Journal
BLOOD
Volume 118, Issue 23, Pages 6057-6067Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2011-06-359448
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Funding
- Department of Defense through Loyola University Chicago [PR080447]
- National Natural Science Foundation of China [81071774]
- Shanghai Institutions of Higher Learning through Shanghai Normal School
- Jimmy Burns Foundation
- CDMRP [PR080447, 546954] Funding Source: Federal RePORTER
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We studied the effects of TNF-alpha 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-alpha 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-alpha-sensitive HSPCs. This TNF-alpha/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-alpha/Fas-RIP-1-dependent necroptosis and TNF-alpha/Fas-independent apoptosis in HSPCs. (Blood. 2011;118(23):6057-6067)
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