Maturation of Human Embryonic Stem Cell–Derived Pancreatic Progenitors Into Functional Islets Capable of Treating Pre-existing Diabetes in Mice

TLDR

Diabetes results from insufficient insulin production by β‑cells, and while islet transplantation can cure the disease, it is limited by the scarcity of donor tissue. The study aimed to create a protocol that efficiently differentiates commercially available hESCs into a highly enriched PDX1⁺ pancreatic progenitor population that matures into endocrine cells after transplantation. Immature progenitors were transplanted into immunodeficient mice and rats with streptozotocin‑induced diabetes, initially supported by exogenous insulin, and allowed to mature in vivo. The grafts produced increasing insulin, enabling mice to discontinue exogenous insulin, with human C‑peptide secretion responding to meals and glucose, and the cells displayed fetal‑pancreas‑like gene and protein profiles, demonstrating the feasibility of hESC‑derived islets as a donor alternative.

Abstract

Diabetes is a chronic debilitating disease that results from insufficient production of insulin from pancreatic β-cells. Islet cell replacement can effectively treat diabetes but is currently severely limited by the reliance upon cadaveric donor tissue. We have developed a protocol to efficiently differentiate commercially available human embryonic stem cells (hESCs) in vitro into a highly enriched PDX1+ pancreatic progenitor cell population that further develops in vivo to mature pancreatic endocrine cells. Immature pancreatic precursor cells were transplanted into immunodeficient mice with streptozotocin-induced diabetes, and glycemia was initially controlled with exogenous insulin. As graft-derived insulin levels increased over time, diabetic mice were weaned from exogenous insulin and human C-peptide secretion was eventually regulated by meal and glucose challenges. Similar differentiation of pancreatic precursor cells was observed after transplant in immunodeficient rats. Throughout the in vivo maturation period hESC-derived endocrine cells exhibited gene and protein expression profiles that were remarkably similar to the developing human fetal pancreas. Our findings support the feasibility of using differentiated hESCs as an alternative to cadaveric islets for treating patients with diabetes.