While stem cells with high regenerative potential exist in many organs, their clinical use in tissue regeneration has been limited as retrieving and successfully delivering the stem cells poses a great challenge in most tissue types. The inherent ability of intravenously infused hematopoietic stem cells (HSCs) to seed and engraft their tissue, the bone marrow, is an exception in this regard and forms the basis for a more than four decades long clinical application of bone marrow transplantation (BMT). BMT is a conceptual and elegant example of stem cell therapy, used successfully in life-saving treatment of malignant and inherited hematological disorders. However, a significant proportion of patients who would benefit from BMT cannot receive treatment due to insufficient numbers of stem cells for so called autologous transfers when the patients own cells are used, or a lack of suitable matched donors for so called allogeneic transplantation (where donor cells are required). Umbilical cord blood is (UCB) a very promising stem cell resource, which can be easily and safely harvested from the umbilical cord of newborn babies. Initiatives have been taken all over the world to bank large quantities of cord blood, providing a rich repertoire of donor cells for transplantation. However, the stem cell numbers in UCB harvests are typically too low for efficient transplantation in adult patients. Insufficient stem cell numbers are, therefore, significant constraints in settings of both autologous and allogeneic transplantation. To tackle this problem, intense efforts are being made to find strategies that would enable the expansion and amplification of the stem cells outside the body (i.e. ex vivo), prior to transplantation but to date these efforts have been met with very limited success. Ex vivo stem cell expansion is therefore one of the most desired, yet elusive goals in experimental hematology and transplantation medicine. Successful development of strategies for expansion of HSCs from cord blood samples would implement cord blood as an accessible and sufficient source of HSCs for large numbers of patients with hematological malignancies currently non-eligible for potentially curable allogeneic transplantation therapy.
Our work is focused on understanding the genes and pathways that regulate blood stem cells in order to be able to develop novel strategies for ex vivo stem cell expansion. We are particl´ularly interested in the basic mechanisms that are responsible for the ability of stem cells to self-renew, i.e. to make new copies of themselves. If we were able to mimic the process of stem cell self-renewal that normally takes place in the bone marrow environment, in a culture dish, we should also be able to amplify the number of stem cells prior to transplantation. My research team has developed several new approaches to study hematopoiesis and stem cells from human sources. Rather than studying one gene or one factor at the time we have developed methods that allow the screening of thousands of genes in parallel for their ability to functionally influence the stem cells. This is achieved by specially designed viruses that can enter into the stem cells and deliver molecules (RNAi or CRISPR/Cas9) that specifically silence any given gene. Using these screens, our aim is to identify the most significant regulators that could be relevant to target in order to achieve stem cell expansion.
