Environment dictates behaviour

The cellular microenvironment is an integral part of our body, which sends essential signals to resident cells to control their fate and behaviours. However, little is known about the molecular identity, dynamics and action of the extracellular space. The aim of our lab is to discover the principles of cell-microenvironment interactions that instruct cellular behaviour and communication, and the formation of organs. By focusing on skin biology, we are currently studying the following two mutually-related themes 1) crosstalk between skin stem cells and their microenvironment or niche and 2) cell–extracellular matrix (ECM) interactions and .
Ref: Baumann K, Nat Rev Mol Cell Biol 2010
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1. Crosstalk between stem cells and their niche

Stem cells are a subset of unique cells that have remarkable abilities to self-renew and differentiate into specialized cell types. During development, tissue precursors become tissue-resident stem cells, the foundation cells for tissue homeostasis and regeneration. Stem cells are surrounded by their own specialized environment, called the stem cell niche. Stem cell fate and behaviours are determined by the signals from their niche. However, little is know about the molecular and cellular compositions of stem cell niches and how they regulate stem cells. Moreover, recent studies reveal that communication between stem cells and their niche is reciprocal: signals from stem cells influence the fate and behaviour of neighboring cells. Mammalian skin contains a variety of tissue stem cells, such as epithelial stem cells, dermal stem cells, adipocyte progenitors, melanocyte stem cells etc. Thus, the skin is a excellent model for studying interactions between stem cells and their microenvironment. This reciprocal signalling events in the skin establish spatially and temporally specialized functional units, which play key roles in the coordinated organ development, homeostasis, repair and functions (Fujiwara et al., Dev Growth Differ 2018). We study the roles of bi-directional signalling events between stem cells and their niches in organization and function of the skin.

Heterogeneous epithelial stem cells act as a niche
Epidermal stem cells are located in the basal layer of the epidermis, and thus they are exposed to a diverse array of dermal cell types. We have showed that the signals from different epithelial stem cell pools provides functional niches for muscle precursors (Fujiwara et al., Cell 2011), nerves (Cheng et al., eLife 2018) and adipocyte progenitors (Donati et al., PNAS 2014) to establish spatially and temporally specialized epidermal-dermal functional units, which play key roles in the skin organization and functions. These recent studies point to a new biological significance of epithelial stem cell heterogeneity and compartmentalization (Fujiwara et al., Dev Growth Differ 2018).

Developmental origin and induction process of tissue stem cells and their niche
One of the important remaining questions in tissue stem cell research field is how heterogeneous and compartmentalized tissue stem cells are induced during development from seemingly homogeneous tissue precursors. The induction of stem cells and their niche is a prerequisite for tissue homeostasis. The skin forms the foundation of homeostasis from no prepattern. We use the mouse hair follicle as a model to address this question by combining 3D long-term live cell imaging and single-cell transcriptomics of developing mouse hair follicles.

We have traced the developmental origins, lineage relationship, and transcriptional dynamics of diverse epithelial cells in the hair follicle. Our study revealed that the origins of different epithelial lineage precursors are arranged in a 2D concentric manner in a hair placode and that they extend to form longitudinally-aligned mature 3D cylindrical compartments, including the epithelial stem cell compartments (Morita et al., Nature 2021). Stem cell were derived from the peripheral ring of the placode. We propose defining this morphogenetic event 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 molecular and lineage roadmap for the emergence of heterogeneous epithelial stem cell pools.

Signals to epithelial and dermal stem cells
We have identified basement membrane molecules that regulate epithelial and dermal stem cells, respectively. We hypothesize that the basement membrane separating the epithelium and the dermis functions as niches for both tissue types by creating different molecular compositions at their epithelial and dermal sides.

2. Cell-ECM interactions

The extracellular matrix (ECM) is a 3D network of extracellular macromolecules that provides structural, physical and biochemical cues to resident cells. It is essential to integrate heterogeneous cells into a functional form, an organ. The ECM is not just a glue holding cells together, but rather functions as an information system that encodes various information to control cell fate and behaviour, such as cell adhesion, proliferation, differentiation, migration, survival etc. Virtually all different types of cells, including stem cells, are surrounded by their tailored ECM and establish special connections with their ECM. However, very little is known about a comprehensive picture of ECM composition and dynamics in any of the organs.

By focusing on skin biology, our team aims to decode the molecular landscape of the ECM "ECM zip codes" in mammalian skin, which can provide a positional information in our body. We have developed research tools and techniques to unveil a comprehensive 3D map of the ECM molecules and their cellular origins (Tsutsui et al., Nature Communications 2021). This ECM mapping has been serving as a powerful foundation that led to the series of discoveries described below. Our studies have demonstrated that the regional specificity of the ECM components is a key to establish distinct cellular niches and mediate inter-tissue interactions, such as epithelial-muscle, epithelial-nerve, and epithelial-fibroblast interactions. In particular, our studies revealed that ECMs from epidermal stem cells control the fate and behaviours of neighbouring cells.

The basement membrane of hair follicle stem cells is a muscle cell niche
We revealed that stem cells in the hair follicle create a special niche in the underlying basement membrane that promotes the maturation of arrector pili muscles and their attachment to hair follicles (Fujiwara et al., Cell 2011).

Hair follicle epidermal stem cells define a niche for tactile sensation via secretion of a special ECM molecule
This study showed that a sub-population of epidermal stem cells in the hair follicle contribute to form a specialized ECM structure, which we named the "collar matrix", that controls the structure and function of tactile sensory end organs (Cheng et al., eLife 2018). This epidermal stem cell–collar matrix–nerve interaction is critical for generating the sense of touch.

Mapping the molecular and structural specialization of the skin basement membrane for inter-tissue interactions
By combining quantitative transcriptomics and immunohistochemistry, we systematically identify the cellular origin, molecular identity and tissue distribution of extracellular matrix molecules in mouse hair follicles, and reveal that BM composition and architecture are exquisitely specialized for distinct inter-tissue interactions. The epithelial–fibroblast interface, namely, hair germ–dermal papilla interface, makes asymmetrically organized side-specific heterogeneity in the BM, defined by the newly characterized interface, hook and mesh BMs. One component of these BMs, laminin α5, is required for hair cycle regulation and hair germ–dermal papilla anchoring (Tsutsui et al., Nature Communications 2021).