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

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.

The science and engineering of stem cell‐derived organoids‐examples from hepatic, biliary, and pancreatic tissues

“…hPSC‐derived pancreatic organoids (hPOs) are more complex than hHOs or hBOs because of the plethora of cells that arise during pancreas differentiation. hPO‐derived pancreatic progenitor cells in a monolayer were incorporated into organoids by day 18 and passaged for long‐term organoid culture every 10–14 days (Hohwieler et al ., 2017; Mochida et al ., 2020). These hPOs and patient‐specific cystic fibrosis‐derived hPOs were orthotopically transplanted into mice and evaluated after 5 weeks.…”

Tailor-made generation of insulin-producing cells from canine mesenchymal stem cells derived from bone marrow and adipose tissue

“…Previous publications reported that small molecule induction could imitate the environment during pancreatic endocrine development 10,16,43,[51][52][53][54][55][56] . Generally, an in vitro pancreatic differentiation from SCs could be categorized into 6 differentiation stages: pluripotent/multipotent SCs, mesendoderm, definitive endoderm, pancreatic endoderm, pancreatic endocrine, and pancreatic beta-cells/IPCs 15,57 .…”

Human Pluripotent Stem Cells to Model Islet Defects in Diabetes

“…Sex hormones may also influence in vivo maturation of pancreatic progenitors since following implant, glucose-stimulated insulin secretion was observed in female mice before males (234). The systemic environment also provides periodic signals, which might entrain the circadian clock of the implanted stem cell-derived islet cells, leading to their functional maturation (235)(236)(237)(238).…”