Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Pharmacological manipulation of the RAR/RXR signaling pathway maintains the repopulating capacity of hematopoietic stem cells in culture. Mol Endocrinol 2009 Feb;23(2):188-201

Date

12/25/2008

Pubmed ID

19106195

Pubmed Central ID

PMC2646618

DOI

10.1210/me.2008-0121

Scopus ID

2-s2.0-58849113213   19 Citations

Abstract

The retinoid X receptor (RXR) contributes to the regulation of diverse biological pathways via its role as a heterodimeric partner of several nuclear receptors. However, RXR has no established role in the regulation of hematopoietic stem cell (HSC) fate. In this study, we sought to determine whether direct modulation of RXR signaling could impact human HSC self-renewal or differentiation. Treatment of human CD34(+)CD38(-)lin(-) cells with LG1506, a selective RXR modulator, inhibited the differentiation of HSCs in culture and maintained long-term repopulating HSCs in culture that were otherwise lost in response to cytokine treatment. Further studies revealed that LG1506 had a distinct mechanism of action in that it facilitated the recruitment of corepressors to the retinoic acid receptor (RAR)/RXR complex at target gene promoters, suggesting that this molecule was functioning as an inverse agonist in the context of this heterodimer. Interestingly, using combinatorial peptide phage display, we identified unique surfaces presented on RXR when occupied by LG1506 and demonstrated that other modulators that exhibited these properties functioned similarly at both a mechanistic and biological level. These data indicate that the RAR/RXR heterodimer is a critical regulator of human HSC differentiation, and pharmacological modulation of RXR signaling prevents the loss of human HSCs that otherwise occurs in short-term culture.

Author List

Safi R, Muramoto GG, Salter AB, Meadows S, Himburg H, Russell L, Daher P, Doan P, Leibowitz MD, Chao NJ, McDonnell DP, Chute JP

Author

Heather A. Himburg PhD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

ADP-ribosyl Cyclase 1
Animals
Benzoates
Biomarkers
Cell Cycle
Cell Differentiation
Cell Lineage
Cells, Cultured
Chromans
Dimerization
Fatty Acids, Unsaturated
Hematopoietic Stem Cells
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Phenyl Ethers
Protein Conformation
Receptors, Retinoic Acid
Retinoid X Receptors
Retinoids
Signal Transduction