Accelerated Maturation of Human Stem Cell-Derived Pancreatic Progenitor Cells into Insulin-Secreting Cells in Immunodeficient Rats Relative to Mice

• Published in: Stem cell reports Vol. 5; no. 6; pp. 1081 - 1096
• Main Authors: Bruin, Jennifer E., Asadi, Ali, Fox, Jessica K., Erener, Suheda, Rezania, Alireza, Kieffer, Timothy J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.12.2015; Elsevier
• Subjects: Animals; C-Peptide - analysis; Cell Differentiation; Cell Line; Cells, Cultured; Embryonic Stem Cells - cytology; Female; Humans; Insulin-Secreting Cells - cytology; Male; Mice; Mice, SCID; Middle Aged; Pancreas - cytology; Rats; Rats, Nude; Species Specificity; Stem Cell Transplantation
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2015.10.013

Pluripotent human embryonic stem cells (hESCs) are a potential source of transplantable cells for treating patients with diabetes. To investigate the impact of the host recipient on hESC-derived pancreatic progenitor cell maturation, cells were transplanted into immunodeficient SCID-beige mice or nude rats. Following the transplant, basal human C-peptide levels were consistently higher in mice compared with rats, but only rats showed robust meal- and glucose-responsive human C-peptide secretion by 19–21 weeks. Grafts from rats contained a higher proportion of insulin:glucagon immunoreactivity, fewer exocrine cells, and improved expression of mature β cell markers compared with mice. Moreover, ECM-related genes were enriched, the collagen network was denser, and blood vessels were more intricately integrated into the engrafted endocrine tissue in rats relative to mice. Overall, hESC-derived pancreatic progenitor cells matured faster in nude rats compared with SCID-beige mice, indicating that the host recipient can greatly influence the fate of immature pancreatic progenitor cells post-transplantation. •hESC-derived pancreatic progenitor cells matured faster in nude rats than in SCID-bg mice•Human C-peptide secretion was meal-regulated in rats but not in mice at 19 weeks•Grafts from rats expressed more mature β cell markers compared with mice•Grafts from rats had a denser ECM and greater vasculature than grafts from mice The potential influence of the in vivo environment on development of endocrine cells from hESC-derived pancreatic progenitor cells is unclear. In this article, Kieffer and colleagues demonstrate that hESC-derived progenitor cells mature significantly faster into glucose-responsive, insulin-secreting cells in immunodeficient rats compared with mice, indicating that the transplant recipient milieu can substantially affect the fate of immature pancreatic progenitor cells.