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Therapeutic effects of paracrine factors secreted by human umbilical cord blood mononuclear cells in myocardial infarctions
Paracrine effects of cord blood cells

1 University of South Florida, 13201 Bruce B. Downs Blvd, Tampa, Florida
2 The University of South Florida and First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

Stem cell paracrine factors are beneficial in myocardial infarction (MI) treatment. However, specific stem cell factor effects on myocardial cytokines and their molecular pathways have not been precisely identified. We treated 44 rats with MIs with intramyocardial Isolyte or 4 × 106 human umbilical cord blood mononuclear cells (hUCBC) without immune suppression. We measured infarct sizes and myocardial cytokines. We then stressed isolated myocytes with H2O2 to simulate MIs in the absence and presence of paracrine factors from hypoxic hUCBC. We measured myocyte Akt protein kinase, which causes survival, and JNK and p38 protein kinases, which cause myocyte death. In Isolyte treated MIs, TNF-α increased from 6.1% to 51.3%, MCP increased from 5.6% to 39.8%, MIP increased from 8.1% to 25.9%, and IL-1 increased from 7.1% to 20.0%. In hUCBC treated MIs, inflammatory cytokines did not change and there was no hUCBC rejection. MI sizes averaged 30% in Isolyte treated rats and 10% in hUCBC treated rats (p < 0.01). Hypoxic hUCBC increased secretion of HGF by 338%, IGF by 200%, VEGF by 192%, PGF by 150%, IL-10 by 150%, and SCF and TIMP by 100% in comparison with non-stressed hUCBC (p < 0.001). H2O2 increased myocyte activation of JNK by 297% and p38 by 83% and increased myocyte necrosis by >60% (all p < 0.01 vs. normal myocytes). In myocytes treated with H2O2 and hUCBC paracrine factors, JNK and p38 activation decreased by ≥ 40%, while Akt activation and myocyte viability increased by >100% (all p < 0.01 vs. myocytes with H2O2) The Akt inhibitor API prevented hUCBC paracrine factor effects on myocytes. Addition of the JNK inhibitor SP600125 or p38 inhibitor SB203580 to myocytes with H2O2 plus hUCBC factors increased myocyte viability. We conclude that hUCBC secrete growth factors and anti-inflammatory cytokines that increase myocyte Akt activation and myocyte survival and decrease myocyte JNK, p38 and myocyte death in MIs.
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