Abstract
The pericardium plays an important homeostatic role for the neighboring heart, providing both lubrication and structural support. In vivo models have further identified a protective role for the pericardium in modulating cardiac remodeling following myocardial infarction, possibly through the actions of tissue-resident pericardial macrophages. Using patient-derived pericardial samples, we establish that human pericardial immune cells directly inhibit cardiac fibroblast fibrotic activity, and this action is dampened following myocardial infarction. Using single-cell RNA sequencing of patient pericardial fluid cells, we identify two pericardial macrophage subsets that are uniquely altered in response to myocardial infarction, which contributes to a shift in their effector molecule expression profiles. We confirm that fibronectin-expressing human pericardial macrophages are the primary driver of the pericardial antifibrotic actions through the release of cystatin C. Finally, we establish cystatin C as a myeloid cell–derived cardioprotective effector molecule in an in vivo model of myocardial infarction. Collectively, we uncover a molecular mechanism of the local immune environment that regulates cardiac remodeling after myocardial infarction.
Authors
Ali Fatehi Hassanabad, Sarthak Sinha, Arzina Jaffer, Darrell Belke, Nicole L. Rosin, Elodie Labit, Daniel Young, Friederike I. Schoettler, Keerthana Chockalingam, Benjamin Haeyul Lee, Jameson A. Dundas, Emilie de Chantal, Carmina A. Isidoro, Alexander Tam, Hanjoo B. Shim, Anna N. Zarzycki, Afshin Derakhshani, Elisabeth Gorgiogianni, Jeannine D. Turnbull, Antoine Dufour, Shalina S. Ousman, Jeff A. Biernaskie, Paul W.M. Fedak, Justin F. Deniset
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