Biological mechanisms of developmental stem cell plasticity

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Stem cells are essential drivers of tissue development, maintenance, and regeneration. To ensure integrity in these processes, stem cells exhibit plasticity in the molecular identities and fate decisions they can adopt, which must be carefully controlled. Stem cell identity is best characterized at the level of gene and protein expression; though the impact of cellular organelles like lysosomes, which integrate multiple biological processes, is poorly understood. Lysosomes are well-established effectors of autophagy, the cell's "waste disposal system". Our understanding of the wider breadth of function of this organelle is still unfolding, though links to processes that are known to impact cell fate decisions have recently emerged, including metabolic, epigenetic, and cell signaling regulation. Thus, elucidating the stem cell populations and corresponding mechanisms that lysosomes impact would fill a critical knowledge gap and open up new avenues for discovery. I recently discovered that the initial specification of NSCs is marked by a sudden activation of lysosomes, which is not observed in parental pluripotent stem cells or developmentally related neural crest cells (NCCs). Subsequently, NSC populations exhibit heterogeneity in lysosome levels as they expand, mature, and begin making fate decisions to self-renew or differentiate. Suggesting a critical requirement for maintenance of `moderate' lysosome content, forced lysosome activation to `high' levels leads to dysfunctional NSC phenotypes and accelerated differentiation. Finely tuned lysosome activation thus appears to be critical for both NSC identity specification and normal lineage development. My team and I will test the hypothesis that lysosome expression dynamics regulate the adoption, maintenance, and plasticity of NSC identity. The over-arching goal of my research program is to elucidate the critical biological regulators of stem cell identity and their impacts on cell fate plasticity. Over the next five years my team will begin to investigate the role of lysosomes in stem cell identity specification and lineage development, using my established two-dimensional (2D) pluripotent and 3D organoid stem cell model systems. Mouse embryo explants will provide secondary validation. We will focus on NSCs and NCCs, but additional stem cell populations will also be investigated. OBJECTIVES: 1. Define the requirement for lysosomes in stem cell identity specification. 2. Elucidate the impacts of lysosome activation on lineage development. 3. Investigate the biological mechanisms by which lysosomes impact stem cell fate. This work will advance basic knowledge on lysosome biology and the processes that control stem cell identity and fate plasticity. It will also reveal tractable cellular factors for translational researchers developing tissue regeneration strategies and identifying biomarkers of stem cell integrity versus dysfunction.