Humanization of autoantigen: 水疱性類天疱瘡の病態解明と新規治療法開発

Hair follicle stem cells provide a functional niche for melanocyte stem cells

Role of aPKC isoforms and their binding partners Par3 and Par6 in epidermal barrier formation. Commentary

Regulation of Cell Polarity and Tissue Architecture in Epidermal Aging and Cancer.

BP180 is a type II collagenous transmembrane protein and is best known as the major autoantigen in the blistering skin disease bullous pemphigoid (BP). The BP180 trimer is a central component in type I hemidesmosomes (HD), which cause the adhesion between epidermal keratinocytes and the basal lamina, but BP180 is also expressed in several non-HD locations, where its functions are poorly characterized. The immunological roles of intact and proteolytically processed BP180, relevant in BP, have been subject to intensive research, but novel functions in cell proliferation, differentiation, and aging have also recently been described. To better understand the multiple physiological functions of BP180, the focus should return to the protein itself. Here, we comprehensively review the properties of the BP180 molecule, present new data on the biochemical features of its intracellular domain, and discuss their significance with regard to BP180 folding and protein–protein interactions.

BP180/Collagen XVII: A Molecular View.

Type XVII collagen (COL17) is a transmembrane protein expressed in the basal epidermis. COL17 serves as a niche for epidermal stem cells, and although its reduction has been implicated in altering cell polarity and ageing of the epidermis, it is unknown how COL17 affects epidermal cell polarity. Here, we uncovered COL17 as a binding partner of the aPKC-PAR complex, which is a key regulating factor of cell polarity. Immunoprecipitation-immunoblot assay and protein-protein binding assay revealed that COL17 interacts with aPKC and PAR3. COL17 deficiency or epidermis-specific aPKCλ deletion destabilized PAR3 distribution in the epidermis, while aPKCζ knockout did not. Asymmetrical cell division was pronounced in COL17-null neonatal paw epidermis. These results show that COL17 is pivotal for maintaining epidermal cell polarity. Our study highlights the previously unrecognized role of COL17 in the basal keratinocytes.

Type XVII collagen interacts with the aPKC-PAR complex and maintains epidermal cell polarity.

Injury in adult tissue generally reactivates developmental programs to foster regeneration, but it is not known whether this paradigm applies to growing tissue. Here, by employing blisters, we show that epidermal wounds heal at the expense of skin development. The regenerated epidermis suppresses the expression of tissue morphogenesis genes accompanied by delayed hair follicle (HF) growth. Lineage tracing experiments, cell proliferation dynamics, and mathematical modeling reveal that the progeny of HF junctional zone stem cells, which undergo a morphological transformation, repair the blisters while not promoting HF development. In contrast, the contribution of interfollicular stem cell progeny to blister healing is small. These findings demonstrate that HF development can be sacrificed for the sake of epidermal wound regeneration. Our study elucidates the key cellular mechanism of wound healing in skin blistering diseases.

Hair follicle stem cell progeny heal blisters while pausing skin development.

Injury in adult tissue generally reactivates developmental programs to foster regeneration, but it is not known whether this paradigm applies to growing tissue. Here, by employing blisters, we show that epidermal wounds heal at the expense of skin development. The regenerated epidermis suppresses the expression of tissue morphogenesis genes accompanied by delayed hair follicle (HF) growth. Lineage tracing experiments, cell proliferation dynamics, and mathematical modeling reveal that the progeny of HF junctional zone stem cells, which undergo a morphological transformation, repair the blisters while not promoting HF development. In contrast, the contribution of interfollicular stem cell progeny to blister healing is small. These findings demonstrate that tissue development can be sacrificed for the sake of wound regeneration and suggest that tissue repair does not coincide with the reactivation of developmental programs in all regenerative contexts. Our study elucidates the key cellular mechanism of wound healing in skin blistering diseases.

https://www.biorxiv.org/content/biorxiv/early/2020/05/03/2020.04.08.032326.full.pdf

Hair follicle stem cell progeny heal blisters while pausing skin development

Subepidermal blisters form through the detachment of the epidermis from the dermis. Despite such blisters being common in clinical practice, how they heal has not been fully elucidated. Here, we uncover the precise cellular contribution to subepidermal blister healing. The growth of hair follicles (HFs) was retarded during the healing processes of subepidermal blisters. The progeny of HF junctional zone stem cells (SCs), rather than those of epidermal SCs, were the main contributors to blister healing, and HF depletion from the wound bed through Col17a1 knockout verified the contribution of epidermal SC progeny. The wedge-shaped morphology of keratinocytes in the blistered skin helped cover the epidermal defects and was reduced by Col7a1 knockout or by extracellular calcium administration, resulting in delayed blister healing. These findings, corroborated by mathematical modeling and human blister samples, demonstrate that subepidermal blisters heal primarily via the replenishment of keratinocytes from HF pools at the expense of HF growth and through the proper morphological transformation of the regenerated cells. Our study paves the way for tailoring therapeutic interventions for subepidermal blistering diseases, including epidermolysis bullosa and pemphigoid diseases.

/pdf/subepidermal-blisters-are-healed-by-wedge-shaped-3gdxad9nbc.pdf

Yunan Wang

Papers

Type XVII collagen interacts with the aPKC-PAR complex and maintains epidermal cell polarity.

Hair follicle stem cell progeny heal blisters while pausing skin development.

Hair follicle stem cell progeny heal blisters while pausing skin development

Subepidermal blisters are healed by wedge-shaped keratinocytes of hair follicle origin