Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging.
Nucleostemin rejuvenates cardiac progenitor cells and antagonizes myocardial aging.
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DOI：
10.1016/j.jacc.2014.09.086
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发表时间：
2015-01-20
影响因子：
24
通讯作者：
Sussman, Mark A.
中科院分区：
文献类型：
--
作者：
Hariharan, Nirmala;Quijada, Pearl;Mohsin, Sadia;Joyo, Anya;Samse, Kaitlen;Monsanto, Megan;De La Torre, Andrea;Avitabile, Daniele;Ormachea, Lucia;McGregor, Michael J.;Tsai, Emily J.;Sussman, Mark A.
干细胞介导的再生功能下降导致与c-kit+心脏祖细胞（CPC）细胞衰老相关的衰老。对老年患者实施基于CPC的治疗的临床实施将极大地受益于了解衰老的分子特征以对抗衰老。核干细胞蛋白（NS）是一种调节干细胞增殖和多能性的核仁蛋白。目的是证明NS保留与CPC中的“干性”相关的特征并拮抗心肌衰老和老化。研究了从人胎儿（FhCPC）和成人衰竭（AhCPC）心脏以及年轻（YCPC）和老年小鼠（OCPC）分离的CPC的衰老特征和NS表达。使用具有NS的一个功能等位基因（NS+/−）的杂合敲除小鼠来证明NS保留心肌结构和功能并减缓衰老特征。相对于FhCPC，AhCPC中NS表达降低，与降低的增殖潜力和缩短的端粒长度相关。AhCPC特征类似于OCPC，其具有由NS沉默诱导的表型，导致细胞扁平化、衰老、多核细胞、S期进展减少、干性标志物表达减少以及p53和p16上调。由NS损失引起的CPC衰老部分依赖于p53，并且通过同时沉默p53来挽救。在机制上，NS诱导与Pim-1激酶介导的c-Myc稳定相关。工程化OCPC和AhCPC以过表达NS减少衰老和多核细胞，恢复形态，并拮抗衰老，从而保留“干性”的表型特性。在NS+/−小鼠中，早期心脏老化伴随心脏功能下降、衰老标志物p53和p16增加、端粒磨损以及伴随的CPC耗竭是明显的。CPC和心肌中衰老的年轻特性和拮抗作用与Pim-1信号转导下游NS增强心脏再生的作用一致。
Functional decline in stem cell-mediated regeneration contributes to aging associated with cellular senescence in c-kit+ cardiac progenitor cells (CPCs). Clinical implementation of CPC-based therapy with elderly patients would benefit tremendously from understanding molecular characteristics of senescence to antagonize aging. Nucleostemin (NS) is a nucleolar protein regulating stem cell proliferation and pluripotency. The goal is to demonstrate that NS preserves characteristics associated with “stemness” in CPCs and antagonizes myocardial senescence and aging. CPCs isolated from human fetal (FhCPC) and adult failing (AhCPC) hearts, as well as young (YCPC) and old mice (OCPC), were studied for senescence characteristics and NS expression. Heterozygous knockout mice with one functional allele of NS (NS+/−) were used to demonstrate that NS preserves myocardial structure and function and slows characteristics of aging. NS expression is decreased in AhCPCs relative to FhCPC, correlating with lowered proliferation potential and shortened telomere length. AhCPC characteristics resemble OCPCs, which have a phenotype induced by NS silencing, resulting in cell flattening, senescence, multinucleated cells, decreased S phase progression, diminished expression of stemness markers and up-regulation of p53 and p16. CPC senescence resulting from NS loss is partially p53 dependent and is rescued by concurrent silencing of p53. Mechanistically, NS induction correlates with Pim-1 kinase-mediated stabilization of c-Myc. Engineering OCPCs and AhCPCs to overexpress NS decreases senescent and multinucleated cells, restores morphology, and antagonizes senescence, thereby preserving phenotypic properties of “stemness.” Early cardiac aging with decline in cardiac function, increase in senescence markers p53 and p16, telomere attrition, and accompanied CPC exhaustion is evident in NS+/− mice. Youthful properties and antagonism of senescence in CPCs and the myocardium is consistent with a role for NS downstream from Pim-1 signaling that enhances cardiac regeneration.
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影响因子：
5.2
作者：
Cottage, Christopher T.;Neidig, Lauren;Sundararaman, Balaji;Din, Shabana;Joyo, Anya Y.;Bailey, Brandi;Gude, Natalie;Hariharan, Nirmala;Sussman, Mark A.
通讯作者：
Sussman, Mark A.
DOI：
10.1083/jcb.201109038
发表时间：
2012-05-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hsu JK;Lin T;Tsai RY
通讯作者：
Tsai RY
影响因子：
20.1
作者：
Mohsin S;Khan M;Nguyen J;Alkatib M;Siddiqi S;Hariharan N;Wallach K;Monsanto M;Gude N;Dembitsky W;Sussman MA
通讯作者：
Sussman MA
影响因子：
64.5
作者：
Sakaue-Sawano, Asako;Kurokawa, Hiroshi;Miyawaki, Atsushi
通讯作者：
Miyawaki, Atsushi
DOI：
10.1073/pnas.1017935108
发表时间：
2011-04-12
影响因子：
11.1
作者：
Avitabile, Daniele;Bailey, Brandi;Sussman, Mark A.
通讯作者：
Sussman, Mark A.