| First Author | Xiao Y | Year | 2011 |
| Journal | Blood | Volume | 118 |
| Issue | 23 | Pages | 6057-67 |
| PubMed ID | 21989986 | Mgi Jnum | J:179087 |
| Mgi Id | MGI:5301052 | Doi | 10.1182/blood-2011-06-359448 |
| Citation | Xiao Y, et al. (2011) TNF-alpha/Fas-RIP-1-induced cell death signaling separates murine hematopoietic stem cells/progenitors into 2 distinct populations. Blood 118(23):6057-67 |
| abstractText | 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. |
