Singapore Type 1 diabetes (T1D) results from the autoimmune destruction 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 differentiation 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 produced alongside β-like cells. Furthermore, differentiation output varied considerably depending on the human
S17
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-toline is to develop tools to capture and stably expand stagespecific, 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 definitive 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 developmentally 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. GU2. 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 pancreatic β-cells. Therapies aiming at block of T cell autoimmunity 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
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 avoiding brittle diabetes. In contrast to the islet allotransplantation, IAT is not vulnerable to immune rejection, recurrent autoimmunity, 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 underwent 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 DUNN1. 1A*STAR Institute of Medical Biology, Singapore Type 1 diabetes (T1D) results from the autoimmune destruction 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 differentiation 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 produced alongside β-like cells. Furthermore, differentiation output varied considerably depending on the human
S17
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-toline is to develop tools to capture and stably expand stagespecific, 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 definitive 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 developmentally 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. GU2. 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 pancreatic β-cells. Therapies aiming at block of T cell autoimmunity 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