Mesenchymal Progenitor Cells for Vascular Network Formation and Cardiac Muscle Regeneration

Abstract

Mammalian bone marrow contains mesenchymal lineage progenitors that have high proliferative capacity, are clonogenic in vitro, and demonstrate the ability to differentiate to multiple mesenchymal lineage tissue types, including bone, cartilage, fat, smooth muscle, and cardiac muscle. Isolation of these cells on the basis of their physical properties results in clonal outgrowth with functional in vitro heterogeneity. Prospective immunoselection of mesenchymal lineage precursor cells enhances reproducible functional outgrowth, and the phenotype STRO-1brightVCAM-1⁺ characterizes a multipotent mesenchymal precursor cell in vivo, which gives rise to a 50% frequency of multipotential clonal outgrowth in vitro. These cells are anatomically located in perivascular niches in the bone marrow and throughout the body and demonstrate phenotypic and genetic identity to vascular pericytes. Consistent with the pivotal role played by pericytes in formation of vascular structures during embryogenesis, cumulative data show that mesenchymal precursors regulate adult vasculature formation. In addition, under appropriate differentiation conditions, mesenchymal precursors give rise to new cardiomyocytes. Because vascular network formation is a prerequisite for long-term survival of cardiomyocyte precursors implanted into ischemic myocardium, mesenchymal lineage precursors appear to be ideal candidates for enhancing both cardiac neovascularization and myogenesis. Clinical protocols using these cells will require optimization of serum-free culture methodologies and biological scaffolds/matrices for enhancing survival of implanted cells. Finally, recent data indicating that mesenchymal lineage precursors evade immune recognition raise the exciting prospect that allogeneic use of these cells may be feasible.