MemOriStem · Origins and Consequences of Hematopoietic Stem Cell Memories

Hematopoiesis has long been modeled as a stepwise hierarchical process, where all blood cells arise from a single group of rare multipotent stem cells. For decades, various reports have contested this unifying paradigm, indicating that hematopoietic stem cells are functionally heterogeneous and differ on the rates and types of blood cells that they produce. However, the origins of stem cell heterogeneity and, importantly, its physiological consequences have remained ambiguous. My recent research suggests that individual stem cell behaviors are deterministic and programmed through long-lasting epigenetic memories, but how these different stem cell memories arise during development or injury is currently unknown. Intriguingly, my preliminary results indicate that stem cell memories instruct not just their fate decisions but also the functional properties of their mature progeny, thus raising the question of how stem cell memories create functional patterns that bias the cellular responses of their mature progeny. Thus, the objectives of MemOriStem are: (1) to uncover the mechanisms that establish the diversity of HSC memories during development; (2) to identify the molecular determinants that maintain specific HSC properties; and (3) to characterize how developmental and acquired HSC memories determine functional patterns in mature blood cell responses. To overcome various challenging aspects of studying cell memories in vivo, I have designed a ground-breaking approach that combines innovative mouse models for transient gene silencing, multiplexed clonal analysis, and molecular recorders of cellular states. In sum, MemOriStem will precisely define the origins, mechanisms, and physiologic consequences of hematopoietic memories, thus allowing a conceptual leap forward in regenerative and stem cell biology. Harnessing the programming of stem cell memories may help in the development of in situ cell therapeutics to treat chronic inflammation, aging, and cancer.