TNF-α/Fas-RIP-1-induced cell death signaling separates murine hematopoietic stem cells/progenitors into 2 distinct populations

Blood. 2011 Dec 1;118(23):6057-67. doi: 10.1182/blood-2011-06-359448. Epub 2011 Oct 11.

Abstract

We studied the effects of TNF-α and Fas-induced death signaling in hematopoietic stem and progenitor cells (HSPCs) by examining their contributions to the development of bone marrow failure syndromes in Tak1-knockout mice (Tak1(-/-)). We found that complete inactivation of TNF-α signaling by deleting both of its receptors, 1 and 2 (Tnfr1(-/-)r2(-/-)), can prevent the death of 30% to 40% of Tak1(-/-) HSPCs and partially repress the bone marrow failure phenotype of Tak1(-/-) mice. Fas deletion can prevent the death of 5% to 10% of Tak1(-/-) HSPCs but fails to further improve the survival of Tak1(-/-)Tnfr1(-/-)r2(-/-) HSPCs, suggesting that Fas might induce death within a subset of TNF-α-sensitive HSPCs. This TNF-α/Fas-induced cell death is a type of receptor-interacting protein-1 (RIP-1)-dependent programmed necrosis called necroptosis, which can be prevented by necrostatin-1, a specific RIP-1 inhibitor. In addition, we found that the remaining Tak1(-/-) HSPCs died of apoptosis mediated by the caspase-8-dependent extrinsic apoptotic pathway. This apoptosis can be converted into necroptosis by the inhibition of caspase-8 and prevented by inhibiting both caspase-8 and RIP-1 activities. We concluded that HSPCs are heterogeneous populations in response to death signaling stimulation. Tak1 mediates a critical survival signal, which protects against both TNF-α/Fas-RIP-1-dependent necroptosis and TNF-α/Fas-independent apoptosis in HSPCs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anemia, Aplastic
  • Animals
  • Antioxidants / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Bone Marrow Diseases
  • Bone Marrow Failure Disorders
  • Caspase 3 / metabolism
  • Caspase 8 / metabolism
  • Caspase Inhibitors
  • Cell Differentiation / physiology
  • GTPase-Activating Proteins / antagonists & inhibitors
  • GTPase-Activating Proteins / metabolism*
  • Hematopoietic Stem Cells* / classification
  • Hematopoietic Stem Cells* / cytology
  • Hematopoietic Stem Cells* / metabolism
  • Hemoglobinuria, Paroxysmal / metabolism*
  • Hemoglobinuria, Paroxysmal / pathology
  • Imidazoles / pharmacology
  • Indoles / pharmacology
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mice, Knockout
  • Necrosis
  • Phenotype
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Receptors, Tumor Necrosis Factor, Type II / genetics
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tumor Necrosis Factor-alpha / metabolism*
  • fas Receptor / metabolism*

Substances

  • Antioxidants
  • Caspase Inhibitors
  • Fas protein, mouse
  • GTPase-Activating Proteins
  • Imidazoles
  • Indoles
  • Ralbp1 protein, mouse
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • necrostatin-1
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Casp3 protein, mouse
  • Casp8 protein, mouse
  • Caspase 3
  • Caspase 8