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TISSUE-SPECIFIC STEM CELLS

Fas Transduces Dual Apoptotic and Trophic Signals in Hematopoietic Progenitors

^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;
^cMinimally-Invasive Surgical Technologies Institute, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA

Key Words. Apoptosis • Bone marrow transplantation • Differentiation • 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 on June 15, 2007; accepted for publication on August 29, 2007.

First published online in STEM CELLS EXPRESS  September 13, 2007.


Stem cells and progenitors are often required to realize their differentiation potential in hostile microenvironments. The Fas/Fas ligand (FasL) interaction is a major effector pathway of apoptosis, which negatively regulates the expansion of differentiated hematopoietic cells. The involvement of this molecular interaction in the function of hematopoietic stem and progenitor cells is not well understood. In the murine syngeneic transplant setting, both Fas and FasL are acutely upregulated in bone marrow-homed donor cells; however, the Fas⁺ cells are largely insensitive to FasL-induced apoptosis. In heterogeneous populations of lineage-negative (lin^–) bone marrow cells and progenitors isolated by counterflow centrifugal elutriation, trimerization of the Fas receptor enhanced the clonogenic activity. Inhibition of caspases 3 and 8 did not affect the trophic signals mediated by Fas, yet it efficiently blocked the apoptotic pathways. Fas-mediated tropism appears to be of physiological significance, as pre-exposure of donor cells to FasL improved the radioprotective qualities of hematopoietic progenitors, resulting in superior survival of myeloablated hosts. Under these conditions, the activity of long-term reconstituting cells was not affected, as determined in sequential secondary and tertiary transplants. Dual caspase-independent tropic and caspase-dependent apoptotic signaling place the Fas receptor at an important junction of activation and death. This regulatory mechanism of hematopoietic homeostasis activates progenitors to promote the recovery from aplasia and converts into a negative regulator in distal stages of cell differentiation.

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