Journal Article

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

Pratt, Gabriel A., Wilhelm, Brian T., Yeo, Gene W., Belew, Muluken S., Rentas, Stefan, Holzapfel, Nicholas T., Voisin, Veronique, Bader, Gary D., Hope, Kristin J.

2016

Overview

The RNA-binding protein Musashi-2 increases the self-renewing abilities of human haematopoietic stem cells, which have the potential to be used for regenerative therapies. Musashi-2 boots stem cell renewal Only a limited number of haematopoietic stem cells can be recovered from umbilical cord blood, limiting their therapeutic use. Little is known about the post-transcriptional mechanisms regulating self-renewal and fate decision in human haematopoietic stem cells. Kristin Hope and colleagues find that the RNA-binding protein Musashi-2 increases the self-renewal properties of human haematopoietic stem cells, including the ability to expand the long-term haematopoietic stem cells ex vivo . The authors use a global approach to identify the RNAs interacting with Musashi-2 and they identify the aryl hydrocarbon receptor (AHR) signalling pathway as a critical downstream component of the effects of Musashi-2 on the regenerative potential of cord blood-derived haematopoietic stem cells. 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 1 . Small molecules that enhance haematopoietic stem and progenitor cell (HSPC) expansion in culture have been identified 2 , 3 , 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 4 , 5 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45 / 631/337/574 / 631/532/1542 / Analysis / Animals / Base Sequence / Basic Helix-Loop-Helix Transcription Factors - genetics / Basic Helix-Loop-Helix Transcription Factors - metabolism / Cell Count / Cell Self Renewal - genetics / Down-Regulation - genetics / Female / Fetal Blood - cytology / Gene expression / Gene Knockdown Techniques / Hematopoietic stem cells / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - metabolism / Humanities and Social Sciences / Humans / letter / Male / Mice / multidisciplinary / Physiological aspects / Physiological research / Protein Binding / Protein expression / Proteins / Receptors, Aryl Hydrocarbon - genetics / Receptors, Aryl Hydrocarbon - metabolism / Regeneration (Biology) / RNA / RNA, Messenger - genetics / RNA, Messenger - metabolism / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Rodents / Science / Signal transduction / Signal Transduction - genetics / Stem cells / Studies / Transplants & implants