Hypoxia-stressed cardiomyocytes promote early cardiac differentiation of cardiac stem cells through HIF-1α/Jagged1/Notch1 signaling

• 来源期刊: 药学学报（英文版）
• 关键词: Cardiac stem cell Cardiomyocyte,Co-culture Hypoxia Notch1 signaling Cell differentiation
• 年，卷（期）: 2018,（5）
• 页码范围: 795-804
• 页数: 10页
• 语种: 英文

摘要

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 Jaggedl 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 Jagged 1 expression in neonatal rat CMs.Pharmacological inhibition of HIF-1 α 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 hypoxiainduced 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 Notchl 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 Jaggedl expression in CMs primarily through ERK signaling,and facilitates early cardiac lineage differentiation of CSCs in CM/CSC co-cultures via HIF-1α/Jaggedl/Notch signaling.