Three-dimensional Vascularized beta-cell Spheroid Tissue Derived From Human Induced Pluripotent Stem Cells for Subcutaneous Islet Transplantation in a Mouse Model of Type 1 Diabetes

Background. Islet transplantation is an effective replacement therapy for type 1 diabetes (T1D) patients. However, shortage of donor organ for allograft is obstacle for further development of the treatment. Subcutaneous transplantation with stem cell-derived beta-cells might overcome this, but poor vascularity in the site is burden for success in the transplantation. We investigated the effect of subcutaneous transplantation of vascularized beta-cell spheroid tissue constructed 3-dimensionally using a layer-by-layer (LbL) cell-coating technique in a T1D model mouse. Methods. We used MIN6 cells to determine optimal conditions for the coculture of beta-cell spheroids, normal human dermal fibroblasts, and human umbilical vein endothelial cells, and then, under those conditions, we constructed vascularized spheroid tissue using human induced pluripotent stem cell-derived beta-cells (hiPS beta cells). The function of insulin secretion of the vascularized hiPS beta-cell spheroid tissue was evaluated in vitro. Furthermore, the function was investigated in T1D model NOD/SCID mice subcutaneously transplanted with the tissue. Results. In vitro, the vascularized hiPS beta-cell spheroid tissue exhibited enhanced insulin secretion. The vascularized hiPS beta-cell spheroid tissue also significantly decreased blood glucose levels in diabetic immunodeficient mice when transplanted subcutaneously. Furthermore, host mouse vessels were observed in the explanted vascularized hiPS beta-cell spheroid tissue. Conclusions. Vascularized hiPS beta-cell spheroid tissue decreased blood glucose levels in the diabetic mice. This therapeutic effect was suggested due to host angiogenesis in the graft. This method could lead to a promising regenerative treatment for T1D patients.