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Mechanisms of stem cell population dynamics and reprogramming

Periodic Reporting for period 2 - STEMpop (Mechanisms of stem cell population dynamics and reprogramming)

Reporting period: 2019-11-01 to 2021-04-30

This project aims to understand how adult stem cells that are present in most of our tissues, are regulated to maintain tissue function and regenerate them after injury. The project focuses on skin epidermis and hair follicle stem cells, which due to the ability of the skin to constantly self-renew and to regenerate, provides a powerful, clinically relevant model system. The project uses a range of methods from mouse genetics to stem cell organoids, live imaging and next generation sequencing to understand how skin stem cell fate is regulated on the single cell level, and in particular how these single cell fates are coordinated on the population level to ensure appropriate responses of the stem cell pool to the changing need of the tissue.
The main aims of the project are to:
1. Understand how the local tissue microenvironment, in particular its geometrical shapes and mechanical properties, control stem cell behavior
2. Identify the transcriptional networks and epigenetic barriers that control stem cell fate and plasticity
3. Identify drugs that could be used to boost stem cell function as means to enhance tissue repair or prevent age-dependent loss of regenerative potential
The project will generate new fundamental knowledge on how cell fate is regulated through population level crosstalk and interactions with the surrounding tissue. The importance of this question is highlighted by clinical studies on the use of stem cell transplantation for tissue regeneration, which report a striking inability of human stem cells to transdifferentiate, expand or survive in vivo. In this respect, the results from this project studies will likely lay important foundations for future research in the field of stem cell therapies, tissue regeneration and repair, where boosting the tissues own regenerative potential might be more effective than stem cell transplantation. Key discoveries so far include identification of mechanisms how mechanical force can alter nuclear and chromatin architecture to regulate stem cell state and protect its DNA from damage (Nava, Miroshnikova et al., Cell 2020) as well as uncovering a critical role for the metabolic state of the stem cell in regulating its state and long term maintenance of the stem cell pool (Kim et al., Cell Metabolism 2020).
The project addresses a fundamental problem in the field of developmental and regenerative biology: what determines stemness and how can this phenotype be dynamically adapted to the changing need of an organ/organism. The combined use of innovative and controlled in vitro systems such as organoids and mechanical manipulation bioreactors has allowed us to uncover new mechanisms of fate regulation both by mechanical forces as well by metabolic signals within the stem cell niche. The remained of this project will focus on the research identifying druggable targets of hair follicle stem cell fate using compund screens and subsequent mechanistic analyses. The results from these studies will lay important foundations for future research in the field of SC therapies, tissue regeneration and repair.
Hair follicle stem cell organoids recapitulate stem cell (magenta) and progenitor (green) dynamics