A serious side effect that cancer patients undergoing chemotherapy experience is myelosuppression. That’s a big word for a process that involves the decreased production of the body’s immune cells from hematopoietic stem cells (HSCs) or blood stem cells in the bone marrow. Without these important cells that make up the immune system, patients are at risk for major infections and even death.
Scientists are trying to find ways to treat cancer patients that have undergone myelosuppressive therapies, as well as patients that need bone marrow transplants to replace their own bone marrow that’s been damaged or removed. One possible solution is boosting the regenerative capacity of HSCs. Transplanting HSCs that are specially primed to reproduce rapidly into cells of the immune system could improve the outcome of bone marrow transplants in patients.
Deleting Grb10 boost blood stem cell regeneration
A CIRM-funded team from the UCLA Broad Stem Cell Research Center and the Jonsson Comprehensive Cancer Center has identified a single gene that can be manipulated to boost HSC regeneration in mice. The study, which was published in Cell Reports, found that deleting or turning off expression of an imprinted gene called Grb10 in HSCs caused these blood stem cells to reproduce more robustly after being transplanted into mice that had their bone marrow removed.
I just used another big word in that last paragraph, so let me explain. An imprinted gene is a gene that is expressed or activated based on which parent it was inherited from. Typically, you receive one copy of a gene from your mother and one from your father and both are expressed – a process called Mendelian inheritance. But imprinted genes are different – they are marked with specific epigenetic tags that silence their expression in the sperm or egg cells of the parents. Thus if you inherited an imprinted gene from your mother, the other copy of that gene from your father would be expressed and vice versa.
Scientists have discovered that imprinted genes are important for human development and also for directing what cell types adult stem cells like HSCs develop into. The team from UCLA led by senior author Dr. John Chute, was interested in answering a different question: are imprinted genes involved in determining the function of HSCs? They compared two different populations of HSCs derived from mouse bone marrow: a normal, healthy population and HSCs exposed to total body irradiation (TBI), which destroys the immune system. They discovered that the expression of an imprinted gene called Grb10 was dramatically higher in HSCs exposed to TBI compared to healthy HSCs.
Because Grb10 is an imprinted gene, the scientists deleted either the paternal or maternal copy of that gene in mice. While deleting the paternal Grb10 gene had no effect on the function of HSCs, maternal deletion dramatically boosted the capacity of HSCs to divide and make more copies of themselves. Without the maternal copy of Grb10, HSCs were able to regenerate at a much faster scale than normal HSCs.
To further prove their point, the team transplanted normal HSCs and HSCs that lacked Grb10 into TBI or fully irradiated mice. HSCs that lacked Grb10 were able to regenerate themselves and produce other immune cells more robustly 20 weeks after transplantation compared to normal HSCs.
Potential applications and future studies
This study offers two important findings. First, they discovered that Grb10 plays an important role “in regulating HSC self-renewal following transplantation and HSC regeneration in response to injury.” Second, they found that inhibiting Grb10 function in HSCs could have potential therapeutic applications for boosting “hematopoietic regeneration in the setting of HSC transplantation or following myelosuppressive injury.” Patients in need of bone marrow transplants could potentially receive more benefit from transplants of HSCs that don’t express the Grb10 gene.
In my opinion, further studies should be done to further understand the role of Grb10 in regulating HSC self-renewal and regeneration. What is the benefit of having this gene expressed in HSCs if inhibiting its expression leads to an increased regenerative capacity? Is it to prevent cancer from forming? Additionally, the authors will need to address the potential long-term side effects of inhibiting Grb10 expression in HSCs. They did report that mice that lacked the Grb10 gene did not develop blood cancers at one year of age which is good news. They also suggested that instead of deleting Grb10, new drugs could be identified that inhibit Grb10 function in HSCs.