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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.

Purpose of Review: Cardiovascular diseases are the leading cause of death worldwide, largely due to the limited regenerative capacity of the adult human heart. In contrast, teleost zebrafish hearts possess natural regeneration capacity by proliferation of pre-existing cardiomyocytes after injury. Hearts of mice can regenerate if injured in a few days after birth, which coincides with the transient capacity for cardiomyocyte proliferation. This review tends to elaborate the roles and mechanisms of Wnt/β-catenin signaling in heart development and regeneration in mammals and non-mammalian vertebrates. Recent Findings: Studies in zebrafish, mice, and human embryonic stem cells demonstrate the binary effect for Wnt/β-catenin signaling during heart development. Both Wnts and Wnt antagonists are induced in multiple cell types during cardiac development and injury repair. In this review, we summarize composites of the Wnt signaling pathway and their different action routes, followed by the discussion of their involvements in cardiac specification, proliferation, and patterning. We provide overviews about canonical and non-canonical Wnt activity during heart homeostasis, remodeling, and regeneration. Summary: Wnt/β-catenin signaling exhibits biphasic and antagonistic effects on cardiac specification and differentiation depending on the stage of embryogenesis. Inhibition of Wnt signaling is beneficial for cardiac wound healing and functional recovery after injury. Understanding of the roles and mechanisms of Wnt signaling pathway in injured animal hearts will contribute to the development of potential therapeutics for human diseased hearts. [ABSTRACT FROM AUTHOR]

The human heart has a markedly low regenerative capacity, leaving patients who suffered from cardiac insults vulnerable to heart failure. The inability to regenerate lost myocardium is accompanied by extensive remodeling that leads to further deterioration in cardiac functions and structure. Although adult mammals seem to lack the ability to regenerate, some lower vertebrates have a cardio-regenerative potential. Emerging studies revealed that mammals do have the ability to undergo endogenous cardiac regeneration during development and shortly after birth. Later, it was proven that the source of the new cardiomyocytes is the proliferation of the pre-existing cardiomyocyte pool. Research is currently focused on finding suitable methods to restore this lost potential in adulthood and enhancing the proliferative capacity of cardiomyocytes. Long non-coding RNAs (lncRNAs) are critical functionally diverse epigenetic regulators capable of either activating or repressing gene expression. LncRNAs have been previously implicated in cardiac development, lineage commitment, and aging. Recent reports suggest that lncRNAs are capable of inducing endogenous cardiac regeneration through manipulating gene expression in cardiomyocytes. This review gives a concise overview of endogenous cardiac regeneration. It further summarizes and critically appraises the current literature on the roles of lncRNAs in endogenous cardiac regeneration and the challenges that face the field. [ABSTRACT FROM AUTHOR]