It is critical to find alternatives to native vein or artery for use in vascular surgery, as adequate tissue for a bypass conduit is often unavailable. Animal studies have shown that a tubing template implanted into the peritoneal cavity becomes covered with tissue, and this newly formed tissue tube can be used as a vascular graft. However, due to the nature of animal models used, it is difficult to investigate the development of this tissue at the cellular/molecular level. To understand this mechanism, we have developed a mouse model where the newly formed vessels were transplanted into the abdominal aortae of the same mice in which they were grown. These grafts remained patent for at least 4 months, and in situ they developed the architecture of normal blood vessels. Comprehensive genotypic and phenotypic analysis revealed that the mouse tissue capsule cells and peritoneal cells have the characteristics of stem/progenitor cells including the expression of transcription factors that are specific to stem cells, the presence of side population cells, as well as Lin-/Sca-1+/c-kit+ cells. Functional analyses revealed that these peritoneal cells are biologically active, as shown by their ability to: stimulate re-perfusion/neovascularization of ischemic hind limb; repopulate the hematopoietic system of lethally irradiated mice; and graft into various organ of recipient mice. We propose to: 1) Determine the contribution of peritoneal-derived stem cells to generation of tissue capsule; 2) D Determine the role of peritoneal-derived stem cells in the remodeling of capsule graft;
Aim 3) Determine functionality of peritoneal stem cell sub-population. Accomplishing these Specific Aims will elucidate the mechanisms by which peritoneal cells contribute to the development of bioengineered tissues and may lead to the development of novel strategies for tissue bioengineering and reperfusion of a variety of ischemic tissues.
Vascular bypass grafting is the mainstay of revascularization for ischemic heart disease and peripheral vascular disease, and in the US alone 1.4 million arterial bypass operations are performed annually. However, 30% of patients who require arterial bypass procedures have no suitable autologous arteries or veins for use. In animal models, it has been shown that tubular structures can be grown in the peritoneal cavity, and that they can function as autologous graft while undergoing extensive remodeling to resemble native vessels. The mechanisms for this process of tissue generation, and subsequent remodeling have been have been poorly understood due to the animals species used thus far; however by using our mouse model in the proposed studies we shall elucidate these mechanisms at a cell and molecular level, which will in turn have significant implications for our ability to treat ischemic vascular diseases. ? ? ?
