Age-related increase in Wnt inhibitor causes a senescence-like phenotype in human cardiac stem cells.
Age-related increase in Wnt inhibitor causes a senescence-like phenotype in human cardiac stem cells.
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DOI：
10.1016/j.bbrc.2017.04.110
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发表时间：
2017-06
影响因子：
3.1
通讯作者：
Tamami Nakamura;Tohru Hosoyama;J. Murakami;M. Samura;Koji Ueno;H. Kurazumi;R. Suzuki;A. Mikamo;K. Hamano
中科院分区：
文献类型：
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作者：
Tamami Nakamura;Tohru Hosoyama;J. Murakami;M. Samura;Koji Ueno;H. Kurazumi;R. Suzuki;A. Mikamo;K. Hamano
心脏干/祖细胞（CSCs）的老化损害心脏再生，并导致基于细胞的治疗结果不令人满意。由于CSC衰老的确切机制尚不清楚，因此老年心力衰竭患者的治疗策略严重延迟。在这项研究中，我们使用人心球衍生细胞（CDCs），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人CDC。比较了年轻和老年患者来源的CDC之间关键可溶性因子的基因表达。在这些因素中，编码Wnt拮抗剂的基因SFRP 1在老年患者（≥65岁）的CDC中显著上调。sFRP 1水平在CDC中也显著增加，其衰老表型由抗癌药物治疗诱导。这些结果表明sFRP 1参与CSC老化。我们发现，重组sFRP 1的管理诱导细胞衰老的CDC来自年轻患者，如标记物，如p16的水平增加，和衰老相关的分泌表型。此外，共同施用重组sFRP 1可以消除由Wnt 3A诱导的CDC加速增殖。综上所述，我们的结果表明，经典的Wnt信号转导及其拮抗剂sFRP 1，调节人类CSCs的增殖。此外，老年患者中过量的sFRP 1导致CSC老化。
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.