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

Abstract

SummaryPluripotent 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.

Hypothyroidism Impairs Human Stem Cell–Derived Pancreatic Progenitor Cell Maturation in Mice

“…), examining protein expression in individual insulin + cells by immunofluorescent staining is a more accurate assessment of the hESCderived b-cell phenotype. The various lines of evidence pointing to a b-cell deficiency in hypothyroid mice are consistent with our previous observations in nude rats implanted with hESC-derived progenitor cells (16). Interestingly, nude rats had significantly higher circulating T3 levels than SCID-beige mice and also had improved glucosestimulated human insulin secretion, a higher proportion of insulin-to-glucagon immunoreactivity in grafts, and more consistent nuclear MAFA expression in hESC-derived b-cells than SCID-beige mice (16).…”

“…The various lines of evidence pointing to a b-cell deficiency in hypothyroid mice are consistent with our previous observations in nude rats implanted with hESC-derived progenitor cells (16). Interestingly, nude rats had significantly higher circulating T3 levels than SCID-beige mice and also had improved glucosestimulated human insulin secretion, a higher proportion of insulin-to-glucagon immunoreactivity in grafts, and more consistent nuclear MAFA expression in hESC-derived b-cells than SCID-beige mice (16). Neonatal rats with hypothyroidism also exhibited decreased islet Mafa expression (12), which is consistent with our findings and suggests a potential role for thyroid hormone in regulating b-cell maturation.…”

MECHANISMS IN ENDOCRINOLOGY: Towards the clinical translation of stem cell therapy for type 1 diabetes

“…However, it must be kept in mind that these cells have not yet been evaluated in large animal models or in humans. In fact, it has been shown that there are species differences even between mice and rats regarding the differentiation and engraftment of insulin-producing cells derived from hESCs (31). From a safety point of view, the cells therefore initially need to be transplanted into a site where they can be radically retrieved if needed.…”

Is Transforming Stem Cells to Pancreatic Beta Cells Still the Holy Grail for Type 2 Diabetes?

“…Subsequently, studies reported enrichment of cells expressing high levels of NKX6.1 from the pancreatic progenitor cell population accelerated in viv o maturation period [34]. Furthermore, transplantation of stem-cell derived endocrine cells into rats relative to mice hastened the in vivo maturation process [35]. However, several unanswered questions remain in the context of maturation of pancreatic progenitors in the rodent system and the relevance of the in vivo maturation process when translating the approach to human clinical trials.…”