Periodic Reporting for period 1 - MemOriStem (Origins and Consequences of Hematopoietic Stem Cell Memories)
Periodo di rendicontazione: 2022-07-01 al 2024-12-31
The MemOriStem project aims to unravel the mechanisms behind the formation, maintenance, and functional consequences of hematopoietic stem cell (HSC) memories. HSCs are responsible for blood production throughout life, and their "memories"—which can be thought of as molecular imprints from earlier life stages—are crucial in determining their future behavior. Understanding how these memories form and how they influence the aging process and the development of diseases, including cancer, is at the heart of our research. By integrating advanced single-cell technologies, molecular lineage tracing, and genetic tools, we seek to decode the origins of HSC diversity, identify key molecular regulators, and assess how these memories impact blood cell function in health and disease.
Over the first two years of the MemOriStem project, we have made substantial progress in all of our main objectives. We have generated the most comprehensive single-cell atlas of HSC states during development, revealing the function of previously unknown HSC subsets. We also developed innovative tools such as the EpiClone system, enabling precise single-cell lineage tracing using targeted profiling of stochastic somatic epimutations, and the STRACK framework, which has provided new insights into how HSC memories influence cancer initiation and progression. Furthermore, we have realized that our field is becoming a very competitive and hot area of research, forcing us to continuously innovate new methodologies that keep our work at the forefront of the field. As an example, we are implementing novel optical recorders to isolate HSC subsets at unprecendented resolution. Our research has also opened new collaborative opportunities, expanding the scope and potential impact of our project.
The MemOriStem project has already led to several key discoveries and technological advancements. Among the most significant is the identification of a new HSC subset emerging during neonatal development, which may play a critical role in aging-related blood disorders - more research will be necessary to identify actionable perturbations to prevent its emergence. Then, our work on the EpiClone system has revolutionized lineage tracing by using naturally occurring and stochastic epimutations - this will help us and other researchers study cellular behaviors across tissues, including in humans, at unprecedented scale - we will explore partnerships to extend its commercial use. Finally, we developed the STRACK framework, providing new perspectives on how pre-existing stem cell states dictate cancer progression - further research will guide personalized modeling of disease and pinpoint early tumor-promoting mechanisms that drive cancer progression and therapy resistance.