UMMS Affiliation
Department of Medicine, Division of Rheumatology
Publication Date
2016-12-21
Document Type
Article
Disciplines
Cell Biology | Developmental Biology
Abstract
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.
Keywords
Haematopoietic stem cells, Stem-cell niche
Rights and Permissions
Copyright © 2016, The Author(s).
DOI of Published Version
10.1038/ncomms13829
Source
Nat Commun. 2016 Dec 21;7:13829. doi: 10.1038/ncomms13829. Link to article on publisher's site
Journal/Book/Conference Title
Nature communications
Related Resources
PubMed ID
28000664
Repository Citation
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.
https://escholarship.umassmed.edu/oapubs/3016
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.