Interdepartmental Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Children's Nutrition Research Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Interdisciplinary Program in Cell and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Children's Nutrition Research Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Dev Cell. 2013 Dec 9;27(5):504-15. doi: 10.1016/j.devcel.2013.11.004.
Delineating the mechanism or mechanisms that regulate the specification of hemogenic endothelial cells from primordial endothelium is critical for optimizing their derivation from human stem cells for clinical therapies. We previously determined that retinoic acid (RA) is required for hemogenic specification, as well as cell-cycle control, of endothelium during embryogenesis. Herein, we define the molecular signals downstream of RA that regulate hemogenic endothelial cell development and demonstrate that cell-cycle control is required for this process. We found that re-expression of c-Kit in RA-deficient (Raldh2(-/-)) primordial endothelium induced Notch signaling and p27 expression, which restored cell-cycle control and rescued hemogenic endothelial cell specification and function. Re-expression of p27 in RA-deficient and Notch-inactivated primordial endothelial cells was sufficient to correct their defects in cell-cycle regulation and hemogenic endothelial cell development. Thus, RA regulation of hemogenic endothelial cell specification requires c-Kit, notch signaling, and p27-mediated cell-cycle control.
阐明调控造血内皮细胞从原始内皮细胞特化的机制对于优化其从人类干细胞中诱导分化用于临床治疗至关重要。我们之前的研究确定，视黄酸（RA）对于胚胎发生过程中内皮细胞的造血特化以及细胞周期控制是必需的。在此，我们确定了 RA 下游调控造血内皮细胞发育的分子信号，并证明细胞周期控制是该过程所必需的。我们发现，在 RA 缺陷型（Raldh2(-/-)）原始内皮细胞中重新表达 c-Kit 诱导了 Notch 信号和 p27 的表达，恢复了细胞周期控制，并挽救了造血内皮细胞的特化和功能。在 RA 缺陷型和 Notch 失活的原始内皮细胞中重新表达 p27足以纠正它们在细胞周期调控和造血内皮细胞发育方面的缺陷。因此，RA 调控造血内皮细胞特化需要 c-Kit、Notch 信号和 p27 介导的细胞周期控制。
