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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Anemia, Aplastic
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Animals
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Antioxidants / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology
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Bone Marrow Diseases
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Bone Marrow Failure Disorders
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Caspase 3 / metabolism
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Caspase 8 / metabolism
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Caspase Inhibitors
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Cell Differentiation / physiology
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GTPase-Activating Proteins / antagonists & inhibitors
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GTPase-Activating Proteins / metabolism*
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Hematopoietic Stem Cells* / classification
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Hematopoietic Stem Cells* / cytology
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Hematopoietic Stem Cells* / metabolism
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Hemoglobinuria, Paroxysmal / metabolism*
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Hemoglobinuria, Paroxysmal / pathology
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Imidazoles / pharmacology
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Indoles / pharmacology
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism
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Mice
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Mice, Knockout
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Necrosis
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Phenotype
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Receptors, Tumor Necrosis Factor, Type I / genetics
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Receptors, Tumor Necrosis Factor, Type II / genetics
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Receptors, Tumor Necrosis Factor, Type II / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Tumor Necrosis Factor-alpha / metabolism*
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fas Receptor / metabolism*
Substances
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Antioxidants
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Caspase Inhibitors
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Fas protein, mouse
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GTPase-Activating Proteins
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Imidazoles
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Indoles
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Ralbp1 protein, mouse
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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Tnfrsf1a protein, mouse
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Tumor Necrosis Factor-alpha
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fas Receptor
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necrostatin-1
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7
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Casp3 protein, mouse
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Casp8 protein, mouse
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Caspase 3
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Caspase 8