Rejuvenating hematopoietic stem cells through partial in vivo reprogramming for improved functionality in aging and bone marrow failure syndromes
Description: Hematopoietic stem cells (HSCs) sustain blood and immune cell production throughout life. As organisms age, the function of HSCs degrades, showing decreased regenerative capacity and a bias towards the production of myeloid over lymphoid cells, which contributes to the overall proinflammatory environment found in old individuals. These deleterious changes are due to cell-intrinsic and cell-extrinsic mechanisms. The former refers to processes within HSCs themselves, such as an increase in DNA damage and accumulation of reactive oxygen species (ROS), while the latter pertains to the deterioration of the HSC microenvironment. Together, they lead to aging-related hematopoietic disorders and hematopoietic/immune impairment contributing to various pathologies such as increased susceptibility to infections, cancer, and cardiovascular disease. In the context of aging, HSCs constitute an attractive target for rejuvenation therapies, since they can be either pharmacologically targeted in vivo or isolated, ex-vivo manipulated, then replaced through autologous bone marrow (BM) transplant. Recently, in vivo partial reprogramming (PR) through transient expression of the Yamanaka factors (Oct4, Sox2, Klf4 and c-Myc) in old mice has demonstrated broad rejuvenating effects in numerous tissues involving metabolic and transcriptomic changes in inflammation, senescence, and stress response pathways. However, the effect of partial reprogramming in HSCs remains undescribed and, given their potential for rejuvenation therapies, potentially underexploited due to the lack of HSC-specific partial reprogramming models. The main goal of the proposal is to address the rejuvenation potential of in vivo HSC PR in aged mice. Towards this goal, we will characterize partially reprogrammed HSCs (prHSCs) molecularly (WP1), and functionally (WP2). We will functionally validate potential rejuvenation candidate genes identified in WP1 and assess the rescue of BM failure syndromes through PR in patient-derived HSCs (WP3). From a more basic perspective, as partial reprogramming has revealed mechanisms involved in differentiation and plasticity, this project will contribute to a better understanding of the molecular mechanisms of HSC aging, and their multiple pathological outcomes.
Amount: CHF 906,800
Funding type: fellowship
Funder scheme: Ambizione
Start date: 2024-12-01
End date: 2028-11-30
Investigator: Desdín Micó, Gabriela
Institution: University of Lausanne – LA
Funded outputs count: 2
Funder award ID: 223607
OpenAlex ID: G408292246