This work demonstrates that CD73 on T cells plays a crucial role in the cardiac wound healing process after myocardial infarction. The underlying mechanism involves a profound increase in the hydrolysis of ATP/NAD and AMP, resulting primarily from the upregulation of pyrophosphatases and CD73. We also define AR/AR-mediated autacoid feedback inhibition of proinflammatory/profibrotic cytokines by T cell-derived CD73.
Type I IFN play a very important role in immunity against viral infections. Murine type I IFN belongs to a multigene family including 14 IFN-a subtypes but the biological functions of IFN-a subtypes in retroviral infections are unknown. We have used the Friend retrovirus model to determine the anti-viral effects of IFN-a subtypes in vitro and in vivo. IFN-a subtypes a1, a4, a6 or a9 suppressed Friend virus (FV) replication in vitro, but differed greatly in their anti-viral efficacy in vivo. Treatment of FV-infected mice with the IFN-a subtypes a1, a4 or a9, but not a6 led to a significant reduction in viral loads. Decreased splenic viral load after IFN-a1 treatment correlated with an expansion of activated FV-specific CD8 1 T cells and NK cells into the spleen, whereas in IFN-a4-and -a9-treated mice it exclusively correlated with the activation of NK cells. The results demonstrate the distinct anti-retroviral effects of different IFN-a subtypes, which may be relevant for new therapeutic approaches.
In the adult heart, the epicardium becomes activated after injury, contributing to cardiac healing by secretion of paracrine factors. Here, we analyzed by single-cell RNA sequencing combined with RNA in situ hybridization and lineage tracing of Wilms tumor protein 1-positive (WT1+) cells, the cellular composition, location, and hierarchy of epicardial stromal cells (EpiSC) in comparison to activated myocardial fibroblasts/stromal cells in infarcted mouse hearts. We identified 11 transcriptionally distinct EpiSC populations, which can be classified into three groups, each containing a cluster of proliferating cells. Two groups expressed cardiac specification markers and sarcomeric proteins suggestive of cardiomyogenic potential. Transcripts of hypoxia-inducible factor (HIF)-1α and HIF-responsive genes were enriched in EpiSC consistent with an epicardial hypoxic niche. Expression of paracrine factors was not limited to WT1+ cells but was a general feature of activated cardiac stromal cells. Our findings provide the cellular framework by which myocardial ischemia may trigger in EpiSC the formation of cardioprotective/regenerative responses.
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