Neutralizing negative epigenetic regulation by HDAC5 enhances human haematopoietic stem cell homing and engraftment

Xinxin Huang, Bin Guo, Sheng Liu, Jun Wan and Hal E. Broxmeyer ()
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Xinxin Huang: Indiana University School of Medicine
Bin Guo: Indiana University School of Medicine
Sheng Liu: Indiana University School of Medicine
Jun Wan: Indiana University School of Medicine
Hal E. Broxmeyer: Indiana University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05178-5

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