The temporal and hierarchical control of transcription factors-induced liver to pancreas transdifferentiation.
The temporal and hierarchical control of transcription factors-induced liver to pancreas transdifferentiation.
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DOI：
10.1371/journal.pone.0087812
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Ferber S
中科院分区：
文献类型：
--
作者：
Berneman-Zeitouni D;Molakandov K;Elgart M;Mor E;Fornoni A;Domínguez MR;Kerr-Conte J;Ott M;Meivar-Levy I;Ferber S
谱系特异性转录因子（TF）在直接将成体细胞重编程为替代发育命运中显示指导性作用，这一过程称为转分化。本研究分析的假设，尽管是快速的，转分化不会发生在一个步骤，而是一个连续的和分层的过程。使用人肝细胞中Pdx 1的异位表达，我们证明，而glugacon和生长抑素表达在一天内启动，胰岛素基因表达变得明显，只有2-3天后。为了提高转分化效率并分析该过程是否确实显示连续和分层特征，成年人肝细胞被三种胰腺转录因子Pdx 1，Pax 4和Mafa（3 pTF）处理，这些转录因子控制胚胎中胰腺发育的不同分层阶段。人肝细胞中3 pTF的异位表达增加了转分化产率，表现为与单独的每种异位因子相比，胰岛素阳性细胞的数量增加了300%。然而，仅当3 pTF以直接分级方式彼此间隔一天依次补充时，转分化的细胞显示出增加的成熟β细胞样特征。Pdx 1的异位表达，随后在第2天由Pax 4表达，并在第3天由Mafa表达，导致转分化产量增加，这与葡萄糖调节的c肽分泌增加有关。相比之下，以间接分级模式协同或顺序施用异位3 pTF导致产生胰岛素和生长激素抑制素共产生细胞，并减少葡萄糖调节的加工胰岛素分泌。总之，转录因子诱导的肝胰腺转分化是一个渐进的、分层次的过程。可以合理地假设，这种特性对于广泛的组织是普遍的。因此，我们的研究结果可以促进包括糖尿病在内的许多退行性疾病的细胞替代疗法的发展。
Lineage-specific transcription factors (TFs) display instructive roles in directly reprogramming adult cells into alternate developmental fates, in a process known as transdifferentiation. The present study analyses the hypothesis that despite being fast, transdifferentiation does not occur in one step but is rather a consecutive and hierarchical process. Using ectopic expression of Pdx1 in human liver cells, we demonstrate that while glugacon and somatostatin expression initiates within a day, insulin gene expression becomes evident only 2–3 days later. To both increase transdifferentiation efficiency and analyze whether the process indeed display consecutive and hierarchical characteristics, adult human liver cells were treated by three pancreatic transcription factors, Pdx1, Pax4 and Mafa (3pTFs) that control distinct hierarchical stages of pancreatic development in the embryo. Ectopic expression of the 3pTFs in human liver cells, increased the transdifferentiation yield, manifested by 300% increase in the number of insulin positive cells, compared to each of the ectopic factors alone. However, only when the 3pTFs were sequentially supplemented one day apart from each other in a direct hierarchical manner, the transdifferentiated cells displayed increased mature β-cell-like characteristics. Ectopic expression of Pdx1 followed by Pax4 on the 2nd day and concluded by Mafa on the 3rd day resulted in increased yield of transdifferentiation that was associated by increased glucose regulated c-peptide secretion. By contrast, concerted or sequential administration of the ectopic 3pTFs in an indirect hierarchical mode resulted in the generation of insulin and somatostatin co-producing cells and diminished glucose regulated processed insulin secretion. In conclusion transcription factors induced liver to pancreas transdifferentiation is a progressive and hierarchical process. It is reasonable to assume that this characteristic is general to wide ranges of tissues. Therefore, our findings could facilitate the development of cell replacement therapy modalities for many degenerative diseases including diabetes.
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影响因子：
23.9
作者：
Ambasudhan R;Talantova M;Coleman R;Yuan X;Zhu S;Lipton SA;Ding S
通讯作者：
Ding S
DOI：
10.1900/rds.2010.7.93
发表时间：
2010-01-01
期刊：
The review of diabetic studies : RDS
影响因子：
--
作者：
Borowiak, Malgorzata
通讯作者：
Borowiak, Malgorzata
影响因子：
13.5
作者：
Meivar-Levy, Irit;Sapir, Tamar;Ferberl, Sarah
通讯作者：
Ferberl, Sarah
影响因子：
7.7
作者：
Du A;Hunter CS;Murray J;Noble D;Cai CL;Evans SM;Stein R;May CL
通讯作者：
May CL
影响因子：
82.9
作者：
Kojima, H;Fujimiya, M;Chan, L
通讯作者：
Chan, L