缺氧有利于心肌损伤干细胞移植分化,但这一好处背后的机制仍未解决。这里,我们报道了缺氧诱导的心肌细胞(CMs)中Jagged1表达对驱动心脏干细胞(CSC)分化的影响。强迫缺氧诱导因子1α(HIF-1α)表达和物理缺氧(5%O2)治疗可诱导新生大鼠CMs中Jagged1的表达。YC-1对HIF-1α的药理抑制作用减弱了CMs中缺氧促进的Jagged1表达。ERK抑制剂(PD98059),但不是JNK(SP600125)的抑制剂,缺口(DAPT),NF-κB(PTDC),JAK(AG490),或STAT3(Stattic)抑制缺氧诱导的Jagged1蛋白表达使用磁激活细胞分选方法从新生大鼠心脏分离的CMs.c-Kit+CSCs表达GATA4,SM22α或vWF,但不是Nkx2.5和cTnI。此外,87.3%的新鲜分离的CSC显示Notch1受体表达。将CMs与BrdU标记的CSC直接共培养可增强CSC的分化,正如BrdU+/Nkx2.5+细胞数量增加所证明的那样,而21天的间歇性缺氧促进共培养触发的CSC分化为CM样细胞。值得注意的是,YC-1和DAPT减弱了缺氧诱导的分化。我们的结果表明,缺氧主要通过ERK信号诱导CMs中的Jagged1表达,并通过HIF-1α/Jagged1/Notch信号传导促进CM/CSC共培养物中CSC的早期心脏谱系分化。
Hypoxia is beneficial for the differentiation of stem cells transplanted for myocardial injury, but mechanisms underlying this benefit remain unsolved. Here, we report the impact of hypoxia-induced Jagged1 expression in cardiomyocytes (CMs) for driving the differentiation of cardiac stem cells (CSCs). Forced hypoxia-inducible factor 1α (HIF-1α) expression and physical hypoxia (5% O2) treatment could induce Jagged1 expression in neonatal rat CMs. Pharmacological inhibition of HIF-1α by YC-1 attenuated hypoxia-promoted Jagged1 expression in CMs. An ERK inhibitor (PD98059), but not inhibitors of JNK (SP600125), Notch (DAPT), NF-κB (PTDC), JAK (AG490), or STAT3 (Stattic) suppressed hypoxia-induced Jagged1 protein expression in CMs. c-Kit+ CSCs isolated from neonatal rat hearts using a magnetic-activated cell sorting method expressed GATA4, SM22α or vWF, but not Nkx2.5 and cTnI. Moreover, 87.3% of freshly isolated CSCs displayed Notch1 receptor expression. Direct co-culture of CMs with BrdU-labeled CSCs enhanced CSCs differentiation, as evidenced by an increased number of BrdU+/Nkx2.5+ cells, while intermittent hypoxia for 21 days promoted co-culture-triggered differentiation of CSCs into CM-like cells. Notably, YC-1 and DAPT attenuated hypoxia-induced differentiation. Our results suggest that hypoxia induces Jagged1 expression in CMs primarily through ERK signaling, and facilitates early cardiac lineage differentiation of CSCs in CM/CSC co-cultures via HIF-1α/Jagged1/Notch signaling.