The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, and Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, China (Yan Li, L.H., X.H., H.Z., S.Z., W.P., X.T., Yi Li, Q.L., W.Y., L.Z., X.L., K.L., J.T., H.Z., B.Z.).
Cardiovascular Division, British Heart Foundation Centre, King's College London, United Kingdom (S.I.B. Q.X.).
Circulation. 2018 Aug 21;138(8):793-805. doi: 10.1161/CIRCULATIONAHA.118.034250.
Whether the adult mammalian heart harbors cardiac stem cells for regeneration of cardiomyocytes is an important yet contentious topic in the field of cardiovascular regeneration. The putative myocyte stem cell populations recognized without specific cell markers, such as the cardiosphere-derived cells, or with markers such as Sca1, Bmi1, Isl1, or Abcg2 cardiac stem cells have been reported. Moreover, it remains unclear whether putative cardiac stem cells with unknown or unidentified markers exist and give rise to de novo cardiomyocytes in the adult heart.
To address this question without relying on a particular stem cell marker, we developed a new genetic lineage tracing system to label all nonmyocyte populations that contain putative cardiac stem cells. Using dual lineage tracing system, we assessed whether nonmyocytes generated any new myocytes during embryonic development, during adult homeostasis, and after myocardial infarction. Skeletal muscle was also examined after injury for internal control of new myocyte generation from nonmyocytes.
By this stem cell marker-free and dual recombinases-mediated cell tracking approach, our fate mapping data show that new myocytes arise from nonmyocytes in the embryonic heart, but not in the adult heart during homeostasis or after myocardial infarction. As positive control, our lineage tracing system detected new myocytes derived from nonmyocytes in the skeletal muscle after injury.
This study provides in vivo genetic evidence for nonmyocyte to myocyte conversion in embryonic but not adult heart, arguing again the myogenic potential of putative stem cell populations for cardiac regeneration in the adult stage. This study also provides a new genetic strategy to identify endogenous stem cells, if any, in other organ systems for tissue repair and regeneration.
成年哺乳动物心脏是否存在用于心肌细胞再生的心脏干细胞，是心血管再生领域一个重要但有争议的话题。已经报道了一些没有特定细胞标志物（如心脏球体细胞）或具有标志物（如 Sca1、Bmi1、Isl1 或 Abcg2 心脏干细胞）的假定心肌干细胞群体。此外，尚不清楚是否存在具有未知或未识别标志物的假定心脏干细胞，并且它们是否在成年心脏中产生新的心肌细胞。
为了解决这个问题，我们不依赖于特定的干细胞标志物，开发了一种新的遗传谱系追踪系统来标记所有包含假定心脏干细胞的非心肌细胞群体。我们使用双谱系追踪系统来评估非心肌细胞在胚胎发育、成年期稳态和心肌梗死后是否产生新的心肌细胞。还检查了骨骼肌损伤后的情况，以作为非心肌细胞产生新心肌细胞的内部对照。
通过这种无干细胞标志物和双重组酶介导的细胞追踪方法，我们的命运图谱数据显示，新的心肌细胞来自胚胎心脏的非心肌细胞，但不在成年心脏的稳态或心肌梗死后产生。作为阳性对照，我们的谱系追踪系统检测到骨骼肌损伤后非心肌细胞衍生的新心肌细胞。
这项研究为胚胎而非成年心脏中非心肌细胞向心肌细胞的转化提供了体内遗传证据，再次证明了假定干细胞群体在成年阶段对心脏再生的成肌潜能。这项研究还提供了一种新的遗传策略，用于鉴定其他器官系统中任何内源性干细胞，如果存在的话，用于组织修复和再生。
