Role of Bone Marrow–Derived Progenitor Cells in Cuff-Induced Vascular Injury in Mice (original) (raw)
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Frontiers in Bioscience, 2007
2. Contribution of smooth muscle cells to vascular lesions 3. Bone marrow-derived smooth muscle like cells in vascular lesions 3.1. Bone marrow-derived smooth muscle like cells in graft vasculopathy 3.2. Contribution of bone marrow-derived cells to neointima hyperplasia after mechanical injury 3.3. Potential mechanism by which bone marrow-derived cells contribute to vascular lesion formation 3.4. Fractions of bone marrow cells that contribute to vascular remodeling 3.5. Controversy on the methods to detect "bone marrow-derived smooth muscle-like cells" 4. Diverse origins of neointimal cells in vascular lesions 5. Cell fusion as a possible mechanism of BMC 'differentiation' 6. Therapeutic strategies targeting circulating vascular progenitor cells 7. Perspectives 8. Acknowledgements 9. References
Circulation Research, 2003
We and others have suggested that bone marrow-derived progenitor cells may contribute to the pathogenesis of vascular diseases. On the other hand, it was reported that bone marrow cells do not participate substantially in vascular remodeling in other experimental systems. In this study, three distinct types of mechanical vascular injuries were induced in the same mouse whose bone marrow had been reconstituted with that of GFP or LacZ mice. All injuries are known to cause smooth muscle cell (SMC) hyperplasia. At 4 weeks after wire-mediated endovascular injury, a significant number of the neointimal and medial cells derived from bone marrow. In contrast, marker-positive cells were seldom detected in the lesion induced by perivascular cuff replacement. There were only a few bone marrow-derived cells in the neointima after ligation of the common carotid artery. These results indicate that the origin of intimal cells is diverse and that contribution of bone marrow-derived cells to neointimal hyperplasia depends on the type of model. (Circ Res. 2003;93:783-790.)
Transplantation, 2003
Background. Recent observations have demonstrated the importance of host cells in neointima formation after transplantation. Because little is known regarding the dynamics of host-derived cells in the graft media, we investigated this question in a mouse carotid artery transplantation model. Methods. C57BL/6 carotid arteries were orthotopically transplanted into BALB/c mice ubiquitously expressing enhanced green fluorescent protein. Grafts were harvested at 1, 2, 4, and 8 weeks after transplantation for histologic examination. No immunosuppression was used. Results. Immunostaining and semiquantitative analysis of cross sections showed that donor medial smooth muscle cells decreased over time in the graft media, whereas green fluorescent protein-positive/ smooth muscle ␣-actin-positive cells (i.e., cells of host origin) increased over time. Interestingly, host cells were located only in the inner media and the neointima at 2 weeks and thereafter also in the outer media, indicating that the host-derived cells entered the media from the luminal side rather than from the adventitia. In longitudinal sections, there were no differences in the accumulation of donor-and host-derived cells between the end and middle regions of the graft media at 8 weeks. Conclusions. After transplantation, medial cells were replaced by ␣-actinexpressing host cells that were probably derived from circulating precursor cells. Our observations differ from the traditional view of a major contribution of donor medial smooth muscle cells to the neointima formation. Thus, circulating progenitor cells may be important for graft vessel disease.
