Formation of pancreatic β-cells from precursor cells contributes to the reversal of established type 1 diabetes

[Display omitted] •T1D causes collateral damage to the islets vascular network.•Bone marrow-derived EPCs mature into ECs that restore islet blood vessel integrity.•Restored vasculature invigorates the formation of new β-cells.•New β-cells emanate from residual and β precursor cells. Ig-GAD2, an antigen-specific immune modulator, requires bone marrow (BM) cell transfer in order to restore beta (β)-cell formation and induce recovery from established type 1 diabetes (T1D). The BM cells provide endothelial precursor cells (EPCs) that give rise to islet resident endothelial cells (ECs). This study shows that, during development of T1D, the immune attack causes collateral damage to the islet vascular network. The EPC-derived ECs repair and restore islet blood vessel integrity. In addition, β-cell genetic tracing indicates that the newly formed β-cells originate from residual β-cells that escaped the immune attack and, unexpectedly, from β-cell precursors. This indicates that the rejuvenated islet microenvironment invigorates formation of new β-cells not only from residual β-cells but also from precursor cells. This is twofold significant from the perspective of precursor cells as a safe reserve for restoration of β-cell mass and its promise for therapy of T1D long after diagnosis.