Pharmacological manipulation of the RAR/RXR signaling pathway maintains the repopulating capacity of hematopoietic stem cells in culture.
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.
Safi
Rachid
R
Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina 27710, USA.
Muramoto
Garrett G
GG
Salter
Alice B
AB
Meadows
Sarah
S
Himburg
Heather
H
Russell
Lauren
L
Daher
Pamela
P
Doan
Phuong
P
Leibowitz
Mark D
MD
Chao
Nelson J
NJ
McDonnell
Donald P
DP
Chute
John P
JP
D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D002839:Chromans / Q000378:metabolism; D019281:Dimerization; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010647:Phenyl Ethers / Q000494:pharmacology; D011487:Protein Conformation; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012176:Retinoids / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
C508470:7-(2-(2,2-difluoroethoxy)-3,5-di-tert-butylbenzene)-3-methylocta-2,4,6-trienoic acid; D001565:Benzoates; D015415:Biomarkers; D002839:Chromans; D005231:Fatty Acids, Unsaturated; D010647:Phenyl Ethers; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; C084904:Ro 41-5253; D051997:ADP-ribosyl Cyclase 1