Periodic Reporting for period 4 - UNEXPECTED (Uncovering targets for ex vivo expansion of hematopoietic stem cells to enhance cell therapies of blood disorders)
Período documentado: 2020-02-01 hasta 2021-01-31
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.
We have further used our new knowledge from the screens to systematically develop better culture conditions for expansion. Indeed, our first screens have identified several highly promising ”druggable” candidates such as the NFkB signaling pathway. We have now found that NFkB inhibition by specific drugs, dramatically enhances the stem cell numbers of cultured cord blood HSCs, compared to our previous “best” culture conditions (submitted).