by Simone Alves

Galphas is vital for engrafting of haematopoietic stem cells

Whether coming from a bone marrow transplant or a patient's own circulating blood, haematopoietic stem cells are remarkably good at finding their way back to the bone marrow niche. David Scadden and his colleagues at the Harvard Stem Cell Institute in Cambridge, Massachusetts, report that a G-protein known as Galphas is necessary to direct these cells to the niche1.

Galphas is essential during development. To be able to look at the effect of its absence, the group developed a chimeric mouse in which some cells in each tissue expressed the protein and some did not; the distribution of cells missing and expressing the protein should have been random. As expected, both types of cells contributed to fetal liver, skin and muscle. However, cells that were missing the protein were also missing in the bone marrow. Surprisingly, in vivo experiments showed that Galphas-/- cells had the same haematopoietic potential as their wild-type counterparts — they were simply unable to engraft in the bone marrow during development.

Next the researchers began using a mouse in which the Galphas gene could be knocked out at any stage after birth, and they found that the protein was needed for successful engraftment in adult mice too. Knocking out the gene didn't affect proliferation, morphology or in vitro migration, but Scadden found that, in vivo, Galphas-/- haematopoietic stem cells (HSCs) couldn't interact with the bone marrow vasculature and so couldn't engraft properly, leaving extra HSCs circulating in the bloodstream. Tinkering with the timing at which the gene was deleted, the group showed that Galphas isn't needed to retain HSCs in the niche; however, in conditions of stress, the proliferative cells could not be trafficked out of the marrow as they normally would, so Galphas is essential to HSCs' homing function.

The localization and successful engraftment of HSCs to the bone marrow after transplantation is critical to the success of clinical treatment for leukaemia. Scadden is a cofounder of Fate Therapeutics, which is pursuing the use of small molecules that improve engraftment. Chemically stimulating Galphas signalling increased the homing and engrafting ability of cells in mice, but how this will be applicable in humans remains to be seen. "What will be interesting to find out is what the G-protein couples to," says Sara Rankin, an expert in leukocyte and stem cell biology at Imperial College London. "It looks like there is one specific factor that regulates homing. Understanding the receptor will be important in determining the relevance to humans."

Defining the receptor is something Scadden is keen to address, but he adds that the protein is well trodden in human pharmacology. "Drugs that target this pathway have been developed for other conditions, but none are in the area of haematology," he says. The group will be taking a closer look at how the pathway can be modified pharmacologically. "Our finding lends itself to ready testing as a means of improving stem cell engraftment in humans," says Scadden, adding that he would like to find out if, by stimulating Galphas, stem cell engraftment can be successful when fewer stem cells are transplanted than are usually needed.


Source: Nature