Spatiotemporal transcriptome analysis reveals critical roles for mechano-sensing genes at the border zone in remodeling after myocardial infarction
Shintaro Yamada, Toshiyuki Ko, Satoshi Hatsuse, Seitaro Nomura, Bo Zhang, Zhehao Dai, Shunsuke Inoue, Masayuki Kubota, Kosuke Sawami, Takanobu Yamada, Tatsuro Sassa, Mikako Katagiri, Kanna Fujita, Manami Katoh, Masamichi Ito, Mutsuo Harada, Haruhiro Toko, Norifumi Takeda, Hiroyuki Morita, Hiroyuki Aburatani, Issei Komuro
Abstract
The underlying mechanisms of ventricular remodeling after myocardial infarction (MI) remain largely unknown. In this study, we performed an integrative analysis of spatial transcriptomics and single-nucleus RNA sequencing (snRNA-seq) in a murine MI model and found that mechanical stress-response genes are expressed at the border zone and play a critical role in left ventricular remodeling after MI. An integrative analysis of snRNA-seq and spatial transcriptome of the heart tissue after MI identified the unique cluster that appeared at the border zone in an early stage, highly expressing mechano-sensing genes, such as Csrp3. AAV9-mediated gene silencing and overexpression of Csrp3 demonstrated that upregulation of Csrp3 plays critical roles in preventing cardiac remodeling after MI by regulation of genes associated with mechano-sensing. Overall, our study not only provides an insight into spatiotemporal molecular changes after MI but also highlights that the mechano-sensing genes at the border zone act as adaptive regulators of left ventricular remodeling.