Adult multipotent stromal cells (MSCs) may repair tissue through the action of secreted factors on endogenous stem/progenitor cells. We determined the effects of MSC-secreted factors on adult cardiac progenitor cells (CPCs). Serum-free conditioned medium (CdM) was collected from MSCs isolated by plastic adherence (MSCs) and by magnetic sorting against the p75 nerve-growth factor receptor (p75MSCs). Compared to serum-free medium (α -MEM), CdM significantly increased adult rat CPC proliferation in a concentration-dependent manner, led to phosphorylation (Tyr705 ) and nuclear localization of signal transducer and activator of transcription 3 (STAT3) and was blocked by both AG490, a Janus kinase 2 (Jak2)/STAT3 inhibitor, and Stattic, a specific STAT3 (Tyr705 ) inhibitor. Also signaling through Jak2/STAT3, MSC CdM cytoprotective factors significantly increased survival of hypoxic CPCs compared to α -MEM. Intra-arterial infusion of p75MSC CdM 24 hours after myocardial infarction (MI) in mice significantly reduced myocardial necrosis at 48 hours after MI compared to α -MEM (vehicle). Echocardiography at 1 week after MI demonstrated significantly better cardiac function in p75MSC CdM-treated mice compared to controls. Thus in vivo benefits of MSCs may be derived in part by the action of their secreted factors on CPCs. Epicardial-derived cells are required for cardiac development, support myogenesis through secreted factors and participate in repair and remodeling after injury. We tested whether factors secreted by epicardial-derived precursor cells (EPDCs) would protect jeopardized ischemic myocardium after myocardial infarction and reperfusion (MI-I4R). Human epicardial progenitor cells, isolated from right atrial appendages removed during cardiac bypass surgery, were keratin-positive, epithelial in morphology and expressed TFs associated with proepicardium, epicardium and cardiac development. Upon progenitor cell epithelial-mesenchymal transition (EMT) into EPDCs, concentrated conditioned medium (EPI CdM) was generated. When compared to α -MEM (vehicle), intra-arterial infusion of human EPI CdM led to a reduction in infarct size of 50% in both immunodeficient and immunocompetent MI-I4R mice and improved cardiac function. These in vivo results were evident as early as 24 hours after MI, sustained for at least 1 month, and may derive in part through paracrine protection of jeopardized coronary microvasculature. Our results indicate that EPI CdM or a combination of its ligands may provide an effective treatment for MI. / acase@tulane.edu
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_27778 |
| Date | January 2014 |
| Contributors | Poole, Charla (Author), Landry, Samuel (Thesis advisor), Prockop, Darwin J. (Thesis advisor) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Format | 146 |
| Rights | Copyright is in accordance with U.S. Copyright law |
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