Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Dev Cell. 2019 Mar 25;48(6):765-779.e7. doi: 10.1016/j.devcel.2019.01.017. Epub 2019 Feb 14.
Specialized adult somatic cells, such as cardiomyocytes (CMs), are highly differentiated with poor renewal capacity, an integral reason underlying organ failure in disease and aging. Among the least renewable cells in the human body, CMs renew approximately 1% annually. Consistent with poor CM turnover, heart failure is the leading cause of death. Here, we show that an active version of the Hippo pathway effector YAP, termed YAP5SA, partially reprograms adult mouse CMs to a more fetal and proliferative state. One week after induction, 19% of CMs that enter S-phase do so twice, CM number increases by 40%, and YAP5SA lineage CMs couple to pre-existing CMs. Genomic studies showed that YAP5SA increases chromatin accessibility and expression of fetal genes, partially reprogramming long-lived somatic cells in vivo to a primitive, fetal-like, and proliferative state.
成体特异性体细胞，如心肌细胞（CMs），高度分化，更新能力差，这是疾病和衰老导致器官衰竭的一个重要原因。在人体内更新能力最差的细胞中，CM 每年大约更新 1%。与 CM 更替不良一致，心力衰竭是主要的死亡原因。在这里，我们发现 Hippo 通路效应物 YAP 的一种活性形式，称为 YAP5SA，可部分将成年小鼠的 CMs 重新编程为更具胎儿和增殖状态。诱导后 1 周，有 19%的进入 S 期的 CMs 会进行两次分裂，CM 数量增加 40%，并且 YAP5SA 谱系的 CMs 与预先存在的 CMs 偶联。基因组研究表明，YAP5SA 增加了染色质的可及性和胎儿基因的表达，部分将长寿的体细胞在体内重新编程为原始的、胎儿样的和增殖状态。
