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Research and Discoveries

The biochemical and mechanical properties of the cellular microenrivonment play a pivotal role in shaping various biological processes, including cellular behaviour, development, physiology and pathology. In our laboratory, guided by the concept that 'environment dictates behaviour', we explore how cellular and tissue microenvironments impact the behaviour and fate of cells in the context of organ development and regeneration, using mammalian skin as a model. Our primary focus is on revealing the principles underlying the interactions between tissue stem cells and their extracellular matrix, which instruct these processes. Our ultimate research goal is to define and design the microenvironment to manipulate biological processes from outside the cells.

1. Defining the molecular and cellular basis of stem cell–niche interactions

Stem cells are established and maintained in niches, which are specialised microenvironments that regulate how stem cells participate in tissue development, maintenance and regeneration. However, the molecular and cellular mechanisms by which stem cells communicate with their local environment remain largely unknown.

The extracellular matrix (ECM) is a 3D network of extracellular macromolecules that provides structural, physical and biochemical cues to resident cells. However, the molecular identity and function of the ECM in the stem cell niche remain elusive in many organs. We have systematically characterised the mRNA and protein tissue localisations of the entire set of ECM molecules 'matrisome' in mouse skin and generated the Skin ECM Atlas (Tsutsui et al., Nat Commun 2021). This ECM mapping has served as a powerful foundation for understanding stem cell-niche crosstalk and has led to the series of discoveries described below.


- The basement membrane of hair follicle stem cells is a muscle cell niche

We have revealed that stem cells in the hair follicle secrete an ECM protein nephronectin (NPNT) in the underlying basement membrane, which promotes the maturation of arrector pili muscle precursors and their attachment to the hair follicle bulge (Fujiwara et al., Cell 2011).

- Hair follicle epithelial stem cells define a niche for tactile sensation
This study has shown that a sub-population of epithelial stem cells in the hair follicle secretes an ECM protein EGFL6, which interacts with sensory end organs and underpins the skin's sense of touch (Cheng et al., eLife 2018). ​


- Mapping the molecular and structural specialization of the skin basement membrane for inter-tissue interactions
We have generated the Skin ECM Atlas and revealed that basement membrane composition and architecture are exquisitely specialized for distinct inter-tissue interactions. The epithelial stem cell–fibroblast interface creates side-specific heterogeneity in the basement membrane, which is defined by the newly characterised interface, hook and mesh basement membranes. Stem cell-derived laminin alpha5 in this interface is required for the temporal regulation of the hair follicle regeneration cycle (Tsutsui et al., Nat Commun 2021).

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- Stem cells act as a niche

Our recent studies demonstrate that stem cells are not simple passive responders to their niches, but also actively send signals to instruct the fate and behaviour of adjacent cells. Skin epithelial stem cells are located in the basal layer of the epithelia, and thus they are in the close vicinity of a diverse array of mesenchymal cell types. Signals from different epithelial stem cell pools provides niches for distinct cells in the mesenchyme, including muscle precursors (Fujiwara et al., Cell 2011), sensory nerves (Cheng et al., eLife 2018), adipocyte precursors (Donati et al., PNAS 2014) and dermal papilla fibroblasts (Tsutsui et al., Nat Commun 2021) (see top figure). These studies provide a novel conceptual advance in the significance of stem cell heterogeneity and compartmentalization in stem cell biology (Fujiwara et al., Dev Growth Differ 2018). Regionally-specialised basement membranes serve as interfaces for stem cell–niche crosstalk.

2. Developmental origin of stem cells and their niche

Determining how stem cells and their niche are first allocated is important for understanding the establishment of a stem cell–niche communication network in adult organs. In most organs, it is unclear how stem cells and their niche emerge during development, mainly due to the lack of markers that exclusively label prospective stem cells.

    By combining marker-independent long-term 4D imaging and single-cell transcriptomics, we traced the developmental origins, cell lineages and transcriptional dynamics of diverse epithelial cells in the hair follicle (bottom left movie). Our study revealed that the precursors of different epithelial stem/progenitor cells are arranged in a 2D concentric manner in the basal layer of hair placode (a primordium of the hair follicle) and that (like a telescope) they extend to form longitudinally aligned mature 3D cylindrical compartments, including the bulge stem cell compartment (bottom right figure). The bulge stem cells are derived from the peripheral ring of the placode, where some properties of adult bulge stem cells is detected. We propose to define this morphogenetic dynamics as the 'telescope model' for coordinated hair follicle morphogenesis and stem cell induction. Our study establishes a foundation for the mechanisms that couple skin morphogenesis with stem cell formation and provides an integrated 4D molecular cell atlas for the emergence of stem cells and their niches (Morita et al., Nature 2021).

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3. Skin phenotypic diversity

​To adapt to diverse environments on earth, the skin has acquired tremendous phenotypic diversity among body sites and species. How do skin precursors and stem cells form and regenerate skin with specific phenotypes?

    We aim to decipher the mechanisms of phenotypic specification in skin development, regeneration and evolution: one of the next frontiers in skin and regenerative biology. The key to this understanding lies in the above mentioned Telescope Model. In this model, hair follicles first form 2D concentric ring zones in placodes and telescope them out to form longitudinally aligned compartments (Morita et al., Nature 2021). Similar ring-like gene expression patterns have also been reported in the placodes of other ectodermal appendages, such as mammary glands in mice and feathers in chickens, and even in the leg imaginal discs of Drosophila. Therefore, we postulate that different ectodermal appendages have a common telescopic morphogenetic mode and that spatiotemporal variations in cell–cell and cell-microenvironment interactions yield different phenotypic outcomes.

    We will address this hypothesis by investigating the spatiotemporal dynamics of the interactions between the epithelium, mesenchyme and ECM in the development and regeneration of various ectodermal appendages and the skin from various body sites and species.

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