How blood stem cells regenerate themselves

It's long been a mystery as to how hematopoietic stem cells (HSC), or blood stem cells, differentiate into the various blood cells and regenerate themselves from the earliest stages of development throughout life.

Now researchers at the Walter and Eliza Hall Institute (WEHI) have revealed the role of the Erg gene in this crucial process, finding that it is vitally important in enabling HSCs to regenerate themselves.

The discovery has various therapeutic implications, such as for tissue repair therapy and transplantations.

The research was led by WEHI chief, Professor Doug Hilton, and Dr Samir Taoudi, along with colleagues from the institute’s Molecular Medicine and Cancer and Haematology divisions.

“One of the key features of blood stem cells, one that could be exploited for therapeutic use, is their ability to regenerate or renew themselves,” Dr Taoudi said.

“However, relatively little is known about how this occurs, or the molecular pathways that specifically control regeneration.”

It was known there is a host of genes that play a role in differentiation and regeneration, but it was not known precisely what role the Erg gene played, or if it was even required.

Past experiments have shown that the lack of the Erg gene in mice and zebrafish didn't prevent blood cells from being created.

The WEHI team found that this is because Erg is not involved in differentiation. So once a cabal of HSCs are created in the embryo, they will differentiate and propagate as normal.

However, without Erg, the HSCs don't renew themselves and eventually become exhausted.

They found that Erg regulates two other genes, Gata2 and Runx1, and these are involved in maintaining the HSCs.

“These genes are called transcription factors, they are the ‘switches’ that turn on and off other genes,” Dr Taoudi said.

“Individually, these genes are not essential for regeneration, but if you lose both, the stem cells are quickly exhausted. This is a key part of the puzzle, but we will continue to work to find out how these genes directly control self-renewal, and the signals that actually tell the stem cell to regenerate.”

HSCs are multipotent, so they can become any of the other blood cells, although they can normally only be isolated in numbers too small for therapeutic use. And when they are isolated, they often lose their ability to differentiate into other cells.

“At the moment, if you take stem cells from a person and try to expand them, many of the stem cells lose their ability to regenerate,” Dr Taoudi said.

“The practical aim of our research is to find ways in which you could take stem cells collected from bone marrow or cord blood and ‘switch on’ expression of particular sets of genes, encouraging the stem cells to expand, essentially creating your own endless supply of blood stem cells.”

The study, published in the February edition of Genes and Development, was funded by the National Health and Medical Research Council, the Australian Cancer Research Foundation, the Australian Stem Cell Centre, the Australian Research Council, the Sylvia and Charles Viertel Charitable Foundation and the Victorian Government.