Year: 2019
Type: article
Abstract: The nuclear protein DEK is an endogenous DNA-binding chromatin factor regulating hematopoiesis. DEK is one of only 2 known secreted nuclear chromatin factors, but whether and how extracellular DEK regulates hematopoiesis is not known. We demonstrated that extracellular DEK greatly enhanced ex vivo expansion of cytokine-stimulated human and mouse hematopoietic stem cells (HSCs) and regulated HSC and hematopoietic progenitor cell (HPC) numbers in vivo and in vitro as determined both phenotypically (by flow cytometry) and functionally (through transplantation and colony formation assays). Recombinant DEK increased long-term HSC numbers and decreased HPC numbers through a mechanism mediated by the CXC chemokine receptor CXCR2 and heparan sulfate proteoglycans (HSPGs) (as determined utilizing Cxcr2-/- mice, blocking CXCR2 antibodies, and 3 different HSPG inhibitors) that was associated with enhanced phosphorylation of ERK1/2, AKT, and p38 MAPK. To determine whether extracellular DEK required nuclear function to regulate hematopoiesis, we utilized 2 mutant forms of DEK: one that lacked its nuclear translocation signal and one that lacked DNA-binding ability. Both altered HSC and HPC numbers in vivo or in vitro, suggesting the nuclear function of DEK is not required. Thus, DEK acts as a hematopoietic cytokine, with the potential for clinical applicability.
DOI: 10.1172/jci127460
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: American Cancer Society, Indiana Clinical and Translational Sciences Institute, University of Michigan, Deutsche Forschungsgemeinschaft, China Scholarship Council, RWTH Aachen University, National Institutes of Health, Medizinische Fakultät, RWTH Aachen University, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Mechanisms of Synergistic Regulation of Stem/Progenitors, The Role of Centromeres in the Molecular Biology of Prostate Cancer, DEK Regulation of Hematopoietic Stem Cell Renewal, Fate, and Hematopoiesis, Regulation of Hematopoietic Cell Production, G5765888351, G605845900, Enhancing Engraftment of Cord Blood by CD26 Inhibition, G6368484973, G721334636, Controlling Influences of Oxygen Tension and CD26/DPP4 Enzymatic Activity on Regulation of Hematopoietic Stem/Progenitor Cells and Hematopoiesis During Health, Ageing, and Disease, G9000044952, Hematopoietic stem and progenitor cell regulation for enhanced clinical efficacy
OpenAlex ID: W2944894501