SkinForce · Mechanisms of epidermal stratification and force-mediated regulation of stem cell fate and positioning
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-03-01 → 2023-02-28
- EU contribution
- €180,693
- Participants
- 2
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Mechanisms of epidermal stratification and force-mediated regulation of stem cell fate and positioning
Understanding how mammalian tissues are formed during embryonic development is fundamental to understand mechanisms of human disease. In this project, we have addressed the central question of how tissue morphogenesis and cell state transitions are coordinated in time and space to produce a functional tissue. The tissue of interest in this study is the skin epidermis, the epithelial component of the skin. It forms a life-essential barrier that prevents pathogens and toxins from entering our bodies and water from being lost due to the temperature difference between our body and the external environment. The epidermis also contains the hair follicles that generate the hair coat. The epidermis and hair follicles form during embryogenesis from a single stem cell layer and they continue to constantly self-renew to replace differentiated, dying or damaged cells throughout adulthood. Disturbances in this self-renewal are associated with cancer, inflammatory skin diseases, as well as age-related tissue degeneration. The central objective of this study was to combine state-of-the-art cell biology, cutting-edge quantitative image analysis methods and physical modelling approaches to understand epidermis development and to unravel the role of mechanical tissue properties in stem cell fate regulation and barrier establishment. The specific aims were to establish principles by which tissue geometry and cell shape/volume changes control stem cell behavior (WP1) and discover molecular mechanisms of force-mediated regulation of epidermal stem cell fate (WP2). Overall, this project has been stupendous for the researcher career. The objective associated to the WP1 of this project has been completed, the resulting study is published as a preprint, and the submitted manuscript is under revision at NCB. The objective associated to the WP2 is nearly complete and a manuscript will be submitted end 2023.
Data: CORDIS, © European Union
Project objective
As a self-renewing organ maintained by multiple distinct stem cell populations, the epidermis represents an outstanding, clinically relevant research paradigm to address mechanisms of stem cell regulation. To achieve the dynamic turnover and maintenance of the critical skin barrier function, epidermal stem cells (SC) commit to differentiate and delaminate from the basal layer to form suprabasal layers. What triggers SC differentiation, how the differentiating cells move upwards, and how differentiation and self-renewing divisions are balanced remain key open questions. Cells within the epidermis are constantly exposed to tissue- and cell-scale forces that result in changes in cell and nuclear shape and volume. Based on the emerging role of cell density and size in regulating SC fate, I hypothesize that dynamic nuclear and cell shape changes play central roles in regulating epidermal SC fate and in coupling fate changes to cell positioning within the tissue. By combining an innovative, live embryo imaging pipeline, quantitative image analysis, and theoretical models, I aim to decipher the dynamics of epidermal morphogenesis. Using transgenic reporter mice for the nucleus, plasma membrane, cytoskeleton, and differentiation, I will map large-scale and local mechanical transitions along the developmental timeline and correlate them with nuclear and cell shape changes, cell division, differentiation and delamination. I will combine these quantitative imaging experiments with computational modeling, genetic manipulation of contractility, spatial single cell transcriptomics and in vitro cell biology to discover the cellular and molecular mechanism by which tissue geometry and cell/nuclear shape guide cell fate and dynamic positioning. Altogether, this project will uncover fundamental mechanisms of epidermal stratification during development and homeostasis.
Original text from CORDIS.
Participants
Links
- View on CORDIS
- DOI: 10.3030/101032331
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5f2cf4bf1&appId=PPGMS
- https://www.mpi-muenster.mpg.de/2377/en
Data: CORDIS, © European Union