The search for a source of endothelial cells (ECs) with translational therapeutic potential remains crucial in regenerative medicine. Human blood-derived endothelial colony-forming cells (ECFCs) represent a promising source of autologous ECs due to their robust capacity to form vascular networks in vivo and their easy accessibility from peripheral blood. However, whether ECFCs have distinct characteristics with translational value compared to other ECs remains unclear. Here, we show that vascular networks generated with human ECFCs exhibited robust paracrine support for human pluripotent stem cell-derived cardiomyocytes (iCMs), significantly improving protection against drug-induced cardiac injury and enhancing engraftment at ectopic (subcutaneous) and orthotopic (cardiac) sites. In contrast, iCM support was notably absent in grafts with vessels lined by mature-ECs. This differential trophic ability was due to a unique high constitutive expression of the cardioprotective growth factor neuregulin-1 (NRG1). ECFCs, but not mature-ECs, were capable of actively releasing NRG1, which, in turn, reduced apoptosis and increased the proliferation of iCMs via the PI3K/Akt signaling pathway. Transcriptional silencing of NRG1 abrogated these cardioprotective effects. Our study suggests that ECFCs are uniquely suited to support human iCMs, making these progenitor cells ideal for cardiovascular regenerative medicine.

寻找具有转化治疗潜力的内皮细胞 (EC) 来源在再生医学中仍然至关重要。人血源性内皮集落形成细胞 (ECFCs) 代表了自体 ECs 的一个有前途的来源，因为它们具有在体内形成血管网络的强大能力，并且它们易于从外周血中获取。然而，与其他 ECs 相比，ECFCs 是否具有具有转化价值的独特特征仍不清楚。在这里，我们表明用人类 ECFC 生成的血管网络对人类多能干细胞衍生的心肌细胞 (iCM) 表现出强大的旁分泌支持，显着提高了对药物诱导的心脏损伤的保护作用，并增强了异位（皮下）和原位（心脏）位点的移植。 . 相比之下，在具有成熟 EC 内衬的血管的移植物中，iCM 支持明显缺失。这种不同的营养能力是由于心脏保护性生长因子 neuregulin-1 (NRG1) 的独特的高组成型表达。ECFCs，而不是成熟的ECs，能够主动释放NRG1，从而通过PI3K/Akt信号通路减少细胞凋亡并增加iCMs的增殖。NRG1 的转录沉默消除了这些心脏保护作用。我们的研究表明，ECFCs 特别适合支持人类 iCM，使这些祖细胞成为心血管再生医学的理想选择。反过来，通过 PI3K/Akt 信号通路减少细胞凋亡并增加 iCM 的增殖。NRG1 的转录沉默消除了这些心脏保护作用。我们的研究表明，ECFCs 特别适合支持人类 iCM，使这些祖细胞成为心血管再生医学的理想选择。反过来，通过 PI3K/Akt 信号通路减少细胞凋亡并增加 iCM 的增殖。NRG1 的转录沉默消除了这些心脏保护作用。我们的研究表明，ECFCs 特别适合支持人类 iCM，使这些祖细胞成为心血管再生医学的理想选择。