Genetic switch essential for blood stem cell regeneration

A genetic switch that can increase blood stem cell regeneration and aid in the treatment of blood disorders has been uncovered.

Fli-1 is a genetic transcription factor, a protein that helps express or silence genes. When activated, it increases the rate at which stem cells are replicated. Researchers from Weill Cornell Medicine, New York, discovered that by using modified mRNA encoded with the Fli-1 transcription factor, they could temporarily upregulate stem cell production without causing a permanent increase in activity.

'The stem cells we prime with Fli-1 modified mRNA in this way wake up from hibernation, expand and functionally and durably engraft in the recipient host, without any evidence of cancer,' said Dr Tomer Itkin, director of Tel Aviv University's Neufeld Cardiovascular Research Institute, Israel, and first author of the paper, published in Nature Immunology.

Previous research has linked excessive stem cell activity to an increased risk of leukaemia. However, the use of the Fli-1-modified mRNA did not show this. To confirm that Fli-1 was responsible for stem cell activation, researchers employed single-cell analysis, among other analytical techniques.

The stem cells in question were haematopoietic stem cells, which can differentiate into any type of blood cell, such as white blood cells, red blood cells or platelets. These stem cells typically reside in the bone marrow in a dormant or 'quiescent' state. Upon activation, they are released into the bloodstream to replace damaged or depleted blood cells.

Previously, it was thought that stem cells received signals from the bone marrow, regulating their activity. Research has now shown that there is two-way communication between the stem cells and their surrounding environment, referred to as the vascular niche.

The authors hope that further research could aid treatments for people undergoing chemotherapy or radiotherapy, which can damage and lower the number of blood cells by suppressing bone marrow activity and require their replenishment through bone marrow transplants, for example. The efficacy of such transplants has been shown to increase when larger quantities of stem cells are transplanted.

'The approach we outlined in this study could substantially improve the efficiency of marrow transplants and marrow-cell-targeted gene therapies, especially in cases where the donor has a very limited supply of viable blood stem cells,' said study senior author Shahin Rafii, professor at Weill Cornell Medical College.

In addition, the authors write that people diagnosed with genetic blood disorders such as sickle cell anaemia may also benefit from receiving genetic therapy using their own blood cells with modified DNA. As with bone marrow transplants, such therapy is more likely to succeed with increased stem cell counts.

The study also revealed that stem cells obtained from newborns' umbilical cords have greater regenerative potential than those found in adults. This is likely because of their higher levels of Fli-1 activity, which further emphasises the role of this transcription factor in stem cell regeneration.

The researchers hope that further preclinical research, and eventually clinical trials, can build on these discoveries to offer improved to blood treatment options for patients in future.