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Abstract 704: Profiling Differential Response to Myocardial Infarction by Single Cell Analysis of the Cardiac Interstitium


 Myocardial infarction (MI) is one of the main causes of mortality in Western Countries. The non-regenerative adult mammalian heart responds to injury with the formation of a scar. The outcome of repair is highly dependent on interstitial cells and on the delicate interplay between the inflammatory response and fibrosis, which leads to adverse ventricular remodeling and heart failure or cardiac rupture in the early phase post-injury. Our data show that inbred mice strains have different reliance to MI, suggesting differences in the cellular response to the injury. To profile the dynamic response of cardiac interstitial cells to MI and their embryological origin, we performed unbiased scRNAseq analysis of cardiac interstitial cells at homeostasis and 1, 3, 5, 7, 14, 28 days post-injury from transgenic mice on C57bl/6j background (B6), expressing ZsGreen under the control of the epicardial marker Wt1 (
 
 Wt1
 Cre
 ;RosaZsgreen
 f/+
 )
 
 . About 38,600 cells were captured using the 10xChromium technology and we distinguished 16 main cell populations that evolved over time. By high resolution sub-clustering of stromal cells, 7 main subpopulations were identified. Of these, one was endocardial derived and present at all time points, the others were epicardial derived (ZsGreen+) and included 3 populations of fibroblasts present at different frequencies at all time points, a transient population of immune-response activating fibroblasts (IR) prevailing at day1 and preceding the appearance of myofibroblasts between day 3 and 7 and matrifibrocytes prevalent at day 14 and day 28. To determine the role of cell composition in different reparative outcomes, we compared the data on the C57BL/6J background with 129S1/SvlmJ (129), the inbred strain presenting the highest frequency of cardiac rupture (70%) among the 9 tested. We observed increased number of activated IR and myofibroblasts in 129 3 days post-MI. 129 also showed higher level of collagens, chemokines, fibrin deposition and acute phase response genes. The hyperactivation of myofibroblasts was possibly mediated by the enhanced responsiveness to the Renin-Angiotensin System, currently one of the main targets of clinical therapies.
