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

Abstract

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 (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.

Transient Depletion of Foxp3+ Regulatory T Cells Selectively Promotes Aggressive β Cell Autoimmunity in Genetically Susceptible DEREG Mice

“…We also addressed the possibility that alleviating the metabolic stress of residual β cells by insulin replacement therapy for the duration of Treg cell recovery may help restoring metabolic homeostasis ( e.g. , by promoting the regeneration of functional β cells) ( 46 , 47 ). However, the administration of exogenous insulin into DT-treated NOD.DEREG mice shortly after diagnosis of overt diabetes restored normoglycemia for several weeks, but all mice returned to high blood glucose levels, once insulin therapy was discontinued (data not shown), further illustrating the destructiveness of β cell autoimmunity.…”

Harnessing the Endogenous Plasticity of Pancreatic Islets: A Feasible Regenerative Medicine Therapy for Diabetes?

“…Interestingly, the abundance of the bihormonal INS+/GCG+ cells after BL001 treatment in this mouse model was markedly higher than in the STZ model, indicating the important contribution of Tregs and M2 macrophages in αto β-cell transdifferentiation [82,84]. Supporting this immunecoupled β-cell regeneration, the combined therapy of induction of MHC-mismatched mixed chimerism to attenuate the immune response together with gastrin and EGF administration resulted in β-cell regeneration and glucose homeostasis recovery in firmly established diabetic NOD mice [85]. Lineage-tracing studies revealed that αto β-cell transdifferentiation is the major source of β-cells, which only reaches these levels of activation after attenuation of the immune response [85].…”

“…Supporting this immunecoupled β-cell regeneration, the combined therapy of induction of MHC-mismatched mixed chimerism to attenuate the immune response together with gastrin and EGF administration resulted in β-cell regeneration and glucose homeostasis recovery in firmly established diabetic NOD mice [85]. Lineage-tracing studies revealed that αto β-cell transdifferentiation is the major source of β-cells, which only reaches these levels of activation after attenuation of the immune response [85]. This integrated non-mutually exclusive and mandatory islet-immune dialogue may provide some clues on failures of clinical trials targeting solely the immune system, which will likely compromise β-cell replenishment [84,86].…”

“…β-cell dedifferentiation and dysfunction under insulin-resistant conditions cause hyperglycemia, which would in turn promote further β-cell dedifferentiation, activating a vicious circle that will eventually lead to frank diabetes [94]. Despite being more studied in T2D [95], dedifferentiation of β-cell is not exclusively a T2D-related process, since dedifferentiated dysfunctional INS LOW β-cells also appear during the progression of autoimmune diabetes both in NOD mice [85,96] and in T1D patients [97].…”

Debates in Pancreatic Beta Cell Biology: Proliferation Versus Progenitor Differentiation and Transdifferentiation in Restoring β Cell Mass

“…Their restoration could be combined with a cell transdifferentiation. A recent study showed that this is precisely what happened when autoimmunity of NOD mice was reversed, and animals were treated with a combination of gastrin and EGF (86).…”