TGFβ restores hematopoietic homeostasis after myelosuppressive chemotherapy.
TGFβ restores hematopoietic homeostasis after myelosuppressive chemotherapy.
复制标题
DOI：
10.1084/jem.20121610
复制
发表时间：
2013-03-11
期刊：
影响因子：
--
通讯作者：
Scandura JM
中科院分区：
文献类型：
--
作者：
Brenet F;Kermani P;Spektor R;Rafii S;Scandura JM
Blocking TGFβ signaling after chemotherapy accelerates hematopoietic reconstitution and delays the return of cycling HSCs to quiescence. Myelosuppression is a life-threatening complication of antineoplastic therapy, but treatment is restricted to a few cytokines with unilineage hematopoietic activity. Although hematopoietic stem cells (HSCs) are predominantly quiescent during homeostasis, they are rapidly recruited into cell cycle by stresses, including myelosuppressive chemotherapy. Factors that induce HSCs to proliferate during stress have been characterized, but it is not known how HSC quiescence is then reestablished. In this study, we show that TGFβ signaling is transiently activated in hematopoietic stem and progenitor cells (HSPCs) during hematopoietic regeneration. Blockade of TGFβ signaling after chemotherapy accelerates hematopoietic reconstitution and delays the return of cycling HSCs to quiescence. In contrast, TGFβ blockade during homeostasis fails to induce cycling of HSPCs. We identified the cyclin-dependent kinase inhibitor Cdkn1c (p57) as a key downstream mediator of TGFβ during regeneration because the recovery of chimeric mice, incapable of expressing p57 in HSPCs, phenocopies blockade of TGFβ signaling after chemotherapy. This study demonstrates that context-dependent activation of TGFβ signaling is central to an unrecognized counterregulatory mechanism that promotes homeostasis once hematopoiesis has sufficiently recovered from myelosuppressive chemotherapy. These results open the door to new, potentially superior, approaches to promote multilineage hematopoietic recovery by blocking the TGFβ signaling that dampens regeneration.
登录
查看更多内容
影响因子：
64.5
作者：
Kiel, MJ;Yilmaz, ÖH;Morrison, SJ
通讯作者：
Morrison, SJ
影响因子：
32.4
作者：
Gorelik, L;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
82.9
作者：
Kollet, Orit;Dar, Ayelet;Lapidot, Tsvee
通讯作者：
Lapidot, Tsvee
影响因子：
56.9
作者：
Cheng, T;Rodrigues, N;Scadden, DT
通讯作者：
Scadden, DT
影响因子：
15.9
作者：
Iwata, Jun-ichi;Hacia, Joseph G.;Chai, Yang
通讯作者：
Chai, Yang