Progenitor Cells Identified by PDGFR-Alpha Expression in the Developing and Diseased Human Heart
Progenitor Cells Identified by PDGFR-Alpha Expression in the Developing and Diseased Human Heart
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DOI：
10.1089/scd.2012.0542
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发表时间：
2013-07-01
影响因子：
4
通讯作者：
Murry, Charles E.
中科院分区：
文献类型：
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作者：
Chong, James J. H.;Reinecke, Hans;Murry, Charles E.
血小板衍生生长因子(PDGFs)及其酪氨酸激酶受体在胚胎器官发生和成人器官疾病中起重要作用。特别是，在小鼠和人类胚胎干细胞系统中，血小板衍生生长因子受体α(PDGFRα)由多潜能的心血管祖细胞表达。虽然心脏PDGFRα在多种物种中的表达已被研究，但对其在人类心脏中的表达知之甚少。利用免疫荧光技术，我们分析了PDGFRα在人胎儿心脏和患病成人心脏中的表达，发现PDGFRα在心外膜、心肌和心内膜的间质细胞以及冠状动脉平滑肌中都有强烈的表达。只有极少数的内皮细胞和心肌细胞表达PDGFRα。这一模式在胎儿和成人患病心脏中都是一致的，尽管在后者中发现了更多的PDGFRAα+心肌细胞。然后对从去心肌细胞的人胎儿心脏分离的PDGFRα+细胞进行体外分化试验。使用以前报道的直接分化为心肌细胞(5-氮胞苷)、平滑肌(PDGF-BB)或内皮细胞命运(血管内皮生长因子[VEGF])的方案。虽然没有观察到明显的心肌细胞分化，但PDGFRα+细胞产生了大量的平滑肌细胞(平滑肌-α-肌动蛋白+和平滑肌肌球蛋白+)和内皮细胞(CD31+)。这些数据表明，心脏PDGFRα+群体中的一小部分是主要为人类心脏的血管和间叶室贡献的祖细胞。有可能控制这些祖细胞的命运，以促进血管形成或限制受损心脏的纤维化。
Platelet-derived growth factors (PDGFs) and their tyrosine kinase receptors play instrumental roles in embryonic organogenesis and diseases of adult organs. In particular, platelet-derived growth factor receptor-alpha (PDGFR alpha) is expressed by multipotent cardiovascular progenitors in mouse and human embryonic stem cell systems. Although cardiac PDGFR alpha expression has been studied in multiple species, little is known about its expression in the human heart. Using immunofluorescence, we analyzed PDGFR alpha expression in both human fetal and diseased adult hearts, finding strong expression in the interstitial cells of the epicardium, myocardium, and endocardium, as well as the coronary smooth muscle. Only rare endothelial cells and cardiomyocytes expressed PDGFR alpha. This pattern was consistent for both the fetal and adult diseased hearts, although more PDGFRa alpha+ cardiomyocytes were noted in the latter. In vitro differentiation assays were then performed on the PDGFR alpha+ cell fraction isolated from the cardiomyocyte-depleted human fetal hearts. Protocols previously reported to direct differentiation to a cardiomyocyte (5-azacytidine), smooth muscle (PDGF-BB), or endothelial cell fates (vascular endothelial growth factor [VEGF]) were used. Although no significant cardiomyocyte differentiation was observed, PDGFR alpha+ cells generated significant numbers of smooth muscle cells (smooth muscle-alpha-actin+ and smooth muscle myosin +) and endothelial cells (CD31 +). These data suggest that a subfraction of the cardiac PDGFR alpha+ populations are progenitors contributing predominantly to the vascular and mesenchymal compartments of the human heart. It may be possible to control the fate of these progenitors to promote vascularization or limit fibrosis in the injured heart.