Musashi-2 attenuates AHR signalling to expand human haematopoietic stem cells.

TitleMusashi-2 attenuates AHR signalling to expand human haematopoietic stem cells.
Publication TypeJournal Article
Year of Publication2016
AuthorsRentas S, Holzapfel NT, Belew MS, Pratt GA, Voisin V, Wilhelm BT, Bader GD, Yeo GW, Hope KJ
JournalNature
Volume532
Issue7600
Pagination508-11
Date Published2016 Apr 28
ISSN1476-4687
KeywordsAnimals, Base Sequence, Basic Helix-Loop-Helix Transcription Factors, Cell Count, Cell Self Renewal, Down-Regulation, Female, Fetal Blood, Gene Knockdown Techniques, Hematopoietic Stem Cells, Humans, Male, Mice, Protein Binding, Receptors, Aryl Hydrocarbon, RNA, Messenger, RNA-Binding Proteins, Signal Transduction
Abstract

Umbilical cord blood-derived haematopoietic stem cells (HSCs) are essential for many life-saving regenerative therapies. However, despite their advantages for transplantation, their clinical use is restricted because HSCs in cord blood are found only in small numbers. Small molecules that enhance haematopoietic stem and progenitor cell (HSPC) expansion in culture have been identified, but in many cases their mechanisms of action or the nature of the pathways they impinge on are poorly understood. A greater understanding of the molecular circuitry that underpins the self-renewal of human HSCs will facilitate the development of targeted strategies that expand HSCs for regenerative therapies. Whereas transcription factor networks have been shown to influence the self-renewal and lineage decisions of human HSCs, the post-transcriptional mechanisms that guide HSC fate have not been closely investigated. Here we show that overexpression of the RNA-binding protein Musashi-2 (MSI2) induces multiple pro-self-renewal phenotypes, including a 17-fold increase in short-term repopulating cells and a net 23-fold ex vivo expansion of long-term repopulating HSCs. By performing a global analysis of MSI2-RNA interactions, we show that MSI2 directly attenuates aryl hydrocarbon receptor (AHR) signalling through post-transcriptional downregulation of canonical AHR pathway components in cord blood HSPCs. Our study gives mechanistic insight into RNA networks controlled by RNA-binding proteins that underlie self-renewal and provides evidence that manipulating such networks ex vivo can enhance the regenerative potential of human HSCs.

DOI10.1038/nature17665
PubMed URLhttp://www.ncbi.nlm.nih.gov/pubmed/27121842?dopt=Abstract
Alternate JournalNature
PubMed ID27121842
PubMed Central IDPMC4880456
Grant ListHG004659 / HG / NHGRI NIH HHS / United States
MOP-126030 / / Canadian Institutes of Health Research / Canada
NS075449 / NS / NINDS NIH HHS / United States
R01 HG004659 / HG / NHGRI NIH HHS / United States
R01 NS075449 / NS / NINDS NIH HHS / United States
Track(s): 
Bioinformatics and Systems Biology