Neutralizing negative epigenetic regulation by HDAC5 enhances human haematopoietic stem cell homing and engraftment
Year: 2018
Type: article
Abstract: Enhancement of hematopoietic stem cell (HSC) homing and engraftment is clinically critical, especially for cord blood (CB) hematopoietic cell transplantation. Here we report that specific HDAC5 inhibition highly upregulates CXCR4 surface expression in human CB HSCs and progenitor cells (HPCs). This results in enhanced SDF-1/CXCR4-mediated chemotaxis and increased homing to the bone marrow environment, with elevated SCID-repopulating cell (SRC) frequency and enhanced long-term and secondary engraftment in NSG mice. HDAC5 inhibition increases acetylated p65 levels in the nucleus, which is important for CXCR4 transcription. Inhibition of nuclear factor-κB (NF-κB) signaling suppresses HDAC5-mediated CXCR4 upregulation, enhanced HSC homing, and engraftment. Furthermore, activation of the NF-κB signaling pathway via TNFα also results in significantly increased CXCR4 surface expression, enhanced HSC homing, and engraftment. These results demonstrate a previously unknown negative epigenetic regulation of HSC homing and engraftment by HDAC5, and allow for a new and simple translational strategy to enhance HSC transplantation.
Source: Nature Communications
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, Walther Cancer Foundation, Eli Lilly and Company, Purdue University, Lilly Endowment, Purdue University Center for Cancer Research, National Institutes of Health, School of Medicine, Indiana 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, G1562509152, G2484759242, G2499798185, G272352002, G5163953653, Cancer Center Support Grant, Enhancing Engraftment of Cord Blood by CD26 Inhibition, G7029611642, G715545143, G76404464, G8952826573, Controlling Influences of Oxygen Tension and CD26/DPP4 Enzymatic Activity on Regulation of Hematopoietic Stem/Progenitor Cells and Hematopoiesis During Health, Ageing, and Disease, G9000304140, Hematopoietic stem and progenitor cell regulation for enhanced clinical efficacy, Indiana University Melvin and Bren Simon Comprehensive Cancer Center Support Grant
OpenAlex ID: W2850552540