Am J Stem Cells 2013;2(3):155-164

Original Article
Activation and crosstalk between TNF family receptors in umbilical cord blood cells
is not responsible for loss of engraftment capacity following culture

Keren Mizrahi, Nadir Askenasy

Frankel Laboratory, Center for Stem Cell Research, Department of Pediatric Hematology-Oncology, Schneider Children’s Medical Center
of Israel, Petach Tikva 49202, Israel

Received November 25, 2013; Accepted December 12, 2013; Epub December 22, 2013; Published December 30, 2013

Abstract: Umbilical cord blood (UCB) is a rich source of hematopoietic progenitors for transplantation. Murine and human progenitors
are insensitive to apoptotic signaling mediated by the TNF family receptors, however extension of culture over 48 hours is accompanied
by severe deterioration in engraftment and hematopoietic reconstituting capacity. In this study we assessed crosstalk between the Fas,
TNF and TRAIL receptors, and questioned whether it contributes to increased mortality and decreased activity of UCB progenitors
following extended ex vivo culture for 72 hours. The well-characterized TNF-induced expression of Fas is mediated by both TNF
receptors, yet the TNF receptors determine survival rather than Fas: superior viability of TNF-R1 progenitors. Additional cross talk
includes upregulation of TRAIL-R1 by Fas-ligand, mediated both by fast cycling and inductive crosstalk. These inductive interactions are
not accompanied by concomitant sensitization of progenitors to receptor-mediated apoptosis during extended culture, but rather
decreased fractional apoptosis in expanded progenitor subsets expressing the receptors. TRAIL upregulates both TRAIL-R1 and TRAIL-
R2, accompanied by commensurate susceptibility to spontaneous apoptosis. The current data reveal inductive crosstalk between TNF
family receptors, which are largely dissociated from the sensitivity of hematopoietic progenitors to apoptosis. Activation of Fas, TNF and
TRAIL receptors and excessive apoptosis are not responsible for loss of engraftment and impaired reconstituting activity of UCB
progenitors following extended culture. (AJSC1311002).

Keywords: Umbilical cord blood, receptor crosstalk, Fas, TNF-α, TRAIL, apoptosis, SCID reconstituting activity

Address correspondence to: Dr. Nadir Askenasy, Frankel Laboratory, Center for Stem Cell Research, Department of Pediatric
Hematology-Oncology, Schneider Children’s Medical Center of Israel, 14 Kaplan Street, Petach Tikva, Israel 49202. Tel: 972-3921-3954;
Fax: 972-3921-4156; E-mail: anadir@012.net.il
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