已发第5篇Nature解析miRNA控制细胞命运

生物通报道，美国旧金山Gladstone心血管疾病研究所，加州大学儿科系，生物化学与生物物理系，罗切斯特大学Aab心血管研究所的科学家在Nature在线版上发表了关于细胞分化命运与细胞可塑性的研究进展miR-145 and miR-143 regulate smooth muscle cell fate and plasticity。

 

文章通讯作者是Gladstone心血管疾病研究所主任Deepak Srivastava，主要从事心脏疾病和心脏发育方面的研究。Deepak Srivastava是一位高产的学者，从2003年开始在Nature上发表了5篇文章，在Cell上发表了3篇文章。

 

microRNAs(miRNAs)的研究正在不断增加，原因是科学家开始认识到这些普遍存在的小分子在真核基因表达调控中有着广泛的作用。在线虫，果蝇，小鼠和人等物种中已经发现的数百个miRNAs中的多数具有和其他参与调控基因表达的分子一样的特征——在不同组织、不同发育阶段中miRNA的水平有显著差异，这种miRNAs表达模式具有分化的位相性和时序性（differential spatial and temporal expression patterns），提示miRNAs有可能作为参与调控基因表达的分子，因而具有重要意义。

 

目前的研究发现，很少存在完全调控干细胞分化的单个microRNA，大部分的情况下是多个调控因子参与一个生物学事件。

 

在本研究中，Deepak Srivastava（Gladstone心血管疾病研究所主任）证实了miR-145和miR-143对小鼠心脏祖细胞发育成心脏平滑肌细胞的调控。miR-145和miR-143通过转录一系列的细胞因子，定向诱导心脏祖细胞分化为心脏平滑肌细胞。

（生物通 小茜）

 

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生物通推荐原文检索：miR-145 and miR-143 regulate smooth muscle cell fate and plasticity

 

Kimberly R. Cordes1,2,3, Neil T. Sheehy1,2,3, Mark P. White1,2,3, Emily C. Berry1,2,3, Sarah U. Morton1,2,3, Alecia N. Muth1,2,3, Ting-Hein Lee4, Joseph M. Miano4, Kathryn N. Ivey1,2,3 & Deepak Srivastava1,2,3

 

Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA

Department of Pediatrics, University of California, San Francisco, California 94543, USA

Department of Biochemistry & Biophysics, University of California, San Francisco, California 94143, USA

Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA

Correspondence to: Deepak Srivastava1,2,3 Correspondence and requests for materials should be addressed to D.S. (Email: [e-mail]).

 

【Abstract】

MicroRNAs (miRNAs) are regulators of myriad cellular events, but evidence for a single miRNA that can efficiently differentiate multipotent stem cells into a specific lineage or regulate direct reprogramming of cells into an alternative cell fate has been elusive. Here we show that miR-145 and miR-143 are co-transcribed in multipotent murine cardiac progenitors before becoming localized to smooth muscle cells, including neural crest stem-cell-derived vascular smooth muscle cells. miR-145 and miR-143 were direct transcriptional targets of serum response factor, myocardin and Nkx2-5 (NK2 transcription factor related, locus 5) and were downregulated in injured or atherosclerotic vessels containing proliferating, less differentiated smooth muscle cells. miR-145 was necessary for myocardin-induced reprogramming of adult fibroblasts into smooth muscle cells and sufficient to induce differentiation of multipotent neural crest stem cells into vascular smooth muscle. Furthermore, miR-145 and miR-143 cooperatively targeted a network of transcription factors, including Klf4 (Kruppel-like factor 4), myocardin and Elk-1 (ELK1, member of ETS oncogene family), to promote differentiation and repress proliferation of smooth muscle cells. These findings demonstrate that miR-145 can direct the smooth muscle fate and that miR-145 and miR-143 function to regulate the quiescent versus proliferative phenotype of smooth muscle cells.

 

Deepak Srivastava的代表作

Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D. (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424: 443–447.

Bock-Marquette I, Saxena A, White MD, Dimaio JM, Srivastava D. (2004) Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature 432: 466–472.

Zhao Y, Samal E, Srivastava D. (2005) Serum response factor regulates a muscle-specific mircroRNA that targets Hand2 during cardiogenesis. Nature 436:214-220.

Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D. (2005) Mutations in NOTCH1 cause aortic valve disease. Nature 437:270–274.

Srivastava D. (2006) Making or breaking the heart: From lineage determination to morphogenesis. Cell126:1037–1048.

Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, Tsuchihashi T, McManus MT, Schwartz RJ, Srivastava D. (2007) Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129:303–317.

Ivey KN, Muth A, Arnold J, King FW, Yeh R-F, Fish JE, HSaio EC, Schwartz RJ, Conklin BR, Bernstein HS, Srivastava D. (2008) MicroRNA regulation of cell lineages in mouse and human embryonic stem cells. Cell Stem Cell 2:219-229.

Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KN, Bruneau BG, Stainier DYR, Srivastva D. (2008) miR-126 regulates angiogenic signaling and vascular integrity. Dev. Cell 15:272-284.

Ieda M, Tsuchihashi T, Ivey KN, Ross RS, Hong T-T, Shaw RM, Srivastava D. (2009) Cardiac fibroblasts regulate myocardial proliferation through beta-1 integrin signaling. Dev. Cell 16:233-244