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New Study Demonstrates Important Role of Endogenous Stem Cells in Angiogenesis

Arteriosclerosis, Thrombosis and Vascular Biology, October 30, 2008

Scientists in Nagoya, Japan have demonstrated the important role that endogenous adult stem cells play in angiogenesis, which is the formation of new blood vessels. The study was led by Dr. Kazuhisa Kondo, who showed that "adipose-derived regenerative cells" (ADRCs) mobilized endogenous progenitor cells to enhance angiogenesis in a mouse model of critical limb ischemia.

Previous animal studies and human clinical trials have demonstrated that neovascularization is inducible by exogenous stem cell transplantation into ischemic muscle, with one clinical trial also demonstrating that human patients with critical limb ischemia respond to exogenous adult stem cell therapy not only with an increased systemic production of chemokines but also with the mobilization of endogenous CD34 stem cells from their bone marrow. It remained unknown, however, whether the resulting angiogenesis was caused directly by differentiation of the exogenous adult stem cells into the newly formed endothelial cells, or indirectly by an interaction between the cytokines and the recipient muscle. A study conducted by Dr. Keith March in 2004 also demonstrated that angiogenesis is mediated via cytokine secretion, although the exact extent of this mediation remained to be determined. Now, Dr. Kondo and his colleagues have demonstrated that the neovascularization which they observed in a mouse model of critical limb ischemia was directly dependent upon the mobilization of endogenous progenitor cells from the bone marrow.

After isolating ADRCs from the adipose tissue of mice in which hind-limb ischemia had been induced, Dr. Kondo and his team then expanded the ADRCs and transplanted them back into the ischemic tissue of the mice. Those mice which received the ADRCs showed a greater laser Doppler blood perfusion index and a higher capillary density when compared to the control mice. Additionally, the ADRCs were also found to increase circulating progenitor cells through the chemokine SDF-1 (stromal cell derived factor). Additionally, the administration of the systemic antibody to SDF-1 by intraperitoneal injection resulted in a blocking of the mobilization and efficacy of the adipose stem cells to induce angiogenesiis, through a mechanism by which the anti-SDF-1 neutralizing antibody caused a reduction in the number of circulating endogenous progenitor cells. Such a discovery highlights the central role that SDF-1 plays in facilitating the mobilization of endogenous progenitor cells.

Dr. Kondo's study has important practical implications, since most people are not eager to have holes drilled in their bones for the harvesting of autologous stem cells from bone marrow. By contrast, adipose-derived stem cells now present an alternative source to autologous stem cell therapy, since the derivation of stem cells from fat is simpler than that from bone marrow. In fact, several companies such as Cytori have patents on self-contained closed systems by which adipose mononuclear cells are quickly and easily purified at the point-of-care.

As Dr. Kondo's study indicates, the dynamics of therapeutic angiogenesis involve complex chemical and molecular interactions between the transplanted exogenous populations and endogenous stem cell reserves. In the stimulation of angiogenesis, adipose-derived adult stem cells offer a promising therapeutic modality, especially as a treatment for severe ischemic disease. Additionally, the chemokine SDF-1 is now recognized as playing a fundamental role in mobilizing endogenous progenitor cells.

Dr. Kazuhisa Kondo and his colleagues are in the Department of Cardiology at the Nagoya University Graduate School of Medicine and the Department of Bioengineering Sciences at the Nagoya University Graduate School of Bioagricultural Sciences.



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