TNF-α has tropic rather than apoptotic activity in human hematopoietic progenitors: involvement of TNF receptor-1 and caspase-8

Stem Cells. 2013 Jan;31(1):156-66. doi: 10.1002/stem.1259.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD34 / metabolism
  • Apoptosis
  • Caspase 8 / metabolism*
  • Cells, Cultured
  • Enzyme Activation
  • Fetal Blood / cytology*
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Mice
  • Mice, SCID
  • Receptors, Tumor Necrosis Factor, Type I / metabolism*
  • Receptors, Tumor Necrosis Factor, Type II
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Antigens, CD34
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha
  • Caspase 8