Department of Medicine, Division of Rheumatology
Cell Biology | Developmental Biology
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.
Haematopoietic stem cells, Stem-cell niche
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Copyright © 2016, The Author(s).
DOI of Published Version
Nat Commun. 2016 Dec 21;7:13829. doi: 10.1038/ncomms13829. Link to article on publisher's site
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; and Butler, Jason M., "Endothelial-specific inhibition of NF-kappaB enhances functional haematopoiesis" (2016). Open Access Articles. 3016.
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