Abstract Body (Do not enter title and authors here): Adverse fibrotic remodeling contributes to high morbidity and mortality in patients following myocardial infarction (MI). Healing after MI requires necrotic tissue to be cleared and replaced with fibrosis, which is driven by the coordinated effort of several distinct cardiac cell populations, including myocytes, immune cells, and cardiac fibroblasts (CFs). While a myriad of stimuli driving fibrotic remodeling post-MI have been identified, the contribution of specific cell populations to the signaling cascade and how these communication networks are tuned in response to chronic stress remains unclear. The cytoskeletal protein, β_IV-spectrin, coordinates a signaling complex with the transcription factor, STAT3 to modulate CF activation and profibrotic signaling. Specifically, stress-induced loss of β_IV-spectrin promotes subcellular redistribution and activation of STAT3 in CFs that increases secretion of profibrotic and proinflammatory factors. Mice expressing degradation-resistant β_IV-spectrin (qv^3J) show increased mortality and incidence of cardiac rupture within the first week after permanent occlusion of the left anterior descending (LAD) artery. Histology at 7 days post-MI shows improper scar formation with incomplete clearance compared to WT. Therefore, we hypothesized that stress-induced loss of β_IV-spectrin in CFs coordinates spatial and temporal regulation of multiple cardiac cell populations to ensure proper healing. In this study, we subjected WT and qv^3J 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 qv^3J 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 qv^3J fibroblast trajectory diverged into a more senescent-like state. The border zone in qv^3J 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 qv^3J 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.