Stanford researchers find structure of master stem cell regulator
Aug 25, 2023
Stanford researchers, working with colleagues have determined the structure of a molecule that is extremely important for controlling the maintenance and development of blood stem cells, and have also designed new molecules that can affect those processes in order to better treat disease.
“Thrombopoietin (TPO) is a master regulator of stem cell biology,” said Chris Garcia, PhD, a professor in the Department of Molecular and Cellular Physiology. “I’ve always been attracted to studying these master switches.”
Precisely regulating the activity of TPO (known as “teepo”) is important in the treatment of a number of diseases. Currently, doctors can use a molecule designed to activate the TPO molecular pathway to promote blood stem cell expansion in diseases such as severe aplastic anemia. But these treatments are imprecise, and also promote the production of platelets , raising the risk of clotting (thrombosis).
After learning the structure of TPO bound to its receptor, Garcia and his colleagues were able to design proteins that could expand the pool of blood stem cells , but prevent them from differentiating into platelet-producing cells.. “The nice thing about understanding the structure and engineering a protein from that structure is that you know exactly what the mechanism of action is,” Garcia said. Other small molecule drugs are usually discovered in a trial and error fashion and it is most often not clear exactly how they are having an effect.
Garcia is also the Younger Family Professor of Structural Biology, an investigator in the Stanford Ludwig Center for Cancer Stem Cell Research and Medicine, and an HHMI investigator. Garcia was joined in the research by former Stanford postdoc Naotaka Tsutsumi (now an assistant professor at Okayama University in Japan), and Ian Hitchcock ( from the University of York in the UK). The researchers’ work was published in the journal Cell.
Garcia points out that precisely promoting the expansion of blood stem cells could also be important part of making blood stem cell transplantation more widely available for other diseases like leukemia, multiple sclerosis or type-1 diabetes. Currently, a small portion of stem cells for a single transplant must be harvested from a matching donor. If blood stem cell proliferation in the lab becomes a reality, one donor could supply stem cells to many patients.
Last year, the Garcia lab gained worldwide recognition for succeeding in a decades-long quest to understand the structure of another important molecule, Janus kinase (JAK), which also binds to the TPO receptor and is critical for TPO activity. “Now we are trying to put the two together, JAK and TPO, get that structure, and see how the whole thing works,” Garcia said.