Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN, USA.
Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, USA.
FASEB J. 2020 Apr;34(4):5642-5657. doi: 10.1096/fj.201902105R. Epub 2020 Feb 25.
The adult mammalian heart has a limited regenerative capacity. Therefore, identification of endogenous cells and mechanisms that contribute to cardiac regeneration is essential for the development of targeted therapies. The side population (SP) phenotype has been used to enrich for stem cells throughout the body; however, SP cells isolated from the heart have been studied exclusively in cell culture or after transplantation, limiting our understanding of their function in vivo. We generated a new Abcg2-driven lineage-tracing mouse model with efficient labeling of SP cells. Labeled SP cells give rise to terminally differentiated cells in bone marrow and intestines. In the heart, labeled SP cells give rise to lineage-traced cardiomyocytes under homeostatic conditions with an increase in this contribution following cardiac injury. Instead of differentiating into cardiomyocytes like proposed cardiac progenitor cells, cardiac SP cells fuse with preexisting cardiomyocytes to stimulate cardiomyocyte cell cycle reentry. Our study is the first to show that fusion between cardiomyocytes and non-cardiomyocytes, identified by the SP phenotype, contribute to endogenous cardiac regeneration by triggering cardiomyocyte cell cycle reentry in the adult mammalian heart.
成年哺乳动物的心脏再生能力有限。因此，鉴定有助于心脏再生的内源性细胞和机制对于开发靶向治疗至关重要。侧群 (SP) 表型已被用于富集全身的干细胞；然而，从心脏分离的 SP 细胞仅在细胞培养或移植后进行了研究，这限制了我们对其在体内功能的理解。我们生成了一种新的 Abcg2 驱动的谱系示踪小鼠模型，可有效标记 SP 细胞。标记的 SP 细胞在骨髓和肠道中产生终末分化细胞。在心脏中，标记的 SP 细胞在稳态条件下产生谱系追踪的心肌细胞，在心脏损伤后这种贡献增加。与提出的心脏祖细胞不同，心脏 SP 细胞不分化为心肌细胞，而是与预先存在的心肌细胞融合，刺激心肌细胞细胞周期重新进入。我们的研究首次表明，通过触发成年哺乳动物心脏中心肌细胞细胞周期重新进入，由 SP 表型鉴定的心肌细胞和非心肌细胞之间的融合有助于内源性心脏再生。
