Endothelial-specific inhibition of NF-kappaB enhances functional haematopoiesis
Authors
Poulos, Michael G.Ramalingam, Pradeep
Gutkin, Michael C.
Kleppe, Maria
Ginsberg, Michael
Crowley, Michael J. P.
Elemento, Olivier
Levine, Ross L.
Rafii, Shahin
Kitajewski, Jan
Greenblatt, Matthew B.
Shim, Jae-Hyuck
Butler, Jason M.
UMass Chan Affiliations
Department of Medicine, Division of RheumatologyDocument Type
Journal ArticlePublication Date
2016-12-21
Metadata
Show full item recordAbstract
Haematopoietic stem cells (HSCs) reside in distinct niches within the bone marrow (BM) microenvironment, comprised of endothelial cells (ECs) and tightly associated perivascular constituents that regulate haematopoiesis through the expression of paracrine factors. Here we report that the canonical NF-kappaB pathway in the BM vascular niche is a critical signalling axis that regulates HSC function at steady state and following myelosuppressive insult, in which inhibition of EC NF-kappaB promotes improved HSC function and pan-haematopoietic recovery. Mice expressing an endothelial-specific dominant negative IkappaBalpha cassette under the Tie2 promoter display a marked increase in HSC activity and self-renewal, while promoting the accelerated recovery of haematopoiesis following myelosuppression, in part through protection of the BM microenvironment following radiation and chemotherapeutic-induced insult. Moreover, transplantation of NF-kappaB-inhibited BM ECs enhanced haematopoietic recovery and protected mice from pancytopenia-induced death. These findings pave the way for development of niche-specific cellular approaches for the treatment of haematological disorders requiring myelosuppressive regimens.Source
Nat Commun. 2016 Dec 21;7:13829. doi: 10.1038/ncomms13829. Link to article on publisher's siteDOI
10.1038/ncomms13829Permanent Link to this Item
http://hdl.handle.net/20.500.14038/40222PubMed ID
28000664Related Resources
Link to Article in PubMedRights
Copyright © 2016, The Author(s).Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1038/ncomms13829