Regulatory functions of TRAIL in hematopoietic progenitors: human umbilical cord blood and murine bone marrow transplantation

Abstract

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway has selective toxicity to malignant cells. The TRAIL receptors DR4 and DR5 are expressed at low levels in human umbilical cord blood cells (3-15%) and are upregulated by incubation with the cognate ligand, triggering apoptosis in 70-80% of receptor-positive cells (Po0.001). Apoptosis is not induced in hematopoietic progenitors, as determined from sustained severe combined immunodeficiency reconstituting potential and clonogenic activity. Furthermore, elimination of dead cells after incubation with TRAIL for 72 h results in a threefold enrichment in myeloid progenitors. Exposure to TRAIL in semisolid cultures showed synergistic activity of DR4 and granulocyte/macrophage colony-stimulating factor in recruiting lineage-negative (lin À ) and CD34 þ progenitors and in promoting the formation of large colonies. In murine bone marrow, B30% of lin À cells express TRAIL-R2 (the only murine receptor), and the receptor is upregulated after transplantation in cycling and differentiating donor cells that home to the host marrow. However, this receptor is almost ubiquitously expressed in the most primitive (lin À SCA-1 þ c-kit þ ) progenitors, and stimulates the clonogenic activity of lin À cells (Po0.001), suggesting a tropic function after transplantation. It is concluded that TRAIL does not trigger apoptosis in hematopoietic progenitors, and upregulation of its cognate receptors under stress conditions mediates tropic signaling that supports recovery from hypoplasia.

Negative selection by apoptosis enriches progenitors in naïve and expanded human umbilical cord blood grafts

“…17,20,21 The identified physiological roles of receptor/ligand interactions in the transplant setting include cell interaction with bone-marrow stroma 24 and autocrine-and paracrine-trophic signaling. [18][19][20][21][22] In addition to these early activities, hematopoietic progenitors deficient in Fas and TNF receptors fail to mediate durablemultilineage reconstitution. 17,18 Insensitivity of hematopoietic progenitors to apoptosis can be used to improve the outcome of transplants, conferring immune privilege to the graft 24,25 and fostering progenitor activity.…”

“…17,18 Insensitivity of hematopoietic progenitors to apoptosis can be used to improve the outcome of transplants, conferring immune privilege to the graft 24,25 and fostering progenitor activity. [19][20][21][22] A pretransplant apoptotic challenge with Fas-ligand (FasL) and TNF-α reduces significantly the incidence and severity of GvHD in haploidentical-and xenogeneic-murine transplants, 26,27 and improves early myeloid reconstitution. 20,22 In this study we assessed possible implementation of apoptotic signaling in several aspects of UCB cell transplantation.…”

“…In contrast to apoptotic signaling in differentiated cells that mediates homeostatic negative regulation, murine and human precursors are inherently insensitive to apoptosis. [17][18][19][20] Signaling mediated by the Fas, TNF and TNF-Related Apoptosis-Inducing Ligand (TRAIL) receptors triggers progenitor activity and synergizes with other inductive factors in promoting hematopoietic differentiation. 19,21,22 This mechanism links injury signals, including TNF-family ligands, with the activation of the hematopoietic system to ensure prompt recovery from hypoplasia.…”

“…[17][18][19][20] Signaling mediated by the Fas, TNF and TNF-Related Apoptosis-Inducing Ligand (TRAIL) receptors triggers progenitor activity and synergizes with other inductive factors in promoting hematopoietic differentiation. 19,21,22 This mechanism links injury signals, including TNF-family ligands, with the activation of the hematopoietic system to ensure prompt recovery from hypoplasia. It also explains the marked upregulation of these receptors under conditions of stress hematopoiesis 23 and ubiquitous expression in most primitive progenitors.…”

“…cells were diluted twofold with medium containing 0.5% human serum albumin and were isolated by centrifugation over a Ficoll-density gradient (1.077-1.08 g/mL, MP Biomedical, Illkirch, France). 19,20 CD34 + progenitors were immunomagnetically isolated using the CD34 Progenitor Cell Isolation Kit (Miltenyi Biotec, Bergisch Gladbach, Germany).…”