Lymphohematopoietic Stem Cell Engraftment

Authors


  • aThis work was supported in part by National Institutes of Health grants No: RO1 DK27424-14, Hematopoietic Cellular Interaction and Lithium, R01 DK49650-04, Repetitive Marrow Transplantation into Normal Mice, P01 DK50222-01A1, Stem Cell Biology and P01 HL56920-02, Hematopoietic Stem Cell Growth and Engraftment.

Correspondence and requests for materials to: Peter J. Quesenberry, M.D., Director, Cancer Center, University of Massachusetts Medical Center and University of Massachusetts Cancer Center, Two BioTech, Suite 202, 373 Plantation Street, Worcester, MA 01605. Phone, 508/856-6956; fax, 508/856-1310; e-mail, Peter.Quesenberry@banyan.ummed.edu

Abstract

Abstract: Traditional dogma has stated that space needs to be opened by cytoxic myeloablative therapy in order for marrow stem cells to engraft. Recent work in murine transplant models, however, indicates that engraftment is determined by the ratio of donor to host stem cells, i.e., stem cell competition. One hundred centigray whole body irradiation is stem cell toxic and nonmyelotoxic, thus allowing for higher donor chimerism in a murine syngeneic transplant setting. This nontoxic stem cell transplantation can be applied to allogeneic transplant with the addition of a tolerizing step; in this case presensitization with donor spleen cells and administration of CD40 ligand antibody to block costimulation.

The stem cells that engraft in the nonmyeloablated are in G0, but are rapidly induced (by 12 hours) to enter the S phase after in vivo engraftment. Exposure of murine marrow to cytokines (IL-3, IL-6, IL-11 and steel factor) expands progenitor clones, induces stem cells into cell cycle, and causes a fluctuating engraftment phenotype tied to phase of cell cycle. These data indicate that the concepts of stem cell competition and fluctuation of stem cell phenotype with cell cycle transit should underlie any new stem cell engraftment strategy.

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