A protein that controls the formation of different types of mature blood cells could play an important role in developing new treatments for blood diseases and helping realize the potential of regenerative medicine.

A study led by researchers from Cincinnati Children’s, published online Oct. 7 in the Journal of Experimental Medicine, sheds new light on the function of RhoA, a GTPase protein that serves as a molecular switch in guiding blood cell formation. 

RhoA is necessary for regulating the final stage of cell division in progenitor cells as they produce several kinds of adult blood cells. Mutations in the RhoA pathway have been linked to certain immune disorders including human combined immunodeficiency, which makes people highly susceptible to infections.

Finding ways to control this pathway could lead to improved treatments for this and other blood diseases, immune disorders and cancers. The new study also could be useful for researching approaches to regenerative medicine, in which pluripotent stem cells could be used to repair or regrow damaged tissues. 

“We show that RhoA deficiency causes hematopoietic failure in all lines of blood cells and results in defective hematopoietic progenitor cells,” said Yi Zheng, PhD, lead investigator and director of Experimental Hematology and Cancer Biology at Cincinnati Children’s. “This is also important to understanding diseases like pancytopenia, in which people don’t produce enough mature red and white blood cells and platelets. In regenerative medicine, it appears RhoA function would need to be artfully controlled to obtain functional blood cells.”

Zheng and colleagues conducted a series of experiments in mouse models to confirm their data. In one test, the team transplanted stem cells from mice bred to lack RhoA into another group of mice. The  RhoA-deficient stem cells achieved long term engraftment, but they were unable to produce new progenitor cells or differentiated blood cells. In another test, the researchers were able to reconstitute RhoA in the cells, which restored the normal function of hematopoietic stem and progenitor cells.

Now Zheng’s team is testing prospective small-molecule inhibitors developed at Cincinnati Children’s that could treat disease by blocking abnormal RhoA pathway functions.

Article written by Nick Miller, Cincinnati Children’s. Contact: nicholas.miller@cchmc.org