Cracking the code for generating stem cells

Part of the mystery of stem cell generation has been unravelled in a study that has found hematopoietic stem cells (HSCs) need buddy cells to generate.

The study, led by researchers at the Australian Regenerative Medicine Institute (ARMI) at Monash University and the Garvan Institute of Medical Research, also identified molecular signals (chemokines) and genes involved in the mechanism that triggers HSC production.

Found in the bone marrow and in umbilical cord blood, HSCs play a critically important role in replenishing the body’s supply of blood cells. Patients with leukaemia are successfully treated using HSC transplants and research is revealing that blood stem cells have the potential to be used more widely.

Professor Peter Currie, lead researcher from ARMI, explained that understanding how HSCs self-renew to replenish blood cells is a ‘Holy Grail’ of stem cell biology.

“HSCs are one of the best therapeutic tools at our disposal because they can make any blood cell in the body. Potentially we could use these cells in many more ways than current transplantation strategies to treat serious blood disorders and diseases, but only if we can figure out how they are generated in the first place. Our study brings this possibility a step closer,” he said.

A key stumbling block to using HSCs more widely has been the inability to produce them in the laboratory setting. Previous research suggests that this is because a molecular ‘switch’ may also be necessary for HSC formation, although the mechanism has remained elusive, until now.

The researchers observed cells in the developing zebra fish - a tropical freshwater fish known for its regenerative abilities and optically clear embryos - and gathered new information on the signalling process responsible for HSC generation.

Using high-resolution microscopy, the researchers filmed the process of stem cell formation inside the zebra fish embryo.

Currie said when they played back the films they noticed the HSCs had a buddy cell that appeared to help them form. These buddy cells, called endotome cells, are endothelial precursor cells with stem cell-inducing properties.

“Endotome cells act like a comfy sofa for pre HSCs to snuggle into, helping them progress to become fully fledged stem cells. Not only did we identify some of the cells and signals required for HSC formation, we also pinpointed the genes required for endotome formation in the first place,” Currie said.

“The really exciting thing about these results is that if we can find the signals present in the endotome cells responsible for embryonic HSC formation then we can use them in vitro to make different blood cells on demand for all sorts of blood-related disorders.

“Potentially it’s imaginable that you could even correct genetic defects in cells and then transplant them back into the body,” Currie said.

Dr Georgina Hollway, from the Garvan Institute of Medical Research, said the work highlights how molecular processes in the body play a key role in HSC formation.

“We now know that these migratory cells are essential in the formation of hematopoietic stem cells, and we have described some of the molecular processes involved. This information is not the whole solution to creating them in the lab, but it will certainly help,” said Hollway.

In the next phase of the research the team aims to identify more of the molecular cues that trigger HSC production.

The study has been published in Nature.