Brunner Rachel, Lai Hsiao-Lei, Deliu Zane, Melman Elan, Geenen David L, Wang Q Tian
Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA.
PTM Biolabs Inc., Chicago, IL 60612, USA.
J Dev Biol. 2016 Nov 3;4(4):32. doi: 10.3390/jdb4040032.
Heart attacks affect more than seven million people worldwide each year. A heart attack, or myocardial infarction, may result in the death of a billion cardiomyocytes within hours. The adult mammalian heart does not have an effective mechanism to replace lost cardiomyocytes. Instead, lost muscle is replaced with scar tissue, which decreases blood pumping ability and leads to heart failure over time. Here, we report that the loss of the chromatin factor ASXL2 results in spontaneous proliferation and cardiogenic differentiation of a subset of interstitial non-cardiomyocytes. The adult heart displays spontaneous overgrowth without cardiomyocyte hypertrophy. Thymidine analog labeling and Ki67 staining of 12-week-old hearts revealed 3- and 5-fold increases of proliferation rate for vimentin⁺ non-cardiomyocytes in over age- and sex-matched wildtype controls, respectively. Approximately 10% of proliferating non-cardiomyocytes in the heart express the cardiogenic marker NKX2-5, a frequency that is ~7-fold higher than that observed in the wildtype. EdU lineage tracing experiments showed that ~6% of pulsed-labeled non-cardiomyocytes in hearts differentiate into mature cardiomyocytes after a four-week chase, a phenomenon not observed for similarly pulse-chased wildtype controls. Taken together, these data indicate de novo cardiomyocyte production in the heart due to activation of a population of proliferative cardiogenic non-cardiomyocytes. Our study suggests the existence of an epigenetic barrier to cardiogenicity in the adult heart and raises the intriguing possibility of unlocking regenerative potential via transient modulation of epigenetic activity.
每年全球有超过700万人遭受心脏病发作。心脏病发作，即心肌梗死，可能在数小时内导致10亿心肌细胞死亡。成年哺乳动物的心脏没有有效的机制来替代丢失的心肌细胞。相反，丢失的肌肉会被瘢痕组织取代，这会降低血液泵送能力，并随着时间的推移导致心力衰竭。在此，我们报告染色质因子ASXL2的缺失导致间质非心肌细胞亚群的自发增殖和心脏发生分化。成年心脏表现出自发性过度生长，而没有心肌细胞肥大。对12周龄心脏进行胸苷类似物标记和Ki67染色显示，与年龄和性别匹配的野生型对照相比，波形蛋白阳性非心肌细胞的增殖率分别增加了3倍和5倍。心脏中约10%的增殖非心肌细胞表达心脏发生标志物NKX2-5，这一频率比野生型中观察到的高约7倍。EdU谱系追踪实验表明，在为期四周的追踪后，心脏中约6%的脉冲标记非心肌细胞分化为成熟心肌细胞，而类似脉冲追踪的野生型对照未观察到这种现象。综上所述，这些数据表明由于一群增殖性心脏发生非心肌细胞的激活，心脏中产生了新生心肌细胞。我们的研究表明成年心脏中存在心脏发生的表观遗传障碍，并提出了通过短暂调节表观遗传活性来释放再生潜力的有趣可能性。
