Periodic Reporting for period 1 - Geometric fate (Niche geometry as the regulator of communal metabolism and cell fate)
Période du rapport: 2022-06-01 au 2024-11-30
Tissues are renewed throughout the life of an individual by tissue resident stem cells. These stem cells divide and give rise to progeny cells that can either remain as stem cells or differentiate into the specialized cells that perform the tissue function. Balancing these two fates, making new stem cell through self-renewal and differentiating into specialized cells, is crucial for maintaining tissue renewal capacity and function. During aging the function of tissue resident stem cells declines leading to reduced tissue renewal, recovery from injury and ultimately functional failure of organs. Understanding how the balance between making new stem cells and differentiated cells is maintained in a tissue could thus have major impact for countering aging-associated vulnerabilities and disease.
Stem cells and differentiated cells have different metabolic demands and we recently discovered that certain stem cells can direct the fate of their daughter cell progeny by segregating metabolically distinct mitochondria, the organelles central to cellular metabolism, asymmetrically between the two daughter cells (Döhla et al. Nature Cell Biology 2022). Thus, at least in some stem cell divisions, metabolism could be among the first traits that drive distinction between self-renewal and differentiation.
Tissue stem cells are found in specialized compartments or niches that are usually highly spatially organized, with stem cells and specialized cells running their different metabolism side by side. Differentiated cells of the niche are important for maintaining stem cell function, but to what extend this is linked to the metabolic needs of the cell types has not been systematically studied. In this project we study how metabolic traits separated when a stem cell divides turn into differences in daughter cell function and to what extent this is supported by the organization and metabolism of the stem cell niche in a tissue.
Stem cells and differentiated cells have different metabolic demands and we recently discovered that certain stem cells can direct the fate of their daughter cell progeny by segregating metabolically distinct mitochondria, the organelles central to cellular metabolism, asymmetrically between the two daughter cells (Döhla et al. Nature Cell Biology 2022). Thus, at least in some stem cell divisions, metabolism could be among the first traits that drive distinction between self-renewal and differentiation.
Tissue stem cells are found in specialized compartments or niches that are usually highly spatially organized, with stem cells and specialized cells running their different metabolism side by side. Differentiated cells of the niche are important for maintaining stem cell function, but to what extend this is linked to the metabolic needs of the cell types has not been systematically studied. In this project we study how metabolic traits separated when a stem cell divides turn into differences in daughter cell function and to what extent this is supported by the organization and metabolism of the stem cell niche in a tissue.
Using state of the art mouse models, we have found that segregation of metabolically distinct organelles is a feature of stem cells of many different tissues and that this is not restricted to mitochondria. Secondly, how these organelles are metabolically different is tissue-dependent, and likely to be related to the metabolic needs of the tissue. In some tissues, we have already identified the mechanism whereby metabolic segregation at stem cell divisions leads to distinct fates of progeny cells. For other tissues we are working on understanding how the metabolic differences ultimately lead to changes in cell identity and function.
Furthermore, we have already found that the shape of the stem cell niche can facilitate communication between stem cells and their differentiated neighbours and that organelles responsible for cell-to-cell signalling, Golgi, are highly organized to optimize stem cell function in a tissue. Importantly, the spatial organization, both of the tissue niche and the Golgi, is disrupted in old animals, with implications for tissue renewal capacity. Currently we are studying to what extent this is linked to the different metabolic properties of the cells in the tissue.
Furthermore, we have already found that the shape of the stem cell niche can facilitate communication between stem cells and their differentiated neighbours and that organelles responsible for cell-to-cell signalling, Golgi, are highly organized to optimize stem cell function in a tissue. Importantly, the spatial organization, both of the tissue niche and the Golgi, is disrupted in old animals, with implications for tissue renewal capacity. Currently we are studying to what extent this is linked to the different metabolic properties of the cells in the tissue.
We are in the process of developing novel methods allowing the systematic study of the effect of tissue organization on cell metabolism and function. Previously, we identified that disrupted signalling in the stem cell niche of old animals can be momentarily boosted to overcome side effects on normal stem cells induced by chemotherapeutic drugs (Pentinmikko et al. Nature 2019). In this project, we unexpectedly found that this protection of normal tissue from chemotherapeutic agents is also achievable through metabolic interventions in mice. Thus, this project may also lead to new, possibly better tolerated, ways to promote tissue repair and recovery in the elderly patients undergoing chemotherapy.