Dissertation/Thesis Abstract

Cardiovascular therapeutics derived from the paracrine biology of adult human progenitor cells
by Poole, Charla N., Ph.D., Tulane University, 2014, 146; 3628932
Abstract (Summary)

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 pro-epicardium, epicardium and cardiac development. Upon progenitor cell epithelial-mesenchymal transition (EMT) into EPDCs, concentrated conditioned medium (EPI CdM) was generated. When compared to á-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.

Indexing (document details)
Advisor: Prockop, Darwin J., Landry, Samuel J.
Commitee: Blake, Diane A., Bunnell, Bruce A., Kelm, Robert F., Morris, Gilbert F.
School: Tulane University
Department: Biochemistry
School Location: United States -- Louisiana
Source: DAI-B 75/11(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Molecular biology, Cellular biology, Biochemistry
Keywords: Conditioned medium, Epicardial-derived precursor cells, Myocardial infarction, Progenitor cell
Publication Number: 3628932
ISBN: 9781321055597
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