Nakamura Tamami, Hosoyama Tohru, Murakami Junichi, Samura Makoto, Ueno Koji, Kurazumi Hiroshi, Suzuki Ryo, Mikamo Akihito, Hamano Kimikazu
Department Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Japan.
Department Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, Japan; Regenerative Medicine Institute, Yamaguchi University Graduate School of Medicine, Japan.
Biochem Biophys Res Commun. 2017 Jun 3;487(3):653-659. doi: 10.1016/j.bbrc.2017.04.110. Epub 2017 Apr 21.
Aging of cardiac stem/progenitor cells (CSCs) impairs heart regeneration and leads to unsatisfactory outcomes of cell-based therapies. As the precise mechanisms underlying CSC aging remain unclear, the use of therapeutic strategies for elderly patients with heart failure is severely delayed. In this study, we used human cardiosphere-derived cells (CDCs), a subtype of CSC found in the postnatal heart, to identify secreted factor(s) associated with CSC aging. Human CDCs were isolated from heart failure patients of various ages (2-83 years old). Gene expression of key soluble factors was compared between CDCs derived from young and elderly patients. Among these factors, SFRP1, a gene encoding a Wnt antagonist, was significantly up-regulated in CDCs from elderly patients (≥65 years old). sFRP1 levels was increased significantly also in CDCs, whose senescent phenotype was induced by anti-cancer drug treatment. These results suggest the participation of sFRP1 in CSC aging. We show that the administration of recombinant sFRP1 induced cellular senescence in CDCs derived from young patients, as indicated by increased levels of markers such as p16, and a senescence-associated secretory phenotype. In addition, co-administration of recombinant sFRP1 could abrogate the accelerated CDC proliferation induced by Wnt3A. Taken together, our results suggest that canonical Wnt signaling and its antagonist, sFRP1, regulate proliferation of human CSCs. Furthermore, excess sFRP1 in elderly patients causes CSC aging.
心脏干细胞/祖细胞（CSCs）的衰老会损害心脏再生，并导致基于细胞的治疗效果不尽人意。由于CSC衰老的精确机制仍不清楚，老年心力衰竭患者治疗策略的应用严重滞后。在本研究中，我们使用人心脏球衍生细胞（CDCs），这是一种在出生后心脏中发现的CSC亚型，来鉴定与CSC衰老相关的分泌因子。从不同年龄（2 - 83岁）的心力衰竭患者中分离出人CDCs。比较了年轻和老年患者来源的CDCs中关键可溶性因子的基因表达。在这些因子中，编码Wnt拮抗剂的基因SFRP1在老年患者（≥65岁）来源的CDCs中显著上调。在经抗癌药物处理诱导出衰老表型的CDCs中，sFRP1水平也显著升高。这些结果表明sFRP1参与了CSC衰老。我们发现，重组sFRP1的给药可诱导年轻患者来源的CDCs发生细胞衰老，表现为p16等标志物水平升高以及衰老相关分泌表型。此外，重组sFRP1与Wnt3A共同给药可消除Wnt3A诱导的CDCs加速增殖。综上所述，我们的结果表明经典Wnt信号及其拮抗剂sFRP1调节人CSCs的增殖。此外，老年患者中过量的sFRP1会导致CSC衰老。
