Understanding the spatial and temporal regulation of the βIV-spectrin/STAT3 complex in ischemic cardiac remodeling with spatial transcriptomics.

Histology at 7 days post-MI shows improper scar formation with incomplete clearance compared to WT. Therefore, we hypothesized that stress-induced loss of βIV-spectrin in CFs coordinates spatial and temporal regulation of multiple cardiac cell populations to ensure proper healing. In this study, we subjected WT and qv3J mice to MI and assessed cardiac function and survival through 28 days and performed spatial transcriptomics at 7 days.

Cell-type deconvolution from spatial transcriptomics analysis revealed dramatic differences in CF populations, with a decrease in the Cthrc1 CF population in qv3J hearts compared to WT. A STAT3-dependent fibroblast trajectory was identified that originates from vascular smooth muscle cells and progresses to Chtrc1 CF population in WT hearts, while qv3J fibroblast trajectory diverged into a more senescent-like state. The border zone in qv3J hearts showed a congregation of immune cells and fibroblasts that could not infiltrate the infarct zone, leading to high concentrations of MMPs at the location where rupture occurs in these mice.

Aberrant CXCL12 signaling was observed in qv3J mice, explaining the lack of infarct zone infiltration. Our work identifies a novel role for spectrin-based STAT3 regulation in facilitating spatial and temporal remodeling in response to ischemic stress.