Three-dimensional Vascularized β-cell Spheroid Tissue Derived From Human Induced Pluripotent Stem Cells for Subcutaneous Islet Transplantation in a Mouse Model of Type 1 Diabetes
Three-dimensional Vascularized β-cell Spheroid Tissue Derived From Human Induced Pluripotent Stem Cells for Subcutaneous Islet Transplantation in a Mouse Model of Type 1 Diabetes
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源自人诱导多能干细胞的三维血管化 β 细胞球体组织用于 1 型糖尿病小鼠模型皮下胰岛移植
DOI：
10.1097/tp.0000000000003745
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发表时间：
2021
期刊：
影响因子：
6.2
通讯作者：
Eguchi Hidetoshi
中科院分区：
文献类型：
--
作者：
Takaichi Shohei;Tomimaru Yoshito;Akagi Takami;Kobayashi Shogo;Fukuda Yasunari;Toya Keisuke;Asaoka Tadafumi;Iwagami Yoshifumi;Yamada Daisaku;Akita Hirofumi;Noda Takehiro;Gotoh Kunihito;Doki Yuichiro;Akashi Mitsuru;Eguchi Hidetoshi
背景：胰岛移植是1型糖尿病（T1 D）患者有效的替代疗法。然而，供者来源的短缺是其进一步发展的障碍。用干细胞衍生的β细胞进行皮下移植可能克服这一点，但该部位的血管供应不足是移植成功的负担。我们研究了在T1 D模型小鼠皮下移植血管化β细胞球体组织的效果，所述血管化β细胞球体组织使用逐层（LbL）细胞包被技术以三维方式构建，方法：我们使用MIN 6细胞确定β细胞球体、正常人真皮成纤维细胞和人脐静脉内皮细胞共培养的最佳条件，然后，在这些条件下，我们使用人诱导多能干细胞衍生的β细胞（hiPS β细胞）构建血管化球体组织。体外评价血管化hiPS β细胞球体组织的胰岛素分泌功能。结果：在体外培养条件下，血管化hiPS β-细胞球体组织可促进胰岛素分泌。当皮下移植时，血管化的hiPS β细胞球体组织还显著降低糖尿病免疫缺陷小鼠的血糖水平。结论：血管化hiPS β细胞球体组织可降低糖尿病小鼠的血糖水平。这种治疗效果是由于移植物中的宿主血管生成而提出的。这种方法可以为T1 D患者带来有希望的再生治疗。
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 β-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 β-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 β-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 β-cells (hiPS β cells). The function of insulin secretion of the vascularized hiPS β-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 β-cell spheroid tissue exhibited enhanced insulin secretion. The vascularized hiPS β-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 β-cell spheroid tissue.Conclusions.Vascularized hiPS β-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.