Though many have demonstrated that adult stem cells have broad regenerative capacity in a variety of non-hematopoietic tissues, there is no information available on the molecular mechanism(s) by which adult stem cells migrate to sites other than bone marrow. To exit the vascular compartment, all circulating cells must first bind to the endothelium at the target tissue. The key initial adhesive interactions between cells in blood and endothelium are generally described as """"""""rolling"""""""", whereby the fast moving cells in flow begin to """"""""brake"""""""" on the endothelial surface. This process is mediated by leukocyte """"""""homing receptors"""""""" which consist of molecules specialized for rolling interactions such as L-selectin, PSGL-1, CD44, and the integrins VLA-4, LFA-1 and alpha4beta7. While much is known about the role(s) of these molecules in regulating mature leukocyte trafficking and the migration of human CD34+ hematopoietic progenitor cells into bone marrow, virtually nothing is known about the expression and activity of these molecules as they relate to migration of human adult stem cells to non-hematopoietic sites. We hypothesize that to achieve adequate tissue delivery of infused adult stem cells for regeneration of damaged organs requires that one or more of the homing receptors on adult stem cells be functionally intact and, moreover, that the relative expression/activity of these molecules will determine in part the capacity of the cells to emigrate to relevant non-hematopoietic tissues. In this proposal, we focus our studies on adult stem cells residing in human bone marrow, as this source provides the most accessible and quantitatively greatest amount of adult stem cells for future clinical applications.
We aim to define the profile of expression and the functional capabilities of known homing receptors on defined populations of human bone marrow-derived adult stem cells including hematopoietic stem cells (HSCs), mesenchymal stem cells (MSC) and multipotential adult progenitor cells (MAPC). Moreover, to determine whether stem cells express novel homing receptors, we will utilize newly developed technology in our laboratory to examine the full spectrum of membrane molecules that can function as mediators of binding interactions under shear conditions. Based on information derived from these studies, we will analyze human adult stem cell-human endothelial interactions and the migration of human adult stem cells to non-hematopoietic tissue using an in vivo model system of human skin transplanted onto immunodeficient mice. It is anticipated that the results of these studies will guide the development of strategies to achieve high efficiency delivery of human adult stem ceils from the vasculature into target organ(s) for clinical applications of regeneration therapy.
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