1. Academic Validation
  2. Insulin-Deficient Diabetic Condition Upregulates the Insulin-Secreting Capacity of Human Induced Pluripotent Stem Cell-Derived Pancreatic Endocrine Progenitor Cells After Implantation in Mice

Insulin-Deficient Diabetic Condition Upregulates the Insulin-Secreting Capacity of Human Induced Pluripotent Stem Cell-Derived Pancreatic Endocrine Progenitor Cells After Implantation in Mice

  • Diabetes. 2020 Apr;69(4):634-646. doi: 10.2337/db19-0728.
Taisuke Mochida 1 2 Hikaru Ueno 3 2 Noriko Tsubooka-Yamazoe 3 2 Hideyuki Hiyoshi 3 2 Ryo Ito 3 2 Hirokazu Matsumoto 3 2 Taro Toyoda 4 5
Affiliations

Affiliations

  • 1 T-CiRA Discovery, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan t.toyoda@cira.kyoto-u.ac.jp taisuke.mochida@takeda.com.
  • 2 Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), Fujisawa, Kanagawa, Japan.
  • 3 T-CiRA Discovery, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
  • 4 Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), Fujisawa, Kanagawa, Japan t.toyoda@cira.kyoto-u.ac.jp taisuke.mochida@takeda.com.
  • 5 Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.
Abstract

The host environment is a crucial factor for considering the transplant of stem cell-derived immature pancreatic cells in patients with type 1 diabetes. Here, we investigated the effect of Insulin (INS)-deficient diabetes on the fate of immature pancreatic endocrine cell grafts and the underlying mechanisms. Human induced pluripotent stem cell-derived pancreatic endocrine progenitor cells (EPCs), which contained a high proportion of chromogranin A+ NK6 homeobox 1+ cells and very few INS+ cells, were used. When the EPCs were implanted under the kidney capsule in immunodeficient mice, INS-deficient diabetes accelerated increase in plasma human C-peptide, a marker of graft-derived INS secretion. The acceleration was suppressed by INS infusion but not affected by partial attenuation of hyperglycemia by dapagliflozin, an INS-independent glucose-lowering agent. Immunohistochemical analyses indicated that the grafts from diabetic mice contained more endocrine cells including proliferative INS-producing cells compared with that from nondiabetic mice, despite no difference in whole graft mass between the two groups. These data suggest that INS-deficient diabetes upregulates the INS-secreting capacity of EPC grafts by increasing the number of endocrine cells including INS-producing cells without changing the graft mass. These findings provide useful insights into postoperative diabetic care for cell therapy using stem cell-derived pancreatic cells.

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