New signaling identified to expand human haematopoietic stem cells

The research team specifically looked at stem cells from umbilical cord blood, a proven but under-utilized source of stem cells for the treatment of adult blood cancers. These stem cells have the potential to become an important therapeutic for the thousands of people suffering from blood cancers who are awaiting the life-saving transplants.

Cells from umbilical cord blood have unique properties that make them easier to use for transplantation, including accessibility and adaptability. As a result, they allow for safer and more effective transplants.

The problem, is that there are very few stem cells available in individual cord blood samples -- only about five per cent of all samples actually contain enough cells for a transplant. 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.

The team's research into the importance of Musashi-2 and its role in expanding the number of stem cells in a given cord blood sample could help ease the current stem cell shortages. They 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, authors show that MSI2 directly attenuates aryl hydrocarbon receptor (AHR) signalling through post-transcriptional downregulation of canonical AHR pathway components in cord blood HSPCs.

The 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.

http://www.nature.com/nature/journal/v532/n7600/full/nature17665.html