Erythropoietin administration after myocardial infarction in mice attenuates ischemic cardiomyopathy associated with enhanced homing of bone marrow‐derived progenitor cells via the CXCR‐4/SDF‐1 axis

Abstract

Mobilization of bone marrow-derived stem cells (BMCs) was shown to have protective effects after myocardial infarction (MI). However, the classical mobilizing agent, granulocyte-colony stimulating factor (G-CSF) relapsed after revealing an impaired homing capacity. In the search for superior cytokines, erythropoietin (EPO) appears to be a promising agent. Therefore, we analyzed in a murine model of surgically induced MI the influence of EPO treatment on survival and functional parameters as well as BMC mobilization, homing, and effect on resident cardiac stem cells (CSCs). Human EPO was injected intraperitoneally after ligation of the left anterior descendens (LAD) for 3 days with a total dose of 5000 IU/kg 6 and 30 days after MI, and pressure volume relationships were investigated in vivo. Cardiac tissues were analyzed by histology. To show the effect on BMCs and CSCs, FACS analyses were performed. Homing factors were analyzed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and ELISA. EPO-treated animals showed a significant improvement of survival post-MI (62 vs. 36%). At days 6 and 30, all hemodynamic parameters associated with attenuated remodeling, enhanced neovascularization, and diminished apoptotic cells in the peri-infarct area were improved. BMC subpopulations (CD31(+), c-kit(+), and Sca-1(+) cells) were mobilized, and homing of Sca-1(+) and CXCR4(+) BMCs toward an SDF-1 gradient into the ischemic myocardium was enhanced. However, there was no beneficial effect on CSCs. We have shown that EPO application after MI shows cardioprotective effects. This may be explained by mobilization of BMCs, which are homing via the CXCR-4/SDF-1 axis. However, EPO has no beneficial effects on resident CSCs. Therefore, new treatment regimes using EPO together with other agents may combine complementary beneficial effects preventing ischemic cardiomyopathy.

Sphingosine kinase regulates the rate of endothelial progenitor cell differentiation

“…The use of EPO is of therapeutic interest for ischemic injury as it is associated with tissue protective effects through activation of EPO receptorrelated antiapoptotic pathways, for example, PI3K/Akt 51 as well as neovascularization of the ischemic tissue. 52 This neovascularization occurs primarily via the CXCR4/SDF-1 axis, which is the key cellular anchor within the BM microenvironment and a pivotal element of EPC mobilization and homing. 52,53 Interestingly, the WT and SK-1-KO groups showed no difference in either the number of Lin Ϫ /ckit ϩ /flk-1 ϩ cells in the BM or their capabilities to migrate toward VEGF.…”

State-of-the-Art Methods for Evaluation of Angiogenesis and Tissue Vascularization

“…There are several models in both small [114][115][116][117] and large animals [118][119][120][121] in which a major coronary artery or multiple branches are occluded for the specific purpose of inducing significant myocardial ischemia and infarction for the subsequent analysis of neovasculogenesis and arteriogenesis in response to experimental therapies (Table 4). These models can entail permanent occlusion or a prolonged occlusion followed by reperfusion.…”

Enhancing the Outcome of Cell Therapy for Cardiac Repair

“…76 Finally, the hematopoietic cytokine erythropoietin, currently being tested in several clinical trials, was shown to mobilize EPCs 77 and to stimulate the recruitment and survival of bone marrow-derived progenitor cells to the heart. 78 Kinases Downstream of the growth factors, antiapoptotic kinases might be additional attractive targets for improving progenitor cell function. Overexpression of Akt, glycogen synthase kinase, and integrin-linked kinase increased the function of delivered cells, probably also as a result of increased survival.…”