Research and Discoveries

Our laboratory studies how organs develop and regenerate using mammalian skin as a model. We are particularly interested in understanding the principles of stem cell-niche interactions in these processes.

1. 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.

1.1 Defining the molecular and cellular identity of the stem cell niche

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 characterized the mRNA and protein tissue localizations 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 been serving as a powerful foundation for understanding stem cell-niche crosstalk and has led to the series of discoveries described below.

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

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

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

- 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 makes asymmetrically organized side-specific heterogeneity in the basement membrane, defined by the newly characterized interface, hook and mesh basement membranes. Stem cell-derived laminin alpha5 in this interface is required for the stem cell-fibroblast interactions and temporal regulation of 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.

1.2 Origin of stem cells and their niche

Determining how stem cells are first allocated holds important implications for understanding the establishment of a stem cell–niche communication network in adult organ. In most organs, it is unclear how stem cells and their niche emerge during development, mainly owing 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 and that-- like a telescope --they extend to form longitudinally-aligned mature 3D cylindrical compartments, including the bulge stem cell compartment (bottom right figure). Bulge stem cells were derived from the peripheral ring of the placode, where some characteristic state of adult bulge stem cells was detected. We propose defining this morphogenetic mode as the “telescope model” for coordinated hair follicle morphogenesis and stem cell induction. Our study establishes a foundation for the mechanisms coupling skin morphogenesis with stem cell induction and provides an integrated 4D molecular cell atlas for the emergence of stem cells and their niche (Morita et al., Nature 2021).

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2. 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. We have recently discovered that 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 leg imaginal discs of Drosophilla. Therefore, we postulate that different ectodermal appendages have a common telescopic morphogenetic mode, and that spatiotemporal variations in cell–cell and cell-microenvironment interactions give rise to the different phenotypic outcomes. We will address this hypothesis by investigating the spatiotemporal dynamics of interactions between the epithelium, mesenchyme and ECM in the development and regeneration of different ectodermal appendages and skins from different body sites and species.

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