Insulin-Deficient Diabetic Condition Upregulates the Insulin-Secreting Capacity of Human Induced Pluripotent Stem Cell-Derived Pancreatic Endocrine Progenitor Cells After Implantation in Mice
Insulin-Deficient Diabetic Condition Upregulates the Insulin-Secreting Capacity of Human Induced Pluripotent Stem Cell-Derived Pancreatic Endocrine Progenitor Cells After Implantation in Mice
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DOI：
10.2337/db19-0728
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发表时间：
2020-04-01
期刊：
影响因子：
7.7
通讯作者：
Toyoda, Taro
中科院分区：
文献类型：
--
作者：
Mochida, Taisuke;Ueno, Hikaru;Toyoda, Taro
宿主环境是考虑1型糖尿病患者干细胞来源的未成熟胰腺细胞移植的关键因素。在这里，我们研究了胰岛素（INS）缺乏糖尿病对未成熟胰腺内分泌细胞移植物命运的影响及其潜在机制。采用人诱导多能干细胞衍生的胰腺内分泌祖细胞（EPCs），其中含有高比例的嗜铬粒蛋白a (+) NK6同源盒1（+）细胞和极少的INS+细胞。将EPCs植入免疫缺陷小鼠的肾包膜后，INS缺陷型糖尿病小鼠血浆人c肽（移植物来源的INS分泌的标志）的增加加快。INS输注抑制了这种加速，但不受不依赖INS的降糖剂达格列净部分抑制高血糖的影响。免疫组化分析表明，与非糖尿病小鼠相比，糖尿病小鼠移植物中含有更多的内分泌细胞，包括增殖性ins生成细胞，尽管两组之间移植物的整体质量没有差异。这些数据表明，在不改变移植物质量的情况下，缺乏ins的糖尿病通过增加包括产生ins的细胞在内的内分泌细胞的数量来上调EPC移植物分泌ins的能力。这些发现为利用干细胞来源的胰腺细胞治疗糖尿病术后护理提供了有用的见解。
The host environment is a crucial factor for considering the transplant of stem cell-derived immature pancreatic cells in patients with type 1 diabetes. Here, we investigated the effect of insulin (INS)-deficient diabetes on the fate of immature pancreatic endocrine cell grafts and the underlying mechanisms. Human induced pluripotent stem cell-derived pancreatic endocrine progenitor cells (EPCs), which contained a high proportion of chromogranin A(+) NK6 homeobox 1(+) cells and very few INS+ cells, were used. When the EPCs were implanted under the kidney capsule in immunodeficient mice, INS-deficient diabetes accelerated increase in plasma human C-peptide, a marker of graft-derived INS secretion. The acceleration was suppressed by INS infusion but not affected by partial attenuation of hyperglycemia by dapagliflozin, an INS-independent glucose-lowering agent. Immunohistochemical analyses indicated that the grafts from diabetic mice contained more endocrine cells including proliferative INS-producing cells compared with that from nondiabetic mice, despite no difference in whole graft mass between the two groups. These data suggest that INS-deficient diabetes upregulates the INS-secreting capacity of EPC grafts by increasing the number of endocrine cells including INS-producing cells without changing the graft mass. These findings provide useful insights into postoperative diabetic care for cell therapy using stem cell-derived pancreatic cells.