Expression of Fas and Fas-ligand in donor hematopoietic stem and progenitor cells is dissociated from the sensitivity to apoptosis.
OBJECTIVE
The interaction between the Fas receptor and its cognate ligand (FasL) has been implicated in the mutual suppression of donor and host hematopoietic cells after transplantation. Following the observation of deficient early engraftment of Fas and FasL-defective donor cells and recipients, we determined the role of the Fas-FasL interaction.


METHODS
Donor cells were recovered after syngeneic (CD45.1-->CD45.2) transplants from various organs and assessed for expression of Fas/FasL in reference to lineage markers, carboxyfluorescein succinimidyl ester dilution, Sca-1 and c-kit expression. Naïve and bone marrow-homed cells were challenged for apoptosis ex vivo.


RESULTS
The Fas receptor and ligand were markedly upregulated to 40% to 60% (p < 0.001 vs 5-10% in naïve cells) within 2 days after syngeneic transplantation, while residual host cells displayed modest and delayed upregulation of these molecules ( approximately 10%). All lin(-)Sca(+)c-kit(+) cells were Fas(+)FasL(+), including 95% of Sca-1(+) and 30% of c-kit(+) cells. Fas and FasL expression varied in donor cells that homed to bone marrow, spleen, liver and lung, and was induced by interaction with the stroma, irradiation, cell cycling, and differentiation. Bone marrow-homed donor cells challenged with supralethal doses of FasL were insensitive to apoptosis (3.2% +/- 1% vs 38% +/- 5% in naïve bone marrow cells), and engraftment was not affected by pretransplantation exposure of donor cells to an apoptotic challenge with FasL.


CONCLUSIONS
There was no evidence of Fas-mediated suppression of donor and host cell activity after transplantation. Resistance to Fas-mediated apoptosis evolves as a functional characteristic of hematopoietic reconstituting stem and progenitor cells, providing them competitive engraftment advantage over committed progenitors.
Pearl-Yafe
Michal
M
Frankel Laboratory, Center for Stem Cell Research, Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
Yolcu
Esma S
ES
Stein
Jerry
J
Kaplan
Ofer
O
Shirwan
Haval
H
Yaniv
Isaac
I
Askenasy
Nadir
N
D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D016026:Bone Marrow Transplantation; D053222:Fas Ligand Protein / Q000096:biosynthesis* / Q000494:pharmacology*; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D014185:Transplantation, Isogeneic; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D019014:fas Receptor / Q000096:biosynthesis*
D000950:Antigens, Ly; D053222:Fas Ligand Protein; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D019014:fas Receptor; D019009:Proto-Oncogene Proteins c-kit; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse