Characterization of venular remodeling in response to bone marrow-derived progenitor cell delivery

Microvascular remodeling occurs through the processes of angiogenesis, arteriogenesis, and venule remodeling. The delivery of bone marrow-derived cells (BMDCs) is used to stimulate these remodeling processes. We evaluated how the delivery of BMDCs to a remodeling tissue can influence microvascular remodeling, specifically venular remodeling since this is a generally unexplored area in microvascular research. The two populations of BMDCs selected for delivery in this study, whole bone marrow and Sca-1+ progenitor cells, represent two main components of bone marrow: the mature inflammatory cells and the undifferentiated progenitor cells. We evaluated BMDC delivery by both injection and encapsulation in sodium alginate. Encapsulation could prolong the presence of delivered cells in the tissue allowing for a stronger impact on remodeling. Upon observation that encapsulated Sca-1+ progenitor cells enhance venular remodeling, we evaluated this response by implementing experiments designed to analyze the cells and tissue on structural, functional, and molecular levels.;The walls of the enlarged venules were thickened and contained more cell nuclei in response to Sca-1+ progenitor cell delivery, indicating increased investment of smooth muscle and/or pericytes in venular walls. Additionally, the remodeled venules responded to a vasodilatory stimulus, an indicator that these remodeled vessels maintain the ability to modulate their tone. Delivered Sca-l+ progenitor cells expressed high levels of chemokine (C-X-C motif) ligand 2 (CXCL2) and interferon gamma (IFNgamma). Tissues that received progenitors expressed higher protein levels of vascular endothelial growth factor (VEGF), monocyte chemotactic protein-1 (MCP-1), and platelet derived growth factor-BB (PDGF-BB). Sca-1+ progenitor cells could enhance venular remodeling through modulation of the immune environment in the tissue, so the density of inflammatory cell investment in the tissue was quantified. Tissue from progenitor recipients contained 40% more CD45 + leukocytes.;This study identifies a role for BMDCs in venular remodeling. Specifically, results show that both BMDC subpopulation and mode of cell delivery determine microvascular response to BMDCs. We identified possible roles for CXCL2 and IFNgamma as cell-derived molecular mediators of venule enlargement, and revealed that the modulation of the local inflammatory environment is an important mechanism by which delivered Sca-1+ cells enhance venular remodeling.