O'Meara Caitlin C, Wamstad Joseph A, Gladstone Rachel A, Fomovsky Gregory M, Butty Vincent L, Shrikumar Avanti, Gannon Joseph B, Boyer Laurie A, Lee Richard T
From the Harvard Stem Cell Institute, the Brigham Regenerative Medicine Center, and the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, and the Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA (C.C.O.M., R.A.G., G.M.F., J.B.G., R.T.L.); and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA (J.A.W., V.L.B., A.S., L.A.B.).
Circ Res. 2015 Feb 27;116(5):804-15. doi: 10.1161/CIRCRESAHA.116.304269. Epub 2014 Dec 4.
Neonatal mice have the capacity to regenerate their hearts in response to injury, but this potential is lost after the first week of life. The transcriptional changes that underpin mammalian cardiac regeneration have not been fully characterized at the molecular level.
The objectives of our study were to determine whether myocytes revert the transcriptional phenotype to a less differentiated state during regeneration and to systematically interrogate the transcriptional data to identify and validate potential regulators of this process.
We derived a core transcriptional signature of injury-induced cardiac myocyte (CM) regeneration in mouse by comparing global transcriptional programs in a dynamic model of in vitro and in vivo CM differentiation, in vitro CM explant model, as well as a neonatal heart resection model. The regenerating mouse heart revealed a transcriptional reversion of CM differentiation processes, including reactivation of latent developmental programs similar to those observed during destabilization of a mature CM phenotype in the explant model. We identified potential upstream regulators of the core network, including interleukin 13, which induced CM cell cycle entry and STAT6/STAT3 signaling in vitro. We demonstrate that STAT3/periostin and STAT6 signaling are critical mediators of interleukin 13 signaling in CMs. These downstream signaling molecules are also modulated in the regenerating mouse heart.
Our work reveals new insights into the transcriptional regulation of mammalian cardiac regeneration and provides the founding circuitry for identifying potential regulators for stimulating heart regeneration.
新生小鼠的心脏具有在受到损伤时进行再生的能力，但这种潜能在出生后的第一周后就会丧失。在分子水平上，支撑哺乳动物心脏再生的转录变化尚未得到充分表征。
我们研究的目的是确定心肌细胞在再生过程中是否会将转录表型转变为分化程度较低的状态，并系统地分析转录数据，以识别和验证这一过程的潜在调节因子。
通过比较体外和体内心肌细胞分化的动态模型、体外心肌外植体模型以及新生小鼠心脏切除模型中的整体转录程序，我们得出了小鼠损伤诱导的心肌细胞（CM）再生的核心转录特征。再生的小鼠心脏显示出CM分化过程的转录逆转，包括类似于在外植体模型中成熟CM表型不稳定期间观察到的潜在发育程序的重新激活。我们确定了核心网络的潜在上游调节因子，包括白细胞介素13，其在体外诱导CM细胞周期进入和STAT6/STAT3信号传导。我们证明STAT3/骨膜蛋白和STAT6信号传导是白细胞介素13在CMs中信号传导的关键介质。这些下游信号分子在再生的小鼠心脏中也受到调节。
我们的工作揭示了对哺乳动物心脏再生转录调控的新见解，并为识别刺激心脏再生的潜在调节因子提供了基础电路。
