Type 1 diabetes (T1D) results from the autoimmune destruction of β cells. Cure of established T1D requires both reversal of autoimmunity and regeneration of β cells. Autoimmune NOD mice closely resemble human T1D. We have reported that administration of gastrin and epidermal growth factor (GE) allows β cell regeneration and cure of late-stage T1D in NOD mice after reversal of autoimmunity by induction of MHC-mismatched mixed chimerism. β cell regeneration in non-autoimmune diabetic mice can come from differentiation of Sox9+ pancreatic ductal progenitors, parenchymal progenitors, and transdifferentiation of α cells. However, the source of β cell regeneration in autoimmune NOD mice remains unclear.
Using NOD mice with inducible Sox9-EGFP, we found that Sox9+ pancreatic ductal progenitors only accounted for a small fraction of total β cell regeneration. Using Nestin-EGFP mice, we did not see any β cells originating from Nestin+ parenchymal progenitor cells.
Using NOD mice with inducible glucagon-RFP, we found that ∼50% of regenerated β cells were from α cell transdifferentiation in mice after induction of mixed chimerism and GE, although mixed chimerism alone induced few α to β cell transdifferentiation in mice. In addition, using NOD mice with inducible insulin-EGFP, we found that the majority of residual β cells in late-stage diabetic NOD mice were insulinlo, and they became insulinhi after induction of mixed chimerism and GE treatment.
Taken together, transdifferentiation of α to β cells and re-differentiation of insulinlo cells are the major sources of β cell regeneration in late-stage diabetic NOD mice after induction of mixed chimerism and administration of GE. How hyperglycemia and GE differentially regulate α cell transdifferentiation and β cell re-differentiation is under investigation. This work is supported by the Wanek Family fund.
S. Tang: None. M. Zhang: None. P. Santamaria: Board Member; Self; Parvus Therapeutics. A.D. Riggs: None. L. Jin: None. D. Zeng: None.
Todd and Karen Wanek Family Foundation Ltd.