Genetic Lineage Tracing of Nonmyocyte Population by Dual Recombinases
Genetic Lineage Tracing of Nonmyocyte Population by Dual Recombinases
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双重组酶对非肌细胞群的遗传谱系追踪
DOI：
10.1161/circulationaha.118.034250
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发表时间：
2018-08-21
期刊：
影响因子：
37.8
通讯作者：
Zhou, Bin
中科院分区：
文献类型：
--
作者：
Li, Yan;He, Lingjuan;Zhou, Bin
背景资料：成年哺乳动物心脏中是否存在心肌干细胞是心血管再生领域的一个重要而有争议的话题。已经报道了在没有特异性细胞标志物的情况下识别的推定的肌细胞干细胞群，例如心圈衍生的细胞，或具有标志物的心肌干细胞群，例如Sca 1+、Bmi 1+、Isl 1+或Abcg 2+心肌干细胞。此外，目前还不清楚是否存在具有未知或未鉴定标记的假定心脏干细胞，并在成人心脏中产生新生心肌细胞。研究方法：为了解决这个问题，而不依赖于一个特定的干细胞标记，我们开发了一个新的遗传谱系追踪系统，以标记所有非肌细胞群体含有推定的心脏干细胞。利用双谱系示踪系统，我们评估了非肌细胞是否产生任何新的心肌细胞在胚胎发育期间，在成人稳态，心肌梗死后。骨骼肌损伤后也检查了新的心肌细胞从非肌细胞生成的内部控制。结果如下：通过这种无干细胞标记和双重组酶介导的细胞追踪方法，我们的命运作图数据显示，新的心肌细胞来自胚胎心脏中的非心肌细胞，但在体内平衡期间或心肌梗死后的成人心脏中并非如此。作为阳性对照，我们的谱系追踪系统检测到新的肌细胞来源于骨骼肌损伤后的非肌细胞。结论：这项研究提供了在胚胎，但不是成人心脏的非肌细胞转化为肌细胞的体内遗传学证据，再次论证了推定的干细胞群体在成人阶段的心脏再生的肌原性潜力。这项研究还提供了一种新的遗传策略，以确定内源性干细胞，如果有的话，在其他器官系统的组织修复和再生。
Background: 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. Methods: 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. Results: 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. Conclusions: 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.