Abstract
IntroductionChemokine-directed migration is crucial for homing of regenerative cells to the infarcted heart and correlates with outcomes of cell therapy trials. Hence, transplantation of chemokine-responsive bone marrow cells may be ideal for treatment of myocardial ischemia. To verify the therapeutic activity of bone marrow mononuclear cells (BM-MNCs) selected by in vitro migration towards the chemokine stromal cell-derived factor-1 (SDF-1) in a mouse model of myocardial infarction (MI), we used BM-MNCs from patients with previous large MI recruited in the TransACT-1&2 cell therapy trials.MethodsUnfractioned BM-MNCs, SDF-1-responsive, and SDF-1-nonresponsive BM-MNCs isolated by patients recruited in the TransACT-1&2 cell therapy trials were tested in Matrigel assay to evaluate angiogenic potential. Secretome and antigenic profile were characterized by flow cytometry. Angiogenin expression was measured by RT-PCR. Cells groups were also intramyocardially injected in an in vivo model of MI (8-week-old immune deficient CD1-FOXN1nu/nu mice). Echocardiography and hemodynamic measurements were performed before and at 14 days post-MI. Arterioles and capillaries density, infiltration of inflammatory cells, interstitial fibrosis, and cardiomyocyte proliferation and apoptosis were assessed by immunohistochemistry.ResultsIn vitro migration enriched for monocytes, while CD34+ and CD133+ cells and T lymphocytes remained mainly confined in the non-migrated fraction. Unfractioned total BM-MNCs promoted angiogenesis on Matrigel more efficiently than migrated or non-migrated cells. In mice with induced MI, intramyocardial injection of unfractionated or migrated BM-MNCs was more effective in preserving cardiac contractility and pressure indexes than vehicle or non-migrated BM-MNCs. Moreover, unfractioned BM-MNCs enhanced neovascularization, whereas the migrated fraction was unique in reducing the infarct size and interstitial fibrosis. In vitro studies on isolated cardiomyocytes suggest participation of angiogenin, a secreted ribonuclease that inhibits protein translation under stress conditions, in promotion of cardiomyocyte survival by migrated BM-MNCs.ConclusionsTransplantation of bone marrow cells helps post-MI healing through distinct actions on vascular cells and cardiomyocytes. In addition, the SDF-1-responsive fraction is enriched with angiogenin-expressing monocytes, which may improve cardiac recovery through activation of cardiomyocyte response to stress. Identification of factors linking migratory and therapeutic outcomes could help refine regenerative approaches.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0028-y) contains supplementary material, which is available to authorized users.
Highlights
Chemokine-directed migration is crucial for homing of regenerative cells to the infarcted heart and correlates with outcomes of cell therapy trials
We reported that peripheral blood (PB) MNCs that migrate in response to chemoattractants such as stromal cell-derived factor 1 (SDF-1) or bradykinin are enriched for CD133+ and CD34+ progenitor cell (PC), release higher amounts of pro-angiogenic cytokines, and generate more nitric oxide and less superoxide in comparison with non-migrated PB-MNCs [23,24]
Stromal cell-derived factor 1-induced migration enriches for viable bone marrow mononuclear cells Quantitative analysis of migration assays indicates that BM-MNCs from patients with previous large myocardial infarction (MI) are functionally responsive to SDF-1
Summary
Chemokine-directed migration is crucial for homing of regenerative cells to the infarcted heart and correlates with outcomes of cell therapy trials. Recent reviews and metaanalyses indicate that BM cell therapy is safe and leads to tangible improvements in cardiac function, ventricular remodeling and clinical outcomes, including incidence of death, recurrent MI and stent thrombosis [2,3,4]. In spite of these encouraging results, the heterogeneity of BM cell products and complexity of intercellular interactions in the treated myocardium fuels major controversies in the field. Isolation protocols may variably impact on BM cell viability and functionality, calling for introduction of quantity and quality control standards [17]
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