Center for Regenerative Medicine, Udine Medical School, Udine, Italy.
Am J Pathol. 2011 Jul;179(1):349-66. doi: 10.1016/j.ajpath.2011.03.036. Epub 2011 May 19.
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.
目前尚不清楚干细胞的生长和分化缺陷是否导致心肌衰老和慢性心力衰竭 (CHF)，以及在失代偿的心脏中是否存在功能正常的人心肌干细胞 (hCSC) 区室。为了确定衰老和 CHF 是否是心脏生长储备丧失的关键决定因素，评估了 18 个对照和 23 个已植入心脏中 hCSC 的特性。年龄和 CHF 导致功能正常的 hCSC 逐渐减少。年龄是 hCSC 衰老的五个生物标志物的主要预测因素：端粒缩短、端粒酶活性减弱、端粒功能障碍诱导焦点以及 p21(Cip1) 和 p16(INK4a) 的表达。CHF 对 hCSC 也有类似的影响，这表明心肌细胞质量和非衰老 hCSC 池之间平衡的缺陷可能影响失代偿性心肌病的演变。先前已经发现循环骨髓细胞中端粒长度与心血管疾病之间存在相关性，但该分析仅限于细胞群体的平均端粒长度，忽略了这样一个事实，即端粒损耗并非在所有细胞中均匀发生。本研究首次证明了 hCSC 中功能失调的端粒是衰老和心力衰竭的生物标志物。这里确定的细胞衰老生物标志物可用于定义 hCSC 的出生日期，并对具有潜在治疗效果的年轻细胞进行分类。
