title: Endothelial-specific inhibition of NF-κB enhances functional haematopoiesis.
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-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.
authors.affiliation: Department of Genetic Medicine, Ansary Stem Cell Institute, Weill Cornell Medical College, New York, New York 10021, USA.|Department of Surgery, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Poulos
authors.affiliation: Department of Genetic Medicine, Ansary Stem Cell Institute, Weill Cornell Medical College, New York, New York 10021, USA.|Department of Surgery, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Pradeep
authors.identifier: http://orcid.org/0000-0002-5943-9670
authors.initials: P
authors.lastname: Ramalingam
authors.affiliation: Department of Genetic Medicine, Ansary Stem Cell Institute, Weill Cornell Medical College, New York, New York 10021, USA.|Department of Surgery, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Gutkin
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Kleppe
authors.affiliation: Angiocrine Bioscience, New York, New York 10065, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Ginsberg
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College, New York, New York 10065, USA.|Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medical College, New York, New York 10065, USA.|Neuberger Berman Lung Cancer Center, Weill Cornell Medical Center, New York, New York 10065, USA.
authors.forename: Michael J P
authors.initials: MJP
authors.lastname: Crowley
authors.affiliation: HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.|Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Department of Medicine, Division of Regenerative Medicine, Ansary Stem Cell Institute, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Department of OB/GYN, Columbia University Medical Center, New York, New York 10032, USA.|Department of Pathology, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Kitajewski
authors.affiliation: Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Greenblatt
authors.affiliation: Department of Medicine, Division of Rheumatology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Jae-Hyuck
authors.initials: JH
authors.lastname: Shim
authors.affiliation: Department of Genetic Medicine, Ansary Stem Cell Institute, Weill Cornell Medical College, New York, New York 10021, USA.|Department of Surgery, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Butler
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism*; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010198:Pancytopenia / Q000628:therapy; D015398:Signal Transduction; D055153:Stem Cell Niche
chemical_list: D016328:NF-kappa B; D000072000:NF-KappaB Inhibitor alpha