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The cellular and molecular microenvironment of epithelial stem/progenitor cells is critical for their long-term self-renewal. We demonstrate that mesenchymal stem cell-like dermal microvascular pericytes are a critical element of the skin's microenvironment influencing human skin regeneration using organotypic models. Specifically, pericytes were capable of promoting homeostatic skin tissue renewal by conferring more planar cell divisions generating two basal cells within the proliferative compartment of the human epidermis, while ensuring complete maturation of the tissue both spatially and temporally. Moreover, we provide evidence supporting the notion that BMP-2, a secreted protein preferentially expressed by pericytes in human skin, confers cell polarity and planar divisions on epidermal cells in organotypic cultures. Our data suggest that human skin regeneration is regulated by highly conserved mechanisms at play in other rapidly renewing tissues such as the bone marrow and in lower organisms such as Drosophila. Our work also provides the means to significantly improve ex vivo skin tissue regeneration for autologous transplantation.

The cellular and molecular microenvironment of epithelial stem/progenitor cells is critical for their long-term self-renewal. We demonstrate that mesenchymal stem cell-like dermal microvascular pericytes are a critical element of the skin's microenvironment influencing human skin regeneration using organotypic models. Specifically, pericytes were capable of promoting homeostatic skin tissue renewal by conferring more planar cell divisions generating two basal cells within the proliferative compartment of the human epidermis, while ensuring complete maturation of the tissue both spatially and temporally. Moreover, we provide evidence supporting the notion that BMP-2, a secreted protein preferentially expressed by pericytes in human skin, confers cell polarity and planar divisions on epidermal cells in organotypic cultures. Our data suggest that human skin regeneration is regulated by highly conserved mechanisms at play in other rapidly renewing tissues such as the bone marrow and in lower organisms such as Drosophila. Our work also provides the means to significantly improve ex vivo skin tissue regeneration for autologous transplantation.

BACKGROUND: The establishment and maintenance of polarity is vital for embryonic development and loss of polarity is a frequent characteristic of epithelial cancers, however the underlying molecular mechanisms remain unclear. Here, we identify a novel role for the polarity protein Scrib as a mediator of epidermal permeability barrier acquisition, skeletal morphogenesis, and as a potent tumor suppressor in cutaneous carcinogenesis. METHODS: To explore the role of Scrib during epidermal development, we compared the permeability of toluidine blue dye in wild-type, Scrib heterozygous and Scrib KO embryonic epidermis at E16.5, E17.5 and E18.5. Mouse embryos were stained with alcian blue and alizarin red for skeletal analysis. To establish whether Scrib plays a tumor suppressive role during skin tumorigenesis and/or progression, we evaluated an autochthonous mouse model of skin carcinogenesis in the context of Scrib loss. We utilised Cre-LoxP technology to conditionally deplete Scrib in adult epidermis, since Scrib KO embryos are neonatal lethal. RESULTS: We establish that Scrib perturbs keratinocyte maturation during embryonic development, causing impaired epidermal barrier formation, and that Scrib is required for skeletal morphogenesis in mice. Analysis of conditional transgenic mice deficient for Scrib specifically within the epidermis revealed no skin pathologies, indicating that Scrib is dispensable for normal adult epidermal homeostasis. Nevertheless, bi-allelic loss of Scrib significantly enhanced tumor multiplicity and progression in an autochthonous model of epidermal carcinogenesis in vivo, demonstrating Scrib is an epidermal tumor suppressor. Mechanistically, we show that apoptosis is the critical effector of Scrib tumor suppressor activity during skin carcinogenesis and provide new insight into the function of polarity proteins during DNA damage repair. CONCLUSIONS: For the first time, we provide genetic evidence of a unique link between skin carcinogenesis a

Keratins are cytoskeletal intermediate filament proteins that are increasingly being recognised for their diverse cellular functions. Here we report the consequences of germ line inactivation of Keratin 76 (Krt76) in mice. Homozygous disruption of this epidermally expressed gene causes neonatal skin flaking, hyperpigmentation, inflammation, impaired wound healing, and death prior to 12 weeks of age. We show that this phenotype is associated with functionally defective tight junctions that are characterised by mislocalization of the integral protein CLDN1. We further demonstrate that KRT76 interacts with CLDN1 and propose that this interaction is necessary to correctly position CLDN1 in tight junctions. The mislocalization of CLDN1 has been associated in various dermopathies, including the inflammatory disease, psoriasis. These observations establish a previously unknown connection between the intermediate filament cytoskeleton network and tight junctions and showcase Krt76 null mice as a possible model to study aberrant tight junction driven skin diseases.