Labatt Family Heart Centre, Hospital for Sick Children, Toronto, Ontario.
Department of Anaesthesia and Pain Medicine, Hospital for Sick Children, Toronto, Ontario.
PLoS One. 2018 Jul 25;13(7):e0200342. doi: 10.1371/journal.pone.0200342. eCollection 2018.
We sought to define the intrinsic stem cell capacity in pediatric heart lesions, and the effects of diagnosis and of age, in order to inform evidence-based use of potential autologous stem cell sources for regenerative medicine therapy.
Ventricular explants derived from patients with hypoplastic left heart syndrome (HLHS), tetralogy of Fallot (TF), dilated cardiomyopathy (DCM) and ventricular septal defect (VSD) were analyzed following standard in vitro culture conditions, which yielded cardiospheres (C-spheres), indicative of endogenous stem cell capacity. C-sphere counts generated per 5 mm3 tissue explant and the presence of cardiac progenitor cells were correlated to patient age, diagnosis and echocardiographic function.
Cardiac explants from patients less than one year of age with TF and DCM robustly generated c-kit- and/or vimentin-positive cardiac mesenchymal cells (CMCs), populating spontaneously forming C-spheres. Beyond one year of age, there was a marked reduction or absence of cardiac explant-derivable cardiac stem cell content in patients with TF, VSD and DCM. Stem cell content in HLHS and DCM strongly correlated to the echocardiographic function in the corresponding ventricular chamber, with better echocardiographic function correlating to a more robust regenerative cellular content.
We conclude that autologous cardiomyogenic potential in pediatric heart lesions is robust during the first year of life and uniformly declines thereafter. Depletion of stem cell content occurs at an earlier age in HLHS with the onset of ventricular failure in a chamber-specific pattern that correlates directly to ventricular dysfunction. These data suggest that regenerative therapies using autologous cellular sources should be implemented in the neonatal period before the potentially rapid onset of single ventricle failure in HLHS or the evolution of biventricular failure in DCM.
我们旨在确定儿科心脏病变中的固有干细胞能力，以及诊断和年龄的影响，以便为再生医学治疗中潜在的自体干细胞来源的合理使用提供依据。
根据标准的体外培养条件，分析来自左心发育不全综合征（HLHS）、法洛四联症（TF）、扩张型心肌病（DCM）和室间隔缺损（VSD）患者的心室组织，以获得心脏球体（C-spheres），这表明内源性干细胞能力。每 5mm3 组织外植体生成的 C-sphere 数量和存在的心脏祖细胞与患者年龄、诊断和超声心动图功能相关。
TF 和 DCM 年龄小于 1 岁的患者的心脏外植体能够强烈生成 c-kit-和/或波形蛋白阳性的心脏间充质细胞（CMCs），并自发形成 C-spheres。超过 1 岁后，TF、VSD 和 DCM 患者的心脏外植体来源的心脏干细胞含量明显减少或缺失。HLHS 和 DCM 中的干细胞含量与相应心室腔的超声心动图功能密切相关，更好的超声心动图功能与更强大的再生细胞含量相关。
我们得出结论，在生命的第一年，儿科心脏病变中的自体心肌生成潜能是强大的，此后则均匀下降。在 HLHS 中，心室衰竭开始时，干细胞含量会更早耗尽，呈特定于心室的模式，与心室功能障碍直接相关。这些数据表明，在 HLHS 中可能迅速出现单心室衰竭或 DCM 中出现双心室衰竭之前的新生儿期，应使用自体细胞来源的再生疗法。
