You are hereApril 2, 2017 | Haematopoetic Stem Cells
Unexpected Findings Reveal a Complex Role for the NF-κB pathway in Hematopoiesis
Review of “Constitutive Activation of NIK Impairs the Self-Renewal of Hematopoietic Stem/Progenitor Cells and Induces Bone Marrow Failure” from Stem Cells by Stuart P. Atkinson
A previous Stem Cells study from the laboratory of Chen Zhao (University of Iowa, USA) described the importance of non-canonical NF-κB signaling in the regulation of hematopoietic stem/progenitor cells (HSPCs) and the stromal/osteoblastic niche they call home . The team now return to Stem Cells with another excellent study in which they investigate the role of the NF-κB Inducing Kinase (NIK), a key signaling molecule in the non-canonical NF-κB pathway. Their unexpected findings reveal a complex role for the NF-κB pathway in hematopoiesis and in the development of bone marrow failure .
The model system employed an engineered HSPC-specific mutation of the tumor necrosis factor receptor-associated factor 3 (TRAF3)-binding domain of NIK which impairs degradation and allows constitutive NIK activity. Unexpectedly, mice overexpressing NIK displayed growth retardation, post-natal mortality, smaller spleen size, and displayed signs of bone marrow failure, all suggesting a detrimental effect of constitutive activation of NIK to normal hematopoiesis. Indeed, the authors soon discovered that NIK activation actually impaired HSPC self-renewal, reduced cell proliferation, increased apoptosis and inflammatory cytokine responses, and disrupted the bone marrow environment via enhanced levels of osteoclast formation.
Importantly, non-canonical signaling through NIK activation displayed distinct phenotypes compared to the activation of canonical NF-κB signaling. Reinforcing this point, RNA-Seq experiments in NIK-overexpressing HSPCs demonstrated changes to non-canonical NF-κB signaling genes and not canonical pathway-associated genes. These experiments also highlighted decreases in genes associated with stemness, HSPC self-renewal, and HSPC differentiation and increases in genes associated with inflammatory responses and cell cycle inhibition.
Overall, these unexpected but vital findings reveals a complex role for the NF-κB pathway in hematopoietic homeostasis and the development of bone marrow failure. Stay tuned to the Stem Cells Portal to find out more!
- Zhao C, Xiu Y, Ashton J, et al. Noncanonical NF-kappaB signaling regulates hematopoietic stem cell self-renewal and microenvironment interactions. Stem Cells 2012;30:709-718.
- Xiu Y, Xue WY, Lambertz A, et al. Constitutive Activation of NIK Impairs the Self-Renewal of Hematopoietic Stem/Progenitor Cells and Induces Bone Marrow Failure. Stem Cells 2017;35:777-786.