Transgenic Expression of a Single Transcription Factor Pdx1 Induces Transdifferentiation of Pancreatic Acinar Cells to Endocrine Cells in Adult Mice.
Transgenic Expression of a Single Transcription Factor Pdx1 Induces Transdifferentiation of Pancreatic Acinar Cells to Endocrine Cells in Adult Mice.
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DOI：
10.1371/journal.pone.0161190
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Miyazaki J
中科院分区：
文献类型：
--
作者：
Miyazaki S;Tashiro F;Miyazaki J
糖尿病新疗法的一种有前途的方法是在体内从其他分化的胰腺细胞中产生β细胞。由于腺泡细胞代表了胰腺中最丰富的细胞类型，因此一种有吸引力的可能性是将腺泡细胞重新编程为β细胞。转录因子 Pdx1（胰腺/十二指肠同源框蛋白 1）对于胰腺发育和细胞谱系测定至关重要。我们的目的是检查成年小鼠腺泡细胞中 Pdx1 的外源表达是否可能诱导腺泡细胞重编程为 β 细胞。我们建立了一个转基因小鼠品系，其中 Pdx1 和 EGFP（增强型绿色荧光蛋白）可以在腺泡细胞中诱导表达。诱导 Pdx1 后，我们使用 EGFP 进行细胞谱系追踪，追踪腺泡细胞的外分泌和内分泌标记物的表达。成年小鼠中 Pdx1 的腺泡细胞特异性表达将腺泡细胞重新编程为内分泌前体细胞，这些细胞迁移到胰岛中并分化为产生胰岛素、生长抑素或 PP（胰多肽）的内分泌细胞，但不分化为产生胰高血糖素的细胞。当接受这种胰腺重编程的小鼠接受链脲佐菌素 (STZ) 治疗时，新产生的胰岛素产生细胞能够改善 STZ 诱导的糖尿病。这种体内重编程的范例表明，腺泡细胞有望成为糖尿病再生疗法中新胰岛细胞的来源。
A promising approach to new diabetes therapies is to generate β cells from other differentiated pancreatic cells in vivo. Because the acinar cells represent the most abundant cell type in the pancreas, an attractive possibility is to reprogram acinar cells into β cells. The transcription factor Pdx1 (Pancreas/duodenum homeobox protein 1) is essential for pancreatic development and cell lineage determination. Our objective is to examine whether exogenous expression of Pdx1 in acinar cells of adult mice might induce reprogramming of acinar cells into β cells. We established a transgenic mouse line in which Pdx1 and EGFP (enhanced green fluorescent protein) could be inducibly expressed in the acinar cells. After induction of Pdx1, we followed the acinar cells for their expression of exocrine and endocrine markers using cell-lineage tracing with EGFP. The acinar cell-specific expression of Pdx1 in adult mice reprogrammed the acinar cells as endocrine precursor cells, which migrated into the pancreatic islets and differentiated into insulin-, somatostatin-, or PP (pancreatic polypeptide)-producing endocrine cells, but not into glucagon-producing cells. When the mice undergoing such pancreatic reprogramming were treated with streptozotocin (STZ), the newly generated insulin-producing cells were able to ameliorate STZ-induced diabetes. This paradigm of in vivo reprogramming indicates that acinar cells hold promise as a source for new islet cells in regenerative therapies for diabetes.