STEM CELLS HOMING AND MOTILITY

Roger Williams Hospital, Providence RI

Investigators

Linked publications & trials

Abstract

Our aim is to define hematopoietic stem cell homing and the impact of cytokine exposure on homing and engraftment after bone marrow transplantation. In addition, we wish to investigate the process of stem cell migration and motility in response to other cells or cytokines and investigate the role of adhesion receptors including integrins in directed movement. We have previously established models for engrafting cells in non-myeloablated and minimally myeloablated murine hosts. We have also studied the effect of different cytokines, most prominently, a combination of interleukeuin-3, interleukin-6, interleukin-11, and steel factor on engraftment of marrow cells in both non-myeloablated and myeloablated hosts. We have found that such cytokine exposure in liquid culture over 48 hours leads to a fluctuation engraftment phenotype with loss of engraftment in late S/early G2 phases of cell cycle and return in G1. Lastly, we have defined numerous adhesion receptors critical to the interaction of stem cell populations with stromal cells in vitro, an determined how cytokines modulate adhesion receptor expression and function. The present grant focuses on defining mechanisms of homing of bone marrow stem cells using fluorescent labels over the first 20 hours of engraftment. A second major aims is to evaluate the impact of cytokine alterations on homing and presumably, adhesion receptor expression. Lastly, we have begun to evaluate in vitro surrogate models of homing looking at stem cell binding to Dexter cultures and visualization using inverted fluorescence and deconvolution fast microscopy of fluorescent labeled highly purified Lin- rho(lo)ho(lo) and Lin-Scn+ murine stem cells isolated by MoFlo high speed sorting. We plan to continue these studies with a focus on the lamellipodial projects from these stem cells and define the distribution and functional role of adhesion receptors including integrins in cell adhesion, cell motility, and directed cell migration. The influence of cytokines on the appearance, localization, and function of cell processes and distribution of adhesion receptors on both stem cells and stromal cells will also be examined.