Effects of hyaluronic acid on differentiation of human amniotic epithelial cells and cell-replacement therapy of type 1 diabetes mice
Effects of hyaluronic acid on differentiation of human amniotic epithelial cells and cell-replacement therapy of type 1 diabetes mice
复制标题
透明质酸对人羊膜上皮细胞分化的影响及1型糖尿病小鼠的细胞替代治疗
DOI：
10.1016/j.yexcr.2019.111642
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发表时间：
2019
影响因子：
3.7
通讯作者：
Jian-Hui Xiao
中科院分区：
文献类型：
--
作者：
Yi Luo;Ya-Wei Cheng;Chang-Yin Yu;Ru-Ming Liu;Yu-Jie Zhao;Dai-Xiong Chen;Jian-Jiang Zhong;Jian-Hui Xiao
我们的假设是，透明质酸可以调节人羊膜上皮细胞（hAECs）分化为胰岛素分泌细胞，并帮助治疗1型糖尿病。在此，通过模拟胰腺发育过程，开发了一种用于hAEC体外逐步分化为功能性胰岛素产生细胞的方案。用透明质酸处理hAEC增强了其定形内胚层和胰腺祖细胞的分化。内胚层标志物Sox17和Foxa2以及胰腺祖细胞标志物Pax6、Nkx6.1和Ngn3在hAEC中上调增强的基因表达，但hAEC不表达β细胞特异性转录因子Pdx 1。有趣的是，透明质酸与常用的干细胞分化为胰岛素产生细胞的诱导剂结合后，促进了主要胰腺发育相关基因和蛋白质的表达。这表明该组合对hAECs体外分化具有有效的协同作用。通过建立一种通过尾静脉注射的多次注射移植策略，hAECs移植显著减轻了1型糖尿病小鼠的高血糖症状，增加了血浆胰岛素含量，并部分修复了胰岛结构。特别地，与胰岛素组和单独的hAEC组相比，hAEC与透明质酸的组合表现出显著的治疗效果。hAECs的旁分泌作用和透明质酸共同调节局部免疫反应，改善1型糖尿病小鼠受损胰腺的炎症微环境，促进胰腺α细胞向β细胞转分化。这些研究结果表明，透明质酸是一种有效的辅助诱导剂的hAECs分化成功能性胰岛素产生细胞，和hAECs治疗与透明质酸可能是一个有前途的细胞替代治疗方法，用于治疗1型糖尿病。
Our hypothesis is that hyaluronic acid may regulate the differentiation of human amniotic epithelial cells (hAECs) into insulin-producing cells and help the treatment of type 1 diabetes. Herein, a protocol for the stepwisein vitrodifferentiation of hAECs into functional insulin-producing cells was developed by mimicking the process of pancreas development. Treatment of hAECs with hyaluronic acid enhanced their differentiation of definitive endoderm and pancreatic progenitors. Endodermal markers Sox17 and Foxa2 and pancreatic progenitor markers Pax6, Nkx6.1, and Ngn3 were upregulated an enhanced gene expression in hAECs, but hAECs did not express the β cell-specific transcription factor Pdx1. Interestingly, hyaluronic acid promoted the expression of major pancreatic development-related genes and proteins after combining with commonly used inducers of stem cells differentiation into insulin-producing cells. This indicated the potent synergistic effects of the combination on hAECs differentiationin vitro. By establishing a multiple injection transplantation strategy via tail vein injections, hAECs transplantation significantly reduced hyperglycemia symptoms, increased the plasma insulin content, and partially repaired the islet structure in type 1 diabetic mice. In particular, the combination of hAECs with hyaluronic acid exhibited a remarkable therapeutic effect compared to both the insulin group and the hAECs alone group. The hAECs’ paracrine action and hyaluronic acid co-regulated the local immune response, improved the inflammatory microenvironment in the damaged pancreas of type 1 diabetic mice, and promoted the trans-differentiation of pancreatic α cells into β cells. These findings suggest that hyaluronic acid is an efficient co-inducer of the differentiation of hAECs into functional insulin-producing cells, and hAECs treatment with hyaluronic acid may be a promising cell-replacement therapeutic approach for the treatment of type 1 diabetes.