CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction

Abstract

We hypothesized that a small molecule CXCR4 antagonist, AMD3100 (AMD), could augment the mobilization of bone marrow (BM)-derived endothelial progenitor cells (EPCs), thereby enhancing neovascularization and functional recovery after myocardial infarction. Single-dose AMD injection administered after the onset of myocardial infarction increased circulating EPC counts and myocardial vascularity, reduced fibrosis, and improved cardiac function and survival. In mice transplanted with traceable BM cells, AMD increased BM-derived cell incorporation in the ischemic border zone. In contrast, continuous infusion of AMD, although increasing EPCs in the circulation, worsened outcome by blocking EPC incorporation. In addition to its effects as a CXCR4 antagonist, AMD also up-regulated VEGF and matrix metalloproteinase 9 (MMP-9) expression, and the benefits of AMD were not observed in the absence of MMP-9 expression in the BM. These findings suggest that AMD3100 preserves cardiac function after myocardial infarction by enhancing BM-EPC-mediated neovascularization, and that these benefits require MMP-9 expression in the BM, but not in the ischemic region. Our results indicate that AMD3100 could be a potentially useful therapy for the treatment of myocardial infarction.angiogenesis | stem cell | vasculogenesis

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

“…This is supported by observations that the augmentation of neovascularizations in MI hearts was closely associated with the prevention of cardiac remodeling (20,43). It is very interesting to evaluate the volume of infarct size over time following the transplantation of CSCs in the MI heart, which is the limitation in our observation.…”

Adult Stem Cell Mobilization Enhances Intramembranous Bone Regeneration: A Pilot Study

“…This technique is considered the standard of care for adult patients who need bone marrow transplants to reconstitute hematopoiesis after chemotherapy for certain cancers [50,51]. The ex vivo phase of expansion and in vivo placement can be avoided with mobilizing endogenous stem and progenitor cells for in situ tissue regeneration as exemplified by improved cardiac function and prolonged survival after myocardial infarction in a mouse model [25].…”

Macrophages in Kidney Repair and Regeneration

“…1,2 Further refinements to GWAS techniques using admixture-mapping linkage disequilibrium also allowed for the identification of a locus on chromosome 22q12 that predisposes individuals of African descent to nondiabetic glomerular injury, 3,4 and recent analyses strongly indicate that the affected gene is ApoL1. 5,6 Undoubtedly, other genes are involved in development of progressive kidney disease.…”

“…EPCs are now widely described to promote capillary repair and restoration by a number of mechanisms, including canalization of new capillary tracts, temporary (days to weeks) replacement of endothelial cells in areas of denuded capillary basement membrane, new capillary basement membrane synthesis, cytokine release that promotes endothelial cell proliferation, and adoption of pericyte functions. 4,5 But can the endogenous reparative functions of macrophages be harnessed for good in the kidney? It seems so.…”