TNF-α Has Tropic Rather than Apoptotic Activity in Human Hematopoietic Progenitors: Involvement of TNF Receptor-1 and Caspase-8§

Authors

  • Keren Mizrahi,

    1. Frankel Laboratory, Center for Stem Cell ResearchDepartment of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
    2. Department of Surgery, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
    Search for more papers by this author
  • Jerry Stein,

    1. Bone marrow Transplant Unit, Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
    Search for more papers by this author
  • Isaac Yaniv,

    1. Bone marrow Transplant Unit, Department of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
    Search for more papers by this author
  • Offer Kaplan,

    1. Department of Surgery, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
    Search for more papers by this author
  • Nadir Askenasy

    Corresponding author
    1. Frankel Laboratory, Center for Stem Cell ResearchDepartment of Pediatric Hematology-Oncology, Schneider Children's Medical Center of Israel, Petach Tikva, Israel
    • Frankel Laboratory, Center for Stem Cell Research, Schneider Children's Medical Center of Israel, 14 Kaplan Street, Petach Tikva 49202, Israel
    Search for more papers by this author
    • Telephone: 972-3921-3954; Fax: 972-3921-4156


  • Author contributions: K.M.: performance of experiments and collection of data; J.S. and I.Y.: collection of data and data analysis and interpretation; O.K.: collection of data and manuscript writing; N.A.: performance of experiments, conception and design, and manuscript writing.

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

  • §

    First published online in STEM CELLSEXPRESS October 18, 2012.

Abstract

Tumor necrosis factor-α (TNF-α) has been suggested to exert detrimental effects on hematopoietic progenitor function that might limit the success of transplants. In this study, we assessed the influences of TNF-α and its two cognate receptors on the function of fresh umbilical cord blood (UCB) and cryopreserved mobilized peripheral blood (mPB). CD34+ progenitors from both sources are less susceptible to spontaneous apoptosis than lineage-committed cells and are not induced into apoptosis by TNF-α. Consequently, the activity of UCB-derived severe combined immune deficiency (SCID) reconstituting cells and long-term culture-initiating cells is unaffected by this cytokine. On the contrary, transient exposure of cells from both sources to TNF-α stimulates the activity of myeloid progenitors, which persists in vivo in UCB cell transplants. Progenitor stimulation is selectively mediated by TNF-R1 and involves activation of caspase-8, without redundant activity of TNF-R2. Despite significant differences between fresh UCB cells and cryopreserved mPB cells in susceptibility to apoptosis and time to activation, TNF-α is primarily involved in tropic signaling in hematopoietic progenitors from both sources. Cytokine-mediated tropism cautions against TNF-α neutralization under conditions of stress hematopoiesis and may be particularly beneficial in overcoming the limitations of UCB cell transplants. Stem Cells2013;31:156–166

Ancillary