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STEM CELLS文章:胞外基质是成纤维细胞编程为多功能干细胞的屏障

日期:2019/06/29  来源:新葡萄京娱乐场官方网站

  LIF和BMP信号通路对维持小鼠胚胎干细胞的自我更新十分重要。与此相反,在培养体系中补充FGF2可以促进小鼠胚胎干细胞的分化。之前有研究指出,在体细胞重新编程为多能性干细胞这一由转录因子介导的过程中,对维持胚胎干细胞自我更新具有副作用的因子可能也对细胞重新编程过程有不利影响。然而,近来有研究证据表明FGF2可以提高细胞重新编程的效率,但是其中的分子机制尚未明确。因此,编辑研究了FGF2在促进小鼠成纤维细胞重新编程中的作用以及此过程的分子机制。在初级诱导和二级诱导性重新编程中,编辑证实在诱导性多功能干细胞的诱导初期补充FGF2可以增加重新编程的效率。此外,编辑采用小鼠全转录本表达谱芯片进行分析,Affymetrix Mouse Gene 1.0 ST Array检测服务北京新葡萄京娱乐场官方网站生物技术有限企业完成。研究发现FGF2可以使许多胞外基质候选基因的表达水平显著下调,尤其是胶原合成的水平被明显地降低。随后,编辑证实胶原是成纤维细胞重新编程为多功能干细胞的屏障。通过降低胶原水平的手段例如使用胶原酶或者下调胶原基因的表达均可显著提高细胞重新程序化的效率。本研究揭示了胞外基质在介导成纤维细胞重新编程过程中的屏障作用,并证实在早期补充FGF2可以明显降低这种屏障作用。该研究成果于2013年发表在STEM CELLS杂志上,影响因子达7.781。


原文摘要:

  Promoting reprogramming FGF2 reveals that the extracellular matrix is a barrier for reprogramming fibroblasts to pluripotency

  Leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP) signaling pathways play important roles in maintaining the self-renewal of mouse embryonic stem (ES) cells. In contrast, the supplementation of basic fibroblast growth factor (FGF2) in culture promotes mouse ES cell differentiation. It has been proposed that factors that are adverse for maintaining the self-renewal of ES cells might play detrimental roles in the transcription factor-mediated reprogramming of somatic cells to pluripotency. However, recent evidence has revealed that reprogramming efficiency could be improved by FGF2, while the underlying molecular mechanism remains unknown. In the present study, we dissected the roles of FGF2 in promoting mouse fibroblast reprogramming and disclosed the molecular mechanism behind this process. We utilized both primary induction and secondary inducible reprogramming systems and demonstrated that supplementation with FGF2 in the early phase of induced pluripotent stem (iPS) cell induction could significantly increase reprogramming efficiency. Moreover, we discovered that many extracellular matrix candidate genes were significantly down-regulated in fibroblasts treated with FGF2, and in particular, the synthesis of collagen could be greatly reduced by FGF2 treatment. Subsequently, we demonstrated that collagen is a barrier for reprogramming fibroblast cells to pluripotency, and the decreasing of collagen either by collagenase treatment or down-regulation of collagen gene expression could significantly improve the reprogramming efficiency. Our results reveal a novel role of the extracellular matrix in mediating fibroblasts reprogramming.

原文出处:http://onlinelibrary.wiley.com/doi/10.1002/stem.1318/abstract

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