Markers of beta cell and alpha cell mass in human stem cell-generated implants with glycemic control at human...

Human stem cell (SC)-generated beta cell implants represent a potential cure for type 1 diabetes. Studies in rodents and patients showed that they can establish a glucose-regulated source of insulin in recipients with depleted pancreatic beta cell mass. Their therapeutic significance is, however, determined by their capacity to restore glycemic control by the human glucostat. It is so far unknown which implant characteristics are needed for this key endpoint. The present study addresses this question in mice. SC-derived preparations with a defined beta cell dose and alpha cell proportion were implanted in the epididymal fat pad of normoglycemic SCID/beige mice (mouse glucostat basal glycemia 166 mg/dL). At post-transplant week 20, 12/25 recipients reached glycemic control at the human glucostat (glycemia ≤ 90 mg/dL) following a time-dependent increase of basal and glucose-induced plasma human C-peptide and decrease of mouse C-peptide towards under detection limit. Formation of their functional human beta cell mass was preceded by formation of a human alpha cell mass that became the source for circulating glucagon and a contributor to glycemic control. The insulin content of the implants reached the values in the pancreas of control mice and were thus identified as in situ markers for implants that established the glycemic endpoint. Co-existence with a functional alpha cell mass places alpha cell formation as a potential additional component for achieving the goal. Our study also demonstrates the relevance of using normoglycemic mice to assess stem cell therapy protocols for beta cell replacement.