Reversal of autoimmunity by mixed chimerism enables reactivation of β cells and transdifferentiation of α cells in diabetic NOD mice

Shanshan Tang, Mingfeng Zhang, Samuel Zeng, Yaxun Huang, Melissa Qin, Ubaydah Nasri, Pere Santamaria, Arthur D. Riggs, Liang Jin, Defu Zeng
2020 Proceedings of the National Academy of Sciences of the United States of America  
Type 1 diabetes (T1D) results from the autoimmune destruction of β cells, so cure of firmly established T1D requires both reversal of autoimmunity and restoration of β cells. It is known that β cell regeneration in nonautoimmune diabetic mice can come from differentiation of progenitors and/or transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune nonobese diabetic (NOD) mice remains unclear. Here, we show that, after reversal of autoimmunity by induction of
more » ... y by induction of haploidentical mixed chimerism, administration of gastrin plus epidermal growth factor augments β cell regeneration and normalizes blood glucose in the firmly established diabetic NOD mice. Using transgenic NOD mice with inducible lineage-tracing markers for insulin-producing β cells, Sox9+ ductal progenitors, Nestin+ mesenchymal stem cells, and glucagon-producing α cells, we have found that both reactivation of dysfunctional low-level insulin expression (insulinlo) β cells and neogenesis contribute to the regeneration, with the latter predominantly coming from transdifferentiation of α cells. These results indicate that, after reversal of autoimmunity, reactivation of β cells and transdifferentiation of α cells can provide sufficient new functional β cells to reach euglycemia in firmly established T1D.
doi:10.1073/pnas.2012389117 pmid:33229527 fatcat:n3lr2f6cqfcvtkxekwlq5onbry