Historically, a lower incidence of cardiovascular diseases (CVD) and related deaths in women as compared with men of the same age has been attributed to female sex hormones, particularly estrogen and its receptors. Autologous bone marrow stem cell (BMSC) clinical trials for cardiac cell therapy overwhelmingly included male patients. However, meta-analysis data from these trials suggest a better functional outcome in postmenopausal women as compared with aged-matched men. Mechanisms governing sex-specific cardiac reparative activity in BMSCs, with and without the influence of sex hormones, remain unexplored. To discover these mechanisms, Male (M), female (F), and ovariectomized female (OVX) mice-derived EPCs were subjected to a series of molecular and epigenetic analyses followed by in vivo functional assessments of cardiac repair. F-EPCs and OVX EPCs show a lower inflammatory profile and promote enhanced cardiac reparative activity after intra-cardiac injections in a male mouse model of myocardial infarction (MI). Epigenetic sequencing revealed a marked difference in the occupancy of the gene repressive H3K9me3 mark, particularly at transcription start sites of key angiogenic and proinflammatory genes in M-EPCs compared with F-EPCs and OVX-EPCs. Our study unveiled that functional sex differences in EPCs are, in part, mediated by differential epigenetic regulation of the proinflammatory and anti-angiogenic gene CCL3, orchestrated by the control of H3K9me3 by histone methyltransferase, G9a/Ehmt2. Our research highlights the importance of considering the sex of donor cells for progenitor-based tissue repair.

从历史上看，与同龄男性相比，女性心血管疾病（CVD）和相关死亡的发病率较低，这归因于女性性激素，特别是雌激素及其受体。用于心脏细胞治疗的自体骨髓干细胞（BMSC）临床试验绝大多数包括男性患者。然而，这些试验的荟萃分析数据表明，与年龄匹配的男性相比，绝经后女性的功能结果更好。无论有或没有性激素的影响，骨髓间充质干细胞中控制性别特异性心脏修复活性的机制仍有待探索。为了发现这些机制，对雄性 (M)、雌性 (F) 和去卵巢雌性 (OVX) 小鼠来源的 EPC 进行了一系列分子和表观遗传学分析，然后进行了心脏修复的体内功能评估。 F-EPC 和 OVX EPC 在雄性心肌梗塞 (MI) 小鼠模型中进行心内注射后，显示出较低的炎症特征并促进增强的心脏修复活性。表观遗传测序显示，与 F-EPC 和 OVX-EPC 相比，M-EPC 中 H3K9me3 基因抑制标记的占据情况存在显着差异，特别是在关键血管生成和促炎基因的转录起始位点。我们的研究揭示了 EPC 中的功能性性别差异部分是由促炎基因和抗血管生成基因 CCL3 的差异表观遗传调控介导的，而 CCL3 是由组蛋白甲基转移酶 G9a/Ehmt2 对 H3K9me3 的控制来协调的。我们的研究强调了考虑供体细胞性别对于基于祖细胞的组织修复的重要性。