Hematopoietic stem cells (HSCs) give rise to all blood and immune cell types. HSC transplantation, usually through bone marrow transplantation, is used in cancer treatment to rescue the life of patients who receive high doses of chemotherapy and/or radiation. To identify factors that regulate stem cells I will alter the functions of genes in purified human HSCs. Changes that lead to the enhancement of stem cell functions will be identified and characterized in detail. A better understanding of stem cell function is necessary in order to significantly improve current cancer treatment.
To sustain life every day the human body produces billions of new blood cells of different types: red blood cells, which carry oxygen, white blood cells which fight infection and platelets which help the blood to clot. All these cells originate from a rare HSCs population which resides in the bone marrow. The unique ability of HSCs to self-renew guarantees that blood production will be sustained throughout the life of the individual. Chemotherapy and irradiation kill cancer cells, however they can also severely damage or destroy the patientâ€™s bone marrow cells, including HSCs. Healthy, transplanted stem cells can restore the bone marrowâ€™s ability to produce the blood cells the patient needs. Unfortunately, extensive and safe use of HSCs in the clinic is hampered by the very low numbers of donor HSCs available. This barrier could be overcome by increasing the ability of existing stem cells to self-renew and survive.
To meet this challenge, genes that regulate human stem cell function should be identified.
Important experimental tools and skills to measure human stem cell functions we already have established in our laboratory.For instance, an experimental mouse model was developed that supports the growth of human blood cells from transplanted human HSCs. Furthermore, during my PhD training I gained much experience with cutting edge molecular tools that allow dissection of molecular mechanisms in the isolated cells.
As a source for human blood stem cells I will use human cord blood that is enriched in HSCs. By means of genetically engineered viruses I will deliver genes into HSCs. Then genetically modified human blood stem cells will be challenged to self-renew, proliferate and produce mature cells. This will be achieved by transplantation of human HSCs into the bone marrow of laboratory mice. This step closely mimics human bone marrow transplantation. In addition we can reliably estimate the effect different genes exert on stem cell functions using a variety of blood tests. When we detect an increase in human blood cell production inside the mouse bone marrow we can track back and isolate the gene that caused this effect. Upon isolation and characterization of these genes we can better understand how to protect healthy stem cells against cancer therapy and preserve or even increase their self-renewal potential.
Impact and relevance:
The tremendous ability of HSCs to regrow the blood system forms the basis of bone marrow transplantation used to rescue cancer patients that receive chemotherapy. However, many aspects of this life-saving procedure require optimization and better understanding. I am using a mouse model which accepts human HSCs as a miniature version of human bone marrow transplantation. My research will provide new insights into HSC survival and self-renewal. These regulators will steer the development of more effective and less toxic cancer drugs.