Loricrin: Past, Present, and Future Ishitsuka, Yosuke; Roop, Dennis R
International journal of molecular sciences,
03/2020, Volume:
21, Issue:
7
Journal Article
Peer reviewed
Open access
The terminal differentiation of the epidermis is a complex physiological process. During the past few decades, medical genetics has shown that defects in the stratum corneum (SC) permeability barrier ...cause a myriad of pathological conditions, ranging from common dry skin to lethal ichthyoses. Contrarily, molecular phylogenetics has revealed that amniotes have acquired a specialized form of cytoprotection cornification that provides mechanical resilience to the SC. This superior biochemical property, along with desiccation tolerance, is attributable to the proper formation of the macromolecular protein-lipid complex termed cornified cell envelopes (CE). Cornification largely depends on the peculiar biochemical and biophysical properties of loricrin, which is a major CE component. Despite its quantitative significance, loricrin knockout (LKO) mice have revealed it to be dispensable for the SC permeability barrier. Nevertheless, LKO mice have brought us valuable lessons. It is also becoming evident that absent loricrin affects skin homeostasis more profoundly in many more aspects than previously expected. Through an extensive review of aggregate evidence, we discuss herein the functional significance of the thiol-rich protein loricrin from a biochemical, genetic, pathological, metabolic, or immunological aspect with some theoretical and speculative perspectives.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The ability to regenerate damaged tissues is a common characteristic of multicellular organisms. We report a role for apoptotic cell death in promoting wound healing and tissue regeneration in mice. ...Apoptotic cells released growth signals that stimulated the proliferation of progenitor or stem cells. Key players in this process were caspases 3 and 7, proteases activated during the execution phase of apoptosis that contribute to cell death. Mice lacking either of these caspases were deficient in skin wound healing and in liver regeneration. Prostaglandin E(2), a promoter of stem or progenitor cell proliferation and tissue regeneration, acted downstream of the caspases. We propose to call the pathway by which executioner caspases in apoptotic cells promote wound healing and tissue regeneration in multicellular organisms the "phoenix rising" pathway.
The epidermis is a stratified epithelium that functions as a barrier protecting the organism from dehydration, mechanical trauma, and microbial insults. This barrier function is established during ...embryogenesis through a complex and tightly controlled stratification program. Whereas the morphological changes that occur during epidermal development have been extensively studied, the molecular mechanisms that govern this process remain poorly understood. In this review we summarize the current advances that have been made in understanding the molecular mechanisms that regulate epidermal morphogenesis.
Induced pluripotent stem cells (iPSCs) hold great promise for regenerative medicine; however, their potential clinical application is hampered by the low efficiency of somatic cell reprogramming. ...Here, we show that the synergistic activity of synthetic modified mRNAs encoding reprogramming factors and miRNA-367/302s delivered as mature miRNA