Endothelial-specific inhibition of NF-κB enhances functional haematopoiesis

Michael G. Poulos, Pradeep Ramalingam, Michael C. Gutkin, Maria Kleppe, Michael Ginsberg, Michael J. P. Crowley, Olivier Elemento, Ross L. Levine, Shahin Rafii, Jan Kitajewski, Matthew B. Greenblatt, Jae-Hyuck Shim and Jason M. Butler ()
Additional contact information
Michael G. Poulos: Ansary Stem Cell Institute, Weill Cornell Medical College
Pradeep Ramalingam: Ansary Stem Cell Institute, Weill Cornell Medical College
Michael C. Gutkin: Ansary Stem Cell Institute, Weill Cornell Medical College
Maria Kleppe: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Michael Ginsberg: Angiocrine Bioscience
Michael J. P. Crowley: Weill Cornell Medical College
Olivier Elemento: HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine, Weill Cornell Medical College
Ross L. Levine: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Shahin Rafii: Ansary Stem Cell Institute, Weill Cornell Medical College
Jan Kitajewski: Columbia University Medical Center
Matthew B. Greenblatt: Pathology and Laboratory Medicine, Weill Cornell Medical College
Jae-Hyuck Shim: University of Massachusetts Medical School
Jason M. Butler: Ansary Stem Cell Institute, Weill Cornell Medical College

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13829

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