Transplantation of marrow-derived cardiac stem cells carried in fibrin improves cardiac function after myocardial infarction.
The high death rate of the transplanted stem cells in the infarcted heart and the low efficiency of differentiation toward cardiomyocytes influence the outcome of stem cell transplantation for treatment of myocardial infarction (MI). Fibrin glue (FG) has been extensively used as a cell implantation matrix to increase cell survival. However, mechanisms of the effects of FG for stem cell transplantation to improve cardiac function are unclear. We have isolated c-kit+/Sca-1+ marrow-derived cardiac stem cells (MCSCs) from rat bone marrow; the cells expressed weakly early cardiac transcription factor Nkx2.5, GATA-4, Mef2C, and Tbx5. Effects of FG on survival, proliferation, and migration of MCSCs were examined in vitro. Cytoprotective effects of FG were assessed by exposure of MCSCs to anoxia. Efficacy of MCSC transplantation in FG was evaluated in the female rat MI model. The MCSCs survived well and proliferated in FG, and they may migrate out from the edge of FG in the wound and nature state. Acridine orange/ethidium bromide staining and lactate dehydrogenase analysis showed that MCSCs in FG were more resistant to anoxia as compared with MCSCs alone. In a rat MI model, cardiac function was improved and scar area was obviously reduced in group of MCSCs in FG compared with group of MCSCs and FG alone, respectively. Y chromosome fluorescence in situ hybridization showed that there were more survived MCSCs in group of MCSCs in FG than those in group of MCSCs alone, and most Y chromosome positive cells expressed cardiac troponin T (cTnT) and connexin-43 (Cx-43). Cx-43 was located between Y chromosome positive cells and recipient cardiomyocytes. Microvessel density in the peri-infarct regions and infarct regions significantly increased in group of MCSCs in FG. These results suggest that FG provide a suitable microenvironment for survival and proliferation of MCSCs and protect cells from apoptosis and necrosis caused by anoxia. MCSCs could differentiate into cardiomyocytes after being transplanted in the border of the infarcted myocardium and form connections with native cardiomyocytes. FG is helpful for MCSC transplantation to repair myocardium and improve cardiac function through promoting the survival, migration, and cardiomyogenic differentiation of MCSCs and inducing angiogenesis.
Guo
Hai-Dong
HD
Department of Anatomy and Histology and Embryology, Shanghai Medical School of Fudan University, Shanghai, People's Republic of China.
Wang
Hai-Jie
HJ
Tan
Yu-Zhen
YZ
Wu
Jin-Hong
JH
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement; D049109:Cell Proliferation; D018031:Connexin 43 / Q000378:metabolism; D005260:Female; D050991:GATA4 Transcription Factor / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D026161:MADS Domain Proteins / Q000378:metabolism; D064326:MEF2 Transcription Factors; D009203:Myocardial Infarction / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D051381:Rats; D033581:Stem Cell Transplantation / Q000379:methods*; D020825:T-Box Domain Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D020107:Troponin T / Q000378:metabolism
D018031:Connexin 43; D050991:GATA4 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D018006:Myogenic Regulatory Factors; C524161:Nkx2-5 protein, rat; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors; D020107:Troponin T