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TISSUE-SPECIFIC STEM CELLS

Fas Ligand Enhances Hematopoietic Cell Engraftment Through Abrogation of Alloimmune Responses and Nonimmunogenic Interactions

^aFrankel Laboratory, Center for Stem Cell Research, Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel;
^bInstitute for Cellular Therapeutics and Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, USA;
^cDepartment of Surgery, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Key Words. Adult stem cells • Apoptosis • Hematopoietic stem cell transplantation • Fas

Correspondence: Nadir Askenasy, M.D., Ph.D., Frankel Laboratory, Center for Stem Cell Research, Schneider Children's Medical Center of Israel, 14 Kaplan Street, Petach Tikva, Israel 49202. Telephone: 972-3921-3954; Fax: 972-3921-4156; e-mail: anadir{at}012.net.il

Received January 17, 2007; accepted for publication March 7, 2007.
First published online in STEM CELLS EXPRESS   March 15, 2007.



Early after transplantation, donor lineage-negative bone marrow cells (lin^– BMC) constitutively upregulated their expression of Fas ligand (FasL), suggesting an involvement of the Fas/FasL axis in engraftment. Following the observation of impaired engraftment in the presence of a dysfunctional Fas/FasL axis in FasL-defective (gld) donors or Fas-defective (lpr) recipients, we expressed a noncleavable FasL chimeric protein on the surface of donor lin^– BMC. Despite a short life span of the protein in vivo, expression of FasL on the surface of all the donor lin^– BMC improved the efficiency of engraftment twofold. The FasL-coated donor cells efficiently blunted the host alloimmune responses in primary recipients and retained their hematopoietic reconstituting potential in secondary transplants. Surprisingly, FasL protein improved the efficiency of engraftment in syngeneic transplants. The deficient engraftment in lpr recipients was not reversed in chimeric mice with Fas^– stroma and Fas⁺ BMC, demonstrating that the host marrow stroma was also a target of donor cell FasL. Hematopoietic stem and progenitor cells are insensitive to Fas-mediated apoptosis and thus can exploit the constitutive expression of FasL to exert potent veto activities in the early stages of engraftment. Manipulation of the donor cells using ectopic FasL protein accentuated the immunogenic and nonimmunogenic interactions between the donor cells and the host, alleviating the requirement for a megadose of transplanted cells to achieve a potent veto effect.

Disclosure of potential conflicts of interest is found at the end of this article.

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