An ever increasing number of cancer patients are receiving hematopoietic stem cell transplantation. Following the infusion of the transplant, the hematopoietic stem cells (HSCs) must find their way into the bone marrow, home in on the appropriate microenvironment, and begin the process of cell production that hopefully leads to durable engraftment. The homing processes that the HSC must undergo are at present incompletely understood. HSCs must undergo several distinct steps in accomplishing their overall task of repopulation. The first few steps will involve finding the bone marrow and the proper microenvironment. This process will rely on HSC motility and chemokine signaling. Once the HSC and the key stroma cells are in physical proximity with one another, the HSC begins its process of replication and differentiation into lineage committed progenitors. The investigators propose a research program and aimed at characterizing and understanding locomotion processes that the HSC must undergo on their journey and to determine their behavior once they have found their microenvironmental niche.
The specific aims that the investigators propose are (1) to determine quantitatively the random motility coefficient for HSCs (defined as CD34+/CD38-); (2) to determine quantitatively the chemotaxis coefficient for isolated HSCs in a gradient of known chemokines, such as IL-8 and SCF; (3) to determine the fate of HSCs in simulated microenvironments that are comprised of accessory cells, and mesenchymal cells. HSC motility and division/ differentiation history will be determined in both short and long-term cultures. The participating investigators have the capability to perform the required research on; the mass transfer of the chemokine (biotransport phenomena), the single cell tracking (long-term time lapse observations), single cell sorts (index sorts with a flow cytometer), and hematopoietic cell culture development. These tasks in turn require bioengineering, hematology, and cell culture expertise. The interdisciplinary team of investigators commands the diverse experience and facilities required to perform the proposed research that is needed to gain the desired knowledge and understanding of the overall HSC homing process.
