Efficient induction of pancreatic alpha cells from human induced pluripotent stem cells by controlling the timing for BMP antagonism and activation of retinoic acid signaling.
Efficient induction of pancreatic alpha cells from human induced pluripotent stem cells by controlling the timing for BMP antagonism and activation of retinoic acid signaling.
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DOI：
10.1371/journal.pone.0245204
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Okochi H
中科院分区：
文献类型：
--
作者：
Yabe SG;Fukuda S;Nishida J;Takeda F;Nashiro K;Okochi H
糖尿病是由血糖稳态的破坏引起的，血糖稳态由分别由胰腺β细胞和α细胞产生的胰岛素和胰高血糖素之间的精确平衡维持。然而，关于诱导人α细胞分泌胰高血糖素的机制知之甚少。已经报道了许多从人多能干细胞（hPSC）产生胰腺β细胞的方法，但是只有两篇论文报道了从hPSC产生胰腺α细胞。由于NKX6.1被认为是决定胰腺β细胞和α细胞之间细胞命运的非常重要的基因，我们在我们的β细胞分化方案中寻找影响NKX6.1表达的因素。我们发现，BMP拮抗作用和视黄酸信号在第2阶段（从定形内胚层到原肠管）的激活有效地抑制了NKX6.1在后期的表达。使用两种不同的hPSC系，在第2阶段用BMP信号传导抑制剂（LDN193189）和视黄酸激动剂（EC23）处理降低了NKX6.1表达，并允许在肾包膜下移植后几乎所有细胞在体内分化为胰腺α细胞。我们的研究表明，胰腺细胞的细胞命运可以通过调节NKX6.1的表达水平，在胰腺分化过程中适当时机的BMP拮抗作用和视黄酸信号的激活来控制。我们的方法可用于从hPSC有效诱导胰腺α细胞。
Diabetes mellitus is caused by breakdown of blood glucose homeostasis, which is maintained by an exquisite balance between insulin and glucagon produced respectively by pancreatic beta cells and alpha cells. However, little is known about the mechanism of inducing glucagon secretion from human alpha cells. Many methods for generating pancreatic beta cells from human pluripotent stem cells (hPSCs) have been reported, but only two papers have reported generation of pancreatic alpha cells from hPSCs. Because NKX6.1 has been suggested as a very important gene for determining cell fate between pancreatic beta and alpha cells, we searched for the factors affecting expression of NKX6.1 in our beta cell differentiation protocols. We found that BMP antagonism and activation of retinoic acid signaling at stage 2 (from definitive endoderm to primitive gut tube) effectively suppressed NKX6.1 expression at later stages. Using two different hPSCs lines, treatment with BMP signaling inhibitor (LDN193189) and retinoic acid agonist (EC23) at Stage 2 reduced NKX6.1 expression and allowed differentiation of almost all cells into pancreatic alpha cells in vivo after transplantation under a kidney capsule. Our study demonstrated that the cell fate of pancreatic cells can be controlled by adjusting the expression level of NKX6.1 with proper timing of BMP antagonism and activation of retinoic acid signaling during the pancreatic differentiation process. Our method is useful for efficient induction of pancreatic alpha cells from hPSCs.
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影响因子：
5.9
作者：
Nostro, M. Cristina;Sarangi, Farida;Yang, Chaoxing;Holland, Andrew;Elefanty, Andrew G.;Stanley, Edouard G.;Greiner, Dale L.;Keller, Gordon
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