期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：49
页码：31219-31230
DOI：10.1073/pnas.2012389117
出版社：The National Academy of Sciences of the United States of America
摘要：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 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 (insulin lo ) 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.
