Effects of Age and Heart Failure on Human Cardiac Stem Cell Function
Effects of Age and Heart Failure on Human Cardiac Stem Cell Function
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DOI：
10.1016/j.ajpath.2011.03.036
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发表时间：
2011-07-01
影响因子：
6
通讯作者：
Leri, Annarosa
中科院分区：
文献类型：
--
作者：
Cesselli, Daniela;Beltrami, Antonio P.;Leri, Annarosa
目前，尚不清楚干细胞生长和分化缺陷是否导致心肌老化和慢性心力衰竭(CHF)，以及功能正常的人类心脏干细胞(HCSCs)是否在失代偿心脏中持续存在。为了确定衰老和充血性心力衰竭是否是心脏生长储备丧失的关键决定因素，对18例对照和23例移植心脏的hCSCs的特性进行了评估。年龄和CHF显示功能正常的hCSCs逐渐减少。年龄是HCSC衰老的五个生物标志物的主要预测因子：端粒缩短、端粒酶活性减弱、端粒功能障碍引起的病灶以及p21(Cip1)和p16(INK4a)的表达。CHF对hCSCs也有类似的后果，提示心肌细胞质量和非衰老hCSCs池之间的平衡缺陷可能会影响失代偿性肌病的演变。以前发现循环中骨髓细胞的端粒长度与心血管疾病之间存在相关性，但这种分析仅限于细胞群体中的平均端粒长度，而忽略了端粒磨损并不是在所有细胞中都均匀发生的事实。本研究首次证明hCSCs中的端粒功能障碍是衰老和心力衰竭的生物标志物。这些细胞衰老的生物标志物可以用来确定hCSCs的出生日期，并对具有潜在治疗效果的年轻细胞进行分类。(Am J Pathol 2011,179：349-364.Doi：10.1016/j.ajpath.2011.03.036)
Currently, it is unknown whether defects in stem cell growth and differentiation contribute to myocardial aging and chronic heart failure (CHF), and whether a compartment of functional human cardiac stem cells (hCSCs) persists in the decompensated heart. To determine whether aging and CHF are critical determinants of the loss in growth reserve of the heart, the properties of hCSCs were evaluated in 18 control and 23 explanted hearts. Age and CHF showed a progressive decrease in functionally competent hCSCs. Chronological age was a major predictor of five biomarkers of hCSC senescence: telomeric shortening, attenuated telomerase activity, telomere dysfunction-induced foci, and p21(cip1) and p16(INK4a) expression. CHF had similar consequences for hCSCs, suggesting that defects in the balance between cardiomyocyte mass and the pool of nonsenescent hCSCs may condition the evolution of the decompensated myopathy. A correlation was found previously between telomere length in circulating bone marrow cells and cardiovascular diseases, but that analysis was restricted to average telomere length in a cell population, neglecting the fact that telomere attrition does not occur uniformly in all cells. The present study provides the first demonstration that dysfunctional telomeres in hCSCs are biomarkers of aging and heart failure. The biomarkers of cellular senescence identified here can be used to define the birth date of hCSCs and to sort young cells with potential therapeutic efficacy. (Am J Pathol 2011, 179:349-364. DOI: 10.1016/j.ajpath.2011.03.036)