Endothelial-specific inhibition of NF-κB enhances functional haematopoiesis.

TitleEndothelial-specific inhibition of NF-κB enhances functional haematopoiesis.
Publication TypeJournal Article
Year of Publication2016
AuthorsPoulos MG, Ramalingam P, Gutkin MC, Kleppe M, Ginsberg M, Crowley MJP, Elemento O, Levine RL, Rafii S, Kitajewski J, Greenblatt MB, Shim J-H, Butler JM
JournalNat Commun
Date Published2016 12 21
KeywordsAnimals, Endothelial Cells, Hematopoiesis, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Mice, Inbred C57BL, Mice, Transgenic, NF-kappa B, NF-KappaB Inhibitor alpha, Pancytopenia, Signal Transduction, Stem Cell Niche

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-κB 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-κB promotes improved HSC function and pan-haematopoietic recovery. Mice expressing an endothelial-specific dominant negative IκBα 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-κB-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.

Alternate JournalNat Commun
PubMed ID28000664
PubMed Central IDPMC5187502
Grant ListDP5 OD021351 / OD / NIH HHS / United States
R01 CA204308 / CA / NCI NIH HHS / United States
R01 HL133021 / HL / NHLBI NIH HHS / United States