Bone marrow-derived cells contribute to infarct remodelling
Cardiovascular Research, 2006
Objective: The paradigm that cardiac myocytes are non-proliferating and terminally differentiated cells has recently been challenged by several studies reporting the ability of bone marrow-derived cells (BMC) to transdifferentiate into cardiomyocytes. However, these results are controversial and could not be reproduced by others. Therefore, we studied the contribution and potential transdifferentiation of BMC into different cell types during the remodelling process in mouse hearts with experimental myocardial infarction. Methods: Mice (C57BL/6J) were sublethally irradiated, and BM from enhanced green fluorescent protein (eGFP)-transgenic mice was transplanted. Coronary artery ligation was performed 3 months later. The hearts were studied 7 days (n = 13) and 21 days (n = 12) after infarction. Immunohistochemical staining was performed using antibodies against titin, connexin 43, vimentin, SMemb α-smooth muscle actin, CD45, CD34, F4/80, BS-1, CD31, and eGFP. Sections were analyzed using fluorescence and confocal laser microscopy. Results: Success of BM transplantation was confirmed by FACS analysis. Occlusion of the coronary artery resulted in infarct sizes of 41 ± 6% of the left ventricle. CD45+/eGFP+ inflammatory cells were found frequently after 7 days and to a lesser degree after 21 days. In 25 examined hearts, only 3 eGFP-positive cardiomyocytes were found. However, numerous BMC-derived fibroblasts and myofibroblasts were found in the infarct area. BMC contributed to scar tissue neoangiogenesis but not to angiogenesis in the periinfarct and remote zones. Conclusion: Transdifferentiation of BMC into viable cardiomyocytes is a negligible event in normal repair processes after myocardial damage. BMC-derived fibroblasts and myofibroblasts as well as neoangiogenesis significantly contribute to post-infarction scar formation and might be important in scar tissue remodelling.
Circulation, 2010
Background— It has been proposed that bone marrow–derived cells infiltrate the neointima, where they differentiate into smooth muscle (SM) cells; however, technical limitations have hindered clear identification of the lineages of bone marrow–derived “SM cell–like” cells. Methods and Results— Using a specific antibody against the definitive SM cell lineage marker SM myosin heavy chain (SM-MHC) and mouse lines in which reporter genes were driven by regulatory programs for either SM-MHC or SM α -actin , we demonstrated that although some bone marrow–derived cells express SM α-actin in the wire injury–induced neointima, those cells did not express SM-MHC, even 30 weeks after injury. Likewise, no SM-MHC + bone marrow–derived cells were found in vascular lesions in apolipoprotein E −/− mice or in a heart transplantation vasculopathy model. Instead, the majority of bone marrow–derived SM α-actin + cells were also CD115 + CD11b + F4/80 + Ly-6C + , which is the surface phenotype of inflamma...
Vascular Regeneration and Remodeling by Circulating Progenitor Cells
Cardiovascular Regeneration Therapies Using Tissue Engineering Approaches
Atherosclerosis is responsible for more than half of all deaths in western countries. Numerous studies have reported that exuberant accumulation of smooth muscle cells play a principal role in the pathogenesis of vascular diseases. It has been assumed that smooth muscle cells derived from the adjacent medial layer migrate, proliferate and synthesize extracellular matrix. Although much effort has been devoted, targeting migration and proliferation of medial smooth muscle cells, no effective therapy to prevent occlusive vascular remodeling has been established. Recently, we reported that bone marrow cells substantially contribute to the pathogenesis of vascular diseases, in models of post-angioplasty restenosis, graft vasculopathy and hyperlipidemia-induced atherosclerosis. It was suggested that bone marrow cells may have the potential to give rise to vascular progenitor cells that home in the damaged vessels and differentiate into smooth muscle cells or endothelial cells, thereby contributing to vascular repair, remodeling, and lesion formation. This article overviews recent findings on circulating vascular precursors and describes potential therapeutic strategies for vascular diseases, targeting mobilization, homing, differentiation and proliferation of circulating progenitor cells.
Transdifferentiation of vascular smooth muscle cells to macrophage-like cells during atherogenesis
Circulation research, 2014
Atherosclerosis is a widespread and devastating disease, but the origins of cells within atherosclerotic plaques are not well defined. To investigate the specific contribution of vascular smooth muscle cells (SMCs) to atherosclerotic plaque formation by genetic inducible fate mapping in mice. Vascular SMCs were genetically pulse-labeled using the tamoxifen-dependent Cre recombinase, CreER(T2), expressed from the endogenous SM22α locus combined with Cre-activatable reporter genes that were integrated into the ROSA26 locus. Mature SMCs in the arterial media were labeled by tamoxifen treatment of young apolipoprotein E-deficient mice before the development of atherosclerosis and then their fate was monitored in older atherosclerotic animals. We found that medial SMCs can undergo clonal expansion and convert to macrophage-like cells that have lost classic SMC marker expression and make up a major component of advanced atherosclerotic lesions. This study provides strong in vivo evidence ...