Local Delivery of Marrow-Derived Stromal Cells Augments Collateral Perfusion Through Paracrine Mechanisms

Abstract

Background— Bone marrow cell therapy is reported to contribute to collateral formation through cell incorporation into new or remodeling vessels. However, the possible role of a paracrine contribution to this effect is less well characterized. Methods and Results— Murine marrow-derived stromal cells (MSCs) were purified by magnetic bead separation of cultured bone marrow. The release of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), and monocyte chemoattractant protein-1 (MCP-1) was demonstrated by analysis of MSC conditioned media (MSC-CM). MSC-CM enhanced proliferation of endothelial cells and smooth muscle cells in a dose-dependent manner; anti-VEGF and anti-FGF antibodies only partly attenuated these effects. Balb/C mice (n=10) underwent distal femoral artery ligation, followed by adductor muscle injection of 1×10 6 MSCs 24 hours later. Compared with controls injected with media (n=10) or mature endothelial cells (n=8), distal limb perfusion improved, and mid-thigh conductance vessels increased in number and total cross-sectional area. MSC injection improved limb function and appearance, reduced the incidence of auto-amputation, and attenuated muscle atrophy and fibrosis. After injection, labeled MSCs were seen dispersed between muscle fibers but were not seen incorporated into mature collaterals. Injection of MSCs increased adductor muscle levels of bFGF and VEGF protein compared with controls. Finally, colocalization of VEGF and transplanted MSCs within adductor tissue was demonstrated. Conclusions— MSCs secrete a wide array of arteriogenic cytokines. MSCs can contribute to collateral remodeling through paracrine mechanisms.

In vivo bone formation by human marrow stromal cells in biodegradable scaffolds that release dexamethasone and ascorbate-2-phosphate

“…Considering that hMSCs are strong inducers of angiogenesis [38], the infiltration of scaffolds by host (mouse) cells such as vascular cells would supply oxygen and nutrients to the implanted hMSCs. Indeed, implanted hMSCs have been reported to cause angiogenesis via host-derived vascular cells rather than via transdifferentiation of the hMSCs into endothelial cells [38,39]. We could not detect mineralized tissue within the osteogenic scaffolds that lacked hMSCs, and, therefore, it is likely that the bone tissue that was formed within the implants originated from the hMSCs.…”

SDF-1/CXCR4 axis modulates bone marrow mesenchymal stem cell apoptosis, migration and cytokine secretion

“…Furthermore, the accessibility, ease of handling, and enormous expansion potential of MSCs, together with their capacity for self-renewal and amenability to allogenic transplantation (Amado et al, 2005;Dai et al, 2005), provide a nearly unlimited supply of cells for therapeutic applications. The effect of MSCs is thought to be mediated by secreting a number of cardio-protective cytokines and growth factors in addition to differentiation (Kinnaird et al, 2004a(Kinnaird et al, , 2004bNagaya et al, 2005). Despite initial optimism, MSC transplant therapy has been stymied by the low cellular survival rate after transplantation in the first few days (Toma et al, 2002).…”

Progress and prospects: Cell based regenerative therapy for cardiovascular disease

“…release of various chemokines and cytokines that can affect endogenous cell differentiation, myocardial remodeling and function). [23][24][25][26][27] It has been shown that endothelium-derived growth factors affect the development of apparently unrelated organs and cells, and a paracrine effect has also been demonstrated for other cell types. Thus, Akt-1-transfected mesenchymal progenitor cells have been shown to protect the ischemic heart via a paracrine mechanism.…”