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
12/25/2008Pubmed ID
19106195Pubmed Central ID
PMC2646618DOI
10.1210/me.2008-0121Scopus ID
2-s2.0-58849113213 (requires institutional sign-in at Scopus site) 24 CitationsAbstract
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 JPAuthor
Heather A. Himburg PhD Professor in the Radiation Oncology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ADP-ribosyl Cyclase 1Animals
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
