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Hobby ARH , Berretta RM , Eaton DM , Kubo H , Feldsott E , Yang Y , Headrick AL , Koch KA , Rubino M , Kurian J , Khan M , Tan Y , Mohsin S , Gallucci S , McKinsey TA , Houser SR
Cortical Bone Stem Cells Modify Cardiac Inflammation After Myocardial Infarction By Inducing a Novel Macrophage Phenotype
Am J Physiol Heart Circ Physiol. 2021 Oct 1;321(4) :H684-H701
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Acute damage to the heart, as in the case of myocardial infarction (MI), triggers a robust inflammatory response to the sterile injury that is part of a complex and highly organized wound healing process. Cortical bone stem cell (CBSC) therapy after MI has been shown to reduce adverse structural and functional remodeling of the heart after MI in both mouse and swine models. The basis for these CBSC treatment effects on wound healing are unknown. The present experiments show that CBSCs secrete paracrine factors known to have immunomodulatory properties, most notably Macrophage Colony Stimulating Factor (M-CSF) and Transforming Growth Factor-b, but not IL-4. CBSC therapy increased the number of Galectin-3+ macrophages, CD4+ T-cells, and fibroblasts in the heart while decreasing apoptosis in an in vivo swine model of MI. Macrophages treated with CBSC medium in vitro polarized to a pro-reparative phenotype characterized by increased CD206 expression, increased efferocytic ability, increased IL-10, TGF-b, and IL-1RA secretion, and increased mitochondrial respiration. Next generation sequencing revealed a transcriptome significantly different from M2a or M2c macrophage phenotypes. Paracrine factors from CBSC-treated macrophages increased proliferation, decreased a-Smooth Muscle Actin expression, and decreased contraction by fibroblasts in vitro. These data support the idea that CBSCs are modulating the immune response to MI to favor cardiac repair through a unique macrophage polarization that ultimately reduces cell death and alters fibroblast populations that may result in smaller scar size and preserved cardiac geometry and function.
1522-1539 Hobby, Alexander R H Berretta, Remus M Eaton, Deborah M Kubo, Hajime Feldsott, Eric Yang, Yijun Headrick, Alaina L Koch, Keith A Rubino, Marcello Kurian, Justin Khan, Mohsin Tan, Yinfei Mohsin, Sadia Gallucci, Stefania McKinsey, Timothy A Houser, Steven R 18PRE33960122/American Heart Association (AHA)/ 5R01HL139960-03/HHS | National Institutes of Health (NIH)/ 5P01HL134608-04/HHS | National Institutes of Health (NIH)/ Journal Article United States Am J Physiol Heart Circ Physiol. 2021 Aug 20. doi: 10.1152/ajpheart.00304.2021.