Role of the microtubule network in the generation and expansion of the first hematopoietic stem cells. (LSBR 1025)
Project leader: Dr. ir. Niels Galjart, Dept. of Cell Biology & Genetics, Erasmus MC, Rotterdam and Dr. Catherine Robin (co-applicant), Hubrecht Institute, Utrecht
Postdoc investigator: Umut Akinci Corbacioglu, PhD (Aug. 2011 – Dec. 2014)
Ph.D. student: Thomas Clapes, MSc (Dec. 2010 – Dec. 2014)
Scientist: Sreya Basu (Oct. 2014 – Dec. 2014)
Every day, blood stem cells in the bone marrow produce billions of new blood cells essential for life. Defects in blood stem cells lead to blood-related disorders and various cancers (e.g. anemia, leukemia). The only long-term treatment is to transplant healthy donor blood stem cells to replace the patient’s defective ones. Less than 30% of patients have matched donors in their family. Therefore, successful transplantation in most patients relies on finding unrelated volunteer donors with the highest compatibility, which is a major hurdle. To circumvent this shortage, huge efforts have been made to expand donor blood stem cells ex vivo or to generate new sources of blood stem cells in vitro. Success has been limited so far. Thus, finding new ways to produce and expand blood stem cells directly from patient/donor cells would be a revolution for both clinical use and fundamental research.
Adult blood stem cells are initially produced during embryonic development. We and others have shown that the first blood stem cells are generated in the embryo from few specialized cells (called hemogenic cells) in the main blood vessels, such as the aorta. Afterwards, blood stem cells massively expand in the fetal liver. The aorta and liver therefore provide the physiological niches for blood stem cell generation and expansion, respectively. Since the production of stem cells and their progeny is accompanied by cell movement and migration, we focused our research on understanding how microtubules (the “skeleton” of a cell that supports and directs migration) and associated molecules control and regulate blood stem cell production and expansion. Our study demonstrates the important role of CLASP2 (a microtubule associated protein and regulator of microtubule behaviour) in the production of the first blood stem cells during embryonic development as well as for their maintenance in the bone marrow, the main site of blood stem cell residence in the adult. Our research has revealed a new key factor in the regulation of the life-saving blood stem cell, whose production is essential for blood stem cell transplantation therapies.