Influence of early life growth-signaling on adult life trajectories of hematopoietic stem cells

• Applicant: Professor Dr. Karl Lenhard Rudolph
• Subject Area: Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 536894616

In humans, the incidence of diseases progressively increases already during middle-age of adult life. While aging research focusses mainly on the development aging-associated disease, the increase in the risk of disease development at middle-age adulthood, is still poorly understood. There is evidence that the age-related selection of subpopulations of hematopoietic stem cells (HSCs) or mutant stem cell clones contributes to disease development. Mechanistically, the reasons for the selection of HSC subpopulations or mutant clones during adult life remain to be better defined. Based on work from us and others, we propose that early life growth signaling, which is needed for full functionality of stem cells during early life, has a downside as it induces a cellular memory that accelerates trajectories of HSC subpopulation selection starting already during early adulthood. The nature of developmental growth signaling induced memory and how it influences the selection of HSCs during the adult lifespan of an organism remains unknown. Here, we propose to address this question by analyzing the influence of early life IGF/growth signals on the installment of epigenetic memory and the selection of molecularly defined subpopulations of HSCs during adult life. We will employ HSC transplantation studies to discriminate HSC intrinsic memory effects from HSC extrinsic effects including that may affect niche cells and systemic acting factors. We will assess HSC subpopulation selection using time-course single cell sequencing analyses of genetic mouse models and dietary interventions that change IGF/growth-signaling during development. We develop new computational methods to reveal how dynamic transcriptional networks change in HSCs of adult mice in response to transient perturbations in developmental growth signals. Finally, we will determine whether transient induction of pluripotency factors (transient reprogramming) can revert memory effects of developmental IGF/growth signaling and whether this would ameliorate developmental influences on epigenetic memory, transcriptional changes, and the selection of molecularly defined HSC subpopulation during adult life. Our study aims to provide a functional, in vivo proof-of-concept that cell memory (induced by early life growth signals) contributes to the trajectories of HSC subpopulation selection during adult life. If this holds true, the targeting of early life memories would represent a new approach to impair age-associated increases in disease development during adult life.

• DFG Programme: Research Grants
• International Connection: USA
• Partner Organisation: National Science Foundation (NSF)
• Cooperation Partner: Professor Adam L. MacLean, Ph.D.