Nadal-Ginard Bernardo, Ellison Georgina M, Torella Daniele
Department of Physiology, School of Biomedical Sciences, King's College, London, UK; Centre for Stem Cells & Regenerative Medicine, King's College, London, UK.
Department of Physiology, School of Biomedical Sciences, King's College, London, UK; Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro 88100, Italy; Centre for Stem Cells & Regenerative Medicine, King's College, London, UK.
Stem Cell Res. 2014 Nov;13(3 Pt B):615-30. doi: 10.1016/j.scr.2014.04.008. Epub 2014 Apr 29.
Resident cardiac stem cells in embryonic, neonatal and adult mammalian heart have been identified by different membrane markers and transcription factors. However, despite a flurry of publications no consensus has been reached on the identity and actual regenerative effects of the adult cardiac stem cells. Intensive research on the adult mammalian heart's capacity for self-renewal of its muscle cell mass has led to a consensus that new cardiomyocytes (CMs) are indeed formed throughout adult mammalian life albeit at a disputed frequency. The physiological significance of this renewal, the origin of the new CMs, and the rate of adult CM turnover are still highly debated. Myocyte replacement, particularly after injury, was originally attributed to differentiation of a stem cell compartment. More recently, it has been reported that CMs are mainly replaced by the division of pre-existing post-mitotic CMs. These latter results, if confirmed, would shift the target of regenerative therapy toward boosting mature CM cell-cycle re-entry. Despite this controversy, it is documented that the adult endogenous c-kit(pos) cardiac stem cells (c-kit(pos) eCSCs) participate in adaptations to myocardial stress, and, when transplanted into the myocardium, regenerate most cardiomyocytes and microvasculature lost in an infarct. Nevertheless, the in situ myogenic potential of adult c-kit(pos) cardiac cells has been questioned. To revisit the regenerative potential of c-kit(pos) eCSCs, we have recently employed experimental protocols of severe diffuse myocardial damage in combination with several genetic murine models and cell transplantation approaches showing that eCSCs are necessary and sufficient for CM regeneration, leading to complete cellular, anatomical, and functional myocardial recovery. Here we will review the available data on adult eCSC biology and their regenerative potential placing it in the context of the different claimed mechanisms of CM replacement. These data are in agreement with and have reinforced our view that most CMs are replaced by de novo CM formation through the activation, myogenic commitment and specification of the eCSC cohort.
胚胎、新生和成年哺乳动物心脏中的心脏驻留干细胞已通过不同的膜标记物和转录因子得以鉴定。然而，尽管有大量相关出版物，但对于成年心脏干细胞的特性和实际再生效应仍未达成共识。对成年哺乳动物心脏肌肉细胞群自我更新能力的深入研究已达成一项共识，即新的心肌细胞（CMs）在成年哺乳动物的整个生命过程中确实会形成，尽管其形成频率存在争议。这种更新的生理意义、新CMs的来源以及成年CMs的更新率仍备受争议。最初认为，心肌细胞的替代，尤其是在损伤后，是由于干细胞区室的分化。最近，有报道称CMs主要通过已存在的有丝分裂后CMs的分裂来替代。如果后一种结果得到证实，那么再生治疗的目标将转向促进成熟CM细胞周期重新进入。尽管存在这一争议，但有文献记载，成年内源性c-kit阳性心脏干细胞（c-kit阳性eCSCs）参与对心肌应激的适应性反应，并且当移植到心肌中时，能再生梗死灶中丢失的大多数心肌细胞和微血管。然而，成年c-kit阳性心脏细胞的原位成肌潜力受到了质疑。为了重新审视c-kit阳性eCSCs的再生潜力，我们最近采用了严重弥漫性心肌损伤的实验方案，并结合多种基因小鼠模型和细胞移植方法，结果表明eCSCs对于CM再生是必要且充分的，能够实现心肌细胞、解剖结构和功能的完全恢复。在此，我们将回顾关于成年eCSC生物学及其再生潜力的现有数据，并将其置于不同的CM替代机制的背景下进行探讨。这些数据与我们的观点一致并进一步强化了我们的观点，即大多数CMs是通过eCSC群体的激活、成肌定向和分化而由新生CM形成所替代的。
