title: TNF-α/Fas-RIP-1-induced cell death signaling separates murine hematopoietic stem cells/progenitors into 2 distinct populations.
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.
authors: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL 60153, USA.
authors: Yechen
authors: Y
authors: Xiao
authors: Hongling
authors: H
authors: Li
authors: Jun
authors: J
authors: Zhang
authors: Andrew
authors: A
authors: Volk
authors: Shubin
authors: S
authors: Zhang
authors: Wei
authors: W
authors: Wei
authors: Shanshan
authors: S
authors: Zhang
authors: Peter
authors: P
authors: Breslin
authors: Jiwang
authors: J
authors: Zhang
mesh_terms: D000741:Anemia, Aplastic; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors; D002454:Cell Differentiation / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000145:classification / Q000166:cytology / Q000378:metabolism; D006457:Hemoglobinuria, Paroxysmal / Q000378:metabolism* / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D010641:Phenotype; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000975:Antioxidants; D053148:Caspase 3; D053181:Caspase 8; D061945:Caspase Inhibitors; D020690:GTPase-Activating Proteins; D007093:Imidazoles; D007211:Indoles; D020930:MAP Kinase Kinase Kinases; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000099151:MAP Kinase Kinase Kinase 7; C491899:Fas protein, mouse; C490620:Ralbp1 protein, mouse; C506236:Tnfrsf1a protein, mouse; C507699:necrostatin-1; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse