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本帖最后由 细胞海洋 于 2013-4-3 08:27 编辑
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* S8 Y/ a) K) i9 i$ AReprogramming of human fibroblasts toward a cardiac fate
% P! g7 m2 r8 sYoung-Jae Nama, Kunhua Songa, Xiang Luob, Edward Daniela, Kaleb Lambetha, Katherine Westa, Joseph A. Hilla,b, J. Michael DiMaioc, Linda A. Bakerd,e, Rhonda Bassel-Dubya, and
6 p% ~# _1 b0 b/ U% V; z; S/ a+ X3 AEric N. Olsona,1
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Contributed by Eric N. Olson, January 30, 2013 (sent for review November 14, 2012)
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Reprogramming of mouse fibroblasts toward a myocardial cell fate by forced expression of cardiac transcription factors or microRNAs has recently been demonstrated. The potential clinical applicability of these findings is based on the minimal regenerative potential of the adult human heart and the limited availability of human heart tissue. An initial but mandatory step toward clinical application of this approach is to establish conditions for conversion of adult human fibroblasts to a cardiac phenotype. Toward this goal, we sought to determine the optimal combination of factors necessary and sufficient for direct myocardial reprogramming of human fibroblasts. Here we show that four human cardiac transcription factors, including GATA binding protein 4, Hand2, T-box5, and myocardin, and two microRNAs, miR-1 and miR-133, activated cardiac marker expression in neonatal and adult human fibroblasts. After maintenance in culture for 4–11 wk, human fibroblasts reprogrammed with these proteins and microRNAs displayed sarcomere-like structures and calcium transients, and a small subset of such cells exhibited spontaneous contractility. These phenotypic changes were accompanied by expression of a broad range of cardiac genes and suppression of nonmyocyte genes. These findings indicate that human fibroblasts can be reprogrammed to cardiac-like myocytes by forced expression of cardiac transcription factors with muscle-specific microRNAs and represent a step toward possible therapeutic application of this reprogramming approach. |
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发表于 2013-4-3 01:20
