Periodic Reporting for period 4 - STEMBAR (Mechanisms and functional significance of diffusion barriers for asymmetric segregation of age in neural stem cells)
Période du rapport: 2021-03-01 au 2022-02-28
Neural stem cells (NSCs) generate new neurons throughout life in the hippocampal dentate gyrus (DG). Newborn neurons have been implicated in hippocampus-dependent functions such as learning and memory and mood control. Moreover, failing or altered neurogenesis has been associated with a number of neuropsychiatric diseases such as major depression, epilepsy and cognitive aging. Indeed, aging and also age-associated neurodegenerative diseases, among others Alzheimer’s disease, result in a massive decrease in the number of neurons generated in the DG. Therefore, understanding the molecular and cellular mechanisms that govern the neurogenic process in the adult brain may hold the potential for future regenerative approaches to treat neurodegenerative disease.
Previous work had suggested that chronological age is unevenly segregated among daughter cells when NSCs divide. We here identified novel mechanisms that guide the behavior of NSCs with advancing age (for example, we showed that LaminB is dysregulated with advancing age and that re-expression of LaminB enhances NSC activity in aged mice) and developed innovative genetic and imaging-based tools to study the life-long behavior of adult hippocampal NSCs. The findings obtained during this project represent the foundation for future approaches to harness the regenerative potential of the aging brain.
Previous work had suggested that chronological age is unevenly segregated among daughter cells when NSCs divide. We here identified novel mechanisms that guide the behavior of NSCs with advancing age (for example, we showed that LaminB is dysregulated with advancing age and that re-expression of LaminB enhances NSC activity in aged mice) and developed innovative genetic and imaging-based tools to study the life-long behavior of adult hippocampal NSCs. The findings obtained during this project represent the foundation for future approaches to harness the regenerative potential of the aging brain.
Since the last reporting period we made substantial progress to reach our challenging aims. We heavily invested into technology development and are now able to track previous cell division histories (e.g. the iCOUNT and modified miCOUNT mice), follow cell divisions long term in vivo using 2-photon microscopy (e.g. Pilz et al., 2018 Science), and generated novel mice analyzing the effects of age on the strength of the barrier in the endoplasmic reticulum (ER; e.g. Moore et al., 2015 Science).
We successfully visualized damaged protein segregation in dividing neural stem cells (NSCs) and continued long-term imaging approaches to study segregation of cellular components in cultures of human and mouse somatic stem cells. Parts of the data were published (Moore et al., 2015 Science). In the course of the ERC-funded project, we established long-term imaging of NSCs in vivo (e.g. Pilz et al., 2018 Science; Bottes et al., 2021 Nature Neuroscience). Further, we correlated cellular behavior and fate with the strength of the diffusion barrier in the aging brain (e.g. Bin Imtiaz et al., 2021 Cell Stem Cell) and also showed that a diffusion barrier is present in human progenitor cells (e.g. Bin Imtiaz et al., 2022 Development). Notably, we developed novel genetic approaches to analyze individual cell division history in vitro and in vivo and generated transgenic iCOUNT mice using CRISPR/Cas9 technology (e.g. Denoth-Lippuner et al., 2021 Cell Stem Cell).
Together, we identified novel mechanisms regulating neural stem cell behavior across life and substantially expanded the available toolbox for the field (e.g. iCOUNT mice and intravital imaging).
Results obtained have been presented in numerous papers: with ERC support we published several papers during the funding period as leading laboratory in leading journals of the natural sciences / stem cell biology (e.g. Science, Cell Stem Cell, Nature Neurosc) and co-authored studies with several colleagues in the field (e.g. Nature, Neuron, Cell Metabolism). OUr work has been presented in numerous lectures in Europe and overseas. The ERC funded project laid the foundation for future efforts to characterize distinct developmental steps in the context of life-long neurogenesis.
We successfully visualized damaged protein segregation in dividing neural stem cells (NSCs) and continued long-term imaging approaches to study segregation of cellular components in cultures of human and mouse somatic stem cells. Parts of the data were published (Moore et al., 2015 Science). In the course of the ERC-funded project, we established long-term imaging of NSCs in vivo (e.g. Pilz et al., 2018 Science; Bottes et al., 2021 Nature Neuroscience). Further, we correlated cellular behavior and fate with the strength of the diffusion barrier in the aging brain (e.g. Bin Imtiaz et al., 2021 Cell Stem Cell) and also showed that a diffusion barrier is present in human progenitor cells (e.g. Bin Imtiaz et al., 2022 Development). Notably, we developed novel genetic approaches to analyze individual cell division history in vitro and in vivo and generated transgenic iCOUNT mice using CRISPR/Cas9 technology (e.g. Denoth-Lippuner et al., 2021 Cell Stem Cell).
Together, we identified novel mechanisms regulating neural stem cell behavior across life and substantially expanded the available toolbox for the field (e.g. iCOUNT mice and intravital imaging).
Results obtained have been presented in numerous papers: with ERC support we published several papers during the funding period as leading laboratory in leading journals of the natural sciences / stem cell biology (e.g. Science, Cell Stem Cell, Nature Neurosc) and co-authored studies with several colleagues in the field (e.g. Nature, Neuron, Cell Metabolism). OUr work has been presented in numerous lectures in Europe and overseas. The ERC funded project laid the foundation for future efforts to characterize distinct developmental steps in the context of life-long neurogenesis.
In the course of the ERC supported project we developed the iCOUNT tool that has received considerable attention and was published prominently (Denoth-Lippuner et al., 2021 Cell Stem Cell). Furthermore, we established intravital stem cell imaging in the adult brain which is considered a substantial breakthrough (e.g. Pilz et al., 2018 Science). Thus, the work supported by the ERC allowed us to gain novel insights into stem cell behavior and substantially expanded the available toolbox for the field to understand life-long activity of neural stem cells.