INSERM U633, Avenir Program, Embryonic Stem Cells and Cardiogenesis, Evry, France.
J Clin Invest. 2010 Apr;120(4):1125-39. doi: 10.1172/JCI40120. Epub 2010 Mar 24.
Cell therapy holds promise for tissue regeneration, including in individuals with advanced heart failure. However, treatment of heart disease with bone marrow cells and skeletal muscle progenitors has had only marginal positive benefits in clinical trials, perhaps because adult stem cells have limited plasticity. The identification, among human pluripotent stem cells, of early cardiovascular cell progenitors required for the development of the first cardiac lineage would shed light on human cardiogenesis and might pave the way for cell therapy for cardiac degenerative diseases. Here, we report the isolation of an early population of cardiovascular progenitors, characterized by expression of OCT4, stage-specific embryonic antigen 1 (SSEA-1), and mesoderm posterior 1 (MESP1), derived from human pluripotent stem cells treated with the cardiogenic morphogen BMP2. This progenitor population was multipotential and able to generate cardiomyocytes as well as smooth muscle and endothelial cells. When transplanted into the infarcted myocardium of immunosuppressed nonhuman primates, an SSEA-1+ progenitor population derived from Rhesus embryonic stem cells differentiated into ventricular myocytes and reconstituted 20% of the scar tissue. Notably, primates transplanted with an unpurified population of cardiac-committed cells, which included SSEA-1- cells, developed teratomas in the scar tissue, whereas those transplanted with purified SSEA-1+ cells did not. We therefore believe that the SSEA-1+ progenitors that we have described here have the potential to be used in cardiac regenerative medicine.
细胞疗法有望实现组织再生,包括在晚期心力衰竭患者中。然而,骨髓细胞和骨骼肌祖细胞治疗心脏病的临床试验仅取得了微小的积极效果,这可能是因为成体干细胞的可塑性有限。如果能在人类多能干细胞中鉴定出早期心血管细胞祖细胞,这些祖细胞是心脏谱系发育所必需的,那么将有助于阐明人类心脏发生机制,并为心脏退行性疾病的细胞疗法铺平道路。在这里,我们报告了一种从经心脏形成素 BMP2 处理的人类多能干细胞中分离出来的早期心血管祖细胞群体的分离,其特征是表达 OCT4、阶段特异性胚胎抗原 1(SSEA-1)和中胚层后 1(MESP1)。该祖细胞群体具有多能性,能够生成心肌细胞以及平滑肌细胞和内皮细胞。当将其移植到免疫抑制的非人类灵长类动物的梗死心肌中时,源自恒河猴胚胎干细胞的 SSEA-1+祖细胞群体分化为心室肌细胞,并重建了 20%的疤痕组织。值得注意的是,移植了包含 SSEA-1-细胞的心脏定向细胞未纯化群体的灵长类动物在疤痕组织中形成了畸胎瘤,而移植了纯化的 SSEA-1+细胞的灵长类动物则没有。因此,我们认为我们在这里描述的 SSEA-1+祖细胞具有用于心脏再生医学的潜力。