title: Protection of bone marrow-derived CD45+/CD34-/lin- stromal cells with immunosuppressant activity against ischemia/reperfusion injury in rats.
abstract: Non-hematopoietic CD45+ precursor cells are not known to differentiate into cardiomyocytes. We found that CD45+/CD34-/lin- stromal cells isolated from mouse bone marrow (BMSCs) potentially differentiated into cardiomyocyte-like cells in vitro. Therefore, we hypothesized that the CD45+/CD34-/ lin- BMSCs might protect rat hearts against ischemia/reperfusion (IR) injury following xeno-transplantation. In the present study, BMSCs were isolated by immunoselection and their cellular phenotype and biochemical properties were characterized. The immunological inertness of BMSCs was examined by the allogeneic and xenogeneic mixed lymphocyte reaction (MLR). The potential role of BMSCs for cardioprotection was evaluated by intravenous introduction of 1 x 10(6) cells into rat IR hearts, induced by left coronary ligation for 45 min and released for 72 h. Changes in cardiac contractility and the degree of myocardial injury were assessed. Our findings indicated that BMSCs expressed the muscle-cell marker alpha-actinin after 5-azacytidine treatment. CD45+/CD34-/lin- stromal cells were characterized as mesenchymal progenitor cells based on the expression of Sca-1 and Rex-1. The MLR assay revealed an immunosuppression of BMSCs on mouse and rat lymphocytes. After xeno-transplantation, the BMSCs engrafted into the infarct area and attenuated IR injury. However, increases in intracardial TGF-beta and IFN-gamma contents of IR hearts were not affected by BMSC treatment. Interestingly, ex vivo evidence indicated that CXCR4, SDF-1 and TGFbeta-1 receptors were up-regulated after the cells were exposed to tissue extracts prepared from rat post-IR hearts. In addition, IFN-gamma treatment also markedly increased Sca-1 expression in BMSCs. Mechanistically, these results indicated that CXCR4/SDF-1 and TGF-beta signals potentially enhanced the interaction of BMSCs with the damaged myocardium, and increased IFN-gamma in post-ischemic hearts might cause BMSC to behave more like stem cells in cardioprotection. These data show that CD45+/CD34-/lin- BMSCs possess cardioprotective capacity. Evidently, the accurate production of soluble factors TGF-beta and IFN-gamma in parallel with increased expression of both TGF-beta and Sca-1 receptors may favor BMSCs to achieve a more efficient protective capacity.
authors.affiliation: Department of Medical Research, Tao-Yuan General Hospital, Taoyuan, Taiwan, Republic of China.
authors.forename: Yuan-Chang
authors.initials: YC
authors.lastname: Chung
authors.forename: Ming-Chieh
authors.initials: MC
authors.lastname: Ma
authors.forename: Bo-Yang
authors.initials: BY
authors.lastname: Huang
authors.forename: Han-Sun
authors.initials: HS
authors.lastname: Chiang
authors.forename: Shiu-Huey
authors.initials: SH
authors.lastname: Chou
mesh_terms: D000185:Actinin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis / Q000276:immunology; D000950:Antigens, Ly / Q000378:metabolism; D001374:Azacitidine / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D005260:Female; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000096:biosynthesis / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control / Q000628:therapy*; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation*; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D018952:Antigens, CD34; D000950:Antigens, Ly; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D019718:Receptors, CXCR4; D018125:Receptors, Transforming Growth Factor beta; C513672:Zfp42 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000185:Actinin; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; D001374:Azacitidine