Suppression of Ptf1a activity induces acinar-to-endocrine conversion.
Suppression of Ptf1a activity induces acinar-to-endocrine conversion.
复制标题
DOI：
10.1016/j.cub.2011.03.041
复制
发表时间：
2011-04-26
期刊：
影响因子：
9.2
通讯作者：
Stainier, Didier Y. R.
中科院分区：
文献类型：
--
作者：
Hesselson, Daniel;Anderson, Ryan M.;Stainier, Didier Y. R.
多能胚胎细胞在发育过程中逐渐受到谱系限制，这一过程最终导致执行特殊功能的稳定器官特定细胞类型的分化。终末分化的胰腺腺泡细胞不具有为内分泌β细胞谱系做出贡献的先天能力，而在自身免疫性糖尿病患者中，这种细胞谱系被破坏。一些细胞类型可以使用单个因子进行重新编程，而其他类型的细胞则需要转录调节因子的持续活动来抑制交替的细胞命运。因此，我们假设转录网络持续维持胰腺腺泡细胞的命运。我们发现，Ptf1a是胰腺发育的主要调节者，也是腺泡细胞命运的指定因素，胚胎后的拮抗作用诱导了包括胰岛素在内的内分泌基因在外分泌室的表达。利用遗传谱系追踪的方法，我们证明了诱导的胰岛素+细胞来源于腺泡细胞。细胞重编程发生在动态平衡条件下，表明胰腺微环境足以促进内分泌分化。因此，可能不需要严格的实验操作来加强胰腺的转分化。这些数据表明，有针对性的胚胎后破坏腺泡细胞的命运可以恢复在发育过程中失去的发育可塑性。
Pluripotent embryonic cells become progressively lineage-restricted during development in a process that culminates in the differentiation of stable organ specific cell types that perform specialized functions. Terminally-differentiated pancreatic acinar cells do not have the innate capacity to contribute to the endocrine β-cell lineage, which is destroyed in individuals with autoimmune diabetes. Some cell types can be reprogrammed using a single factor, whereas other cell types require continuous activity of transcriptional regulators to repress alternate cell fates. Thus, we hypothesized that a transcriptional network continuously maintains the pancreatic acinar cell fate. We found that post-embryonic antagonism of Ptf1a, a master regulator of pancreatic development and acinar cell fate specification, induced the expression of endocrine genes including insulin in the exocrine compartment. Using a genetic lineage tracing approach, we show that the induced insulin+ cells are derived from acinar cells. Cellular reprogramming occurred under homeostatic conditions, suggesting that the pancreatic micro-environment is sufficient to promote endocrine differentiation. Thus, severe experimental manipulations may not be required to potentiate pancreatic transdifferentiation. These data indicate that targeted post-embryonic disruption of the acinar cell fate can restore the developmental plasticity that is lost during development.
登录
查看更多内容
影响因子：
3.7
作者：
Wan, Haiyan;Korzh, Suitlana;Gong, Zhiyuan
通讯作者：
Gong, Zhiyuan
影响因子：
11.8
作者：
Schaffer, Ashleigh E.;Freude, Kristine K.;Nelson, Shelley B.;Sander, Maike
通讯作者：
Sander, Maike
影响因子：
64.5
作者：
Uhlenhaut, N. Henriette;Jakob, Susanne;Treier, Mathias
通讯作者：
Treier, Mathias
影响因子：
30.8
作者：
Kawaguchi, Y;Cooper, B;Wright, CVE
通讯作者：
Wright, CVE
影响因子：
2.5
作者：
KIMMEL, CB;BALLARD, WW;SCHILLING, TF
通讯作者：
SCHILLING, TF