Fas transduces dual apoptotic and trophic signals in hematopoietic progenitors

Michal Pearl-Yafe, Jerry Stein, Esma S. Yolcu, Daniel L. Farkas, Haval Shirwan, Isaac Yaniv, Nadir Askenasy*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)3194-3203
Number of pages10
JournalStem Cells
Volume25
Issue number12
DOIs
StatePublished - Dec 2007
Externally publishedYes

Funding

FundersFunder number
National Institute of Allergy and Infectious DiseasesR01AI047864

    Keywords

    • Apoptosis
    • Bone marrow transplantation
    • Differentiation
    • Fas

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