Complete repair of dystrophic skeletal muscle by mesoangioblasts with enhanced migration ability

Efficient delivery of cells to target tissues is a major problem in cell therapy. We report that enhancing delivery of mesoangioblasts leads to a complete reconstitution of downstream skeletal muscles in a mouse model of severe muscular dystrophy (α-sarcoglycan ko). Mesoangioblasts, vessel-associated stem cells, were exposed to several cytokines, among which stromal- derived factor (SDF) 1 or tumor necrosis factor (TNF) α were the most potent in enhancing transmigration in vitro and migration into dystrophic muscle in vivo. Transient expression of α4 integrins or L-selectin also increased several fold migration both in vitro and in vivo. Therefore, combined pretreatment with SDF-1 or TNF-α and expression of α4 integrin leads to massive colonization (>50%) followed by reconstitution of >80% of α-sarcoglycan–expressing fibers, with a fivefold increase in efficiency in comparison with control cells. This study defines the requirements for efficient engraftment of mesoangioblasts and offers a new potent tool to optimize future cell therapy protocols for muscular dystrophies

Human cardiac mesoangioblasts isolated from hypertrophic cardiomyopathies are greatly reduced in proliferation and differentiation potency

AIMS: Our objective was to test whether progenitor cell proliferation and differentiation potential may vary depending upon the disease of the donor. METHODS AND RESULTS: Human cardiac mesoangioblasts were isolated from cardiac muscle biopsies of patients undergoing open heart surgery for correction of mitral regurgitation following an acute myocardial infarction (MR-MI) or correction of mitral and aortic regurgitation with ensuing left ventricular hypertrophy (MAR-LVH). The cells express surface markers and cardiac genes similar to mouse cardiac mesoangioblasts; they have limited self-renewing and clonogenic activity and are committed mainly to cardiogenesis. Although cardiac differentiation can be induced by 5-azacytidine or by co-culture with rat neonatal cardiomyocytes, human cells do not contract spontaneously like their mouse counterparts. When locally injected in the infarcted myocardium of immunodeficient mice, cardiac mesoangioblasts generate a chimeric heart that contains human myocytes and some capillaries; likewise, they colonize chick embryo hearts when transplanted in ovo. At variance with cells from patients with MR-MI, when isolation was performed on biopsies from MAR-LVH, cells could be isolated in much lower numbers, proliferated less extensively and failed to differentiate. CONCLUSION: Cardiac mesoangioblasts are present in the human heart but this endogenous progenitor population is progressively exhausted, possibly by continuous and inefficient regeneration attempts

Human cardiac mesoangioblasts isolated from hypertrophic cardiomyopathies are greatly reduced in proliferation and differentiation potency

AIMS: Our objective was to test whether progenitor cell proliferation and differentiation potential may vary depending upon the disease of the donor. METHODS AND RESULTS: Human cardiac mesoangioblasts were isolated from cardiac muscle biopsies of patients undergoing open heart surgery for correction of mitral regurgitation following an acute myocardial infarction (MR-MI) or correction of mitral and aortic regurgitation with ensuing left ventricular hypertrophy (MAR-LVH). The cells express surface markers and cardiac genes similar to mouse cardiac mesoangioblasts; they have limited self-renewing and clonogenic activity and are committed mainly to cardiogenesis. Although cardiac differentiation can be induced by 5-azacytidine or by co-culture with rat neonatal cardiomyocytes, human cells do not contract spontaneously like their mouse counterparts. When locally injected in the infarcted myocardium of immunodeficient mice, cardiac mesoangioblasts generate a chimeric heart that contains human myocytes and some capillaries; likewise, they colonize chick embryo hearts when transplanted in ovo. At variance with cells from patients with MR-MI, when isolation was performed on biopsies from MAR-LVH, cells could be isolated in much lower numbers, proliferated less extensively and failed to differentiate. CONCLUSION: Cardiac mesoangioblasts are present in the human heart but this endogenous progenitor population is progressively exhausted, possibly by continuous and inefficient regeneration attempts.status: publishe

Mesoangioblasts at 20: From the embryonic aorta to the patient bed

In 2002 we published an article describing a population of vessel-associated progenitors that we termed mesoangioblasts (MABs). During the past decade evidence had accumulated that during muscle development and regeneration things may be more complex than a simple sequence of binary choices (e.g., dorsal vs. ventral somite). LacZ expressing fibroblasts could fuse with unlabelled myoblasts but not among themselves or with other cell types. Bone marrow derived, circulating progenitors were able to participate in muscle regeneration, though in very small percentage. Searching for the embryonic origin of these progenitors, we identified them as originating at least in part from the embryonic aorta and, at later stages, from the microvasculature of skeletal muscle. While continuing to investigate origin and fate of MABs, the fact that they could be expanded in vitro (also from human muscle) and cross the vessel wall, suggested a protocol for the cell therapy of muscular dystrophies. We tested this protocol in mice and dogs before proceeding to the first clinical trial on Duchenne Muscular Dystrophy patients that showed safety but minimal efficacy. In the last years, we have worked to overcome the problem of low engraftment and tried to understand their role as auxiliary myogenic progenitors during development and regeneration.Depto. de Bioquímica y Biología MolecularTRUEpu