Mafa Enables Pdx1 to Effectively Convert Pancreatic Islet Progenitors and Committed Islet α-Cells Into β-Cells In Vivo.
Mafa Enables Pdx1 to Effectively Convert Pancreatic Islet Progenitors and Committed Islet α-Cells Into β-Cells In Vivo.
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DOI：
10.2337/db16-0887
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发表时间：
2017-05
期刊：
影响因子：
7.7
通讯作者：
Shimomura I
中科院分区：
文献类型：
--
作者：
Matsuoka TA;Kawashima S;Miyatsuka T;Sasaki S;Shimo N;Katakami N;Kawamori D;Takebe S;Herrera PL;Kaneto H;Stein R;Shimomura I
在正在探索的替代1型糖尿病(T1D)中丢失的功能性胰岛β细胞团的治疗途径中，将成体细胞类型重新编程为新的β细胞一直在积极进行。值得注意的是，小鼠胰岛α细胞将在接近β细胞丢失的情况下转分化为β细胞，这一条件类似于T1D。此外，人类胰岛α细胞似乎也准备重新编程为胰岛素阳性细胞。在这里，我们建立了有条件地表达胰岛β细胞丰富的MafA和/或Pdx1转录因子的转基因小鼠，以检测它们将胚胎胰岛细胞Ngn3阳性祖细胞和后来的高血糖素阳性α细胞群转分化为β细胞的潜力。研究发现，MAFA既能增强Pdx1从NGN_3阳性的内分泌前体细胞诱导β细胞形成的能力，又能使Pdx1从β-细胞产生α细胞。这些结果为在体内影响胰岛细胞可塑性的基本机制提供了有价值的见解。
Among the therapeutic avenues being explored for replacement of the functional islet β-cell mass lost in type 1 diabetes (T1D), reprogramming of adult cell types into new β-cells has been actively pursued. Notably, mouse islet α-cells will transdifferentiate into β-cells under conditions of near β-cell loss, a condition similar to T1D. Moreover, human islet α-cells also appear to poised for reprogramming into insulin-positive cells. Here we have generated transgenic mice conditionally expressing the islet β-cell–enriched Mafa and/or Pdx1 transcription factors to examine their potential to transdifferentiate embryonic pan–islet cell Ngn3-positive progenitors and the later glucagon-positive α-cell population into β-cells. Mafa was found to both potentiate the ability of Pdx1 to induce β-cell formation from Ngn3-positive endocrine precursors and enable Pdx1 to produce β-cells from α-cells. These results provide valuable insight into the fundamental mechanisms influencing islet cell plasticity in vivo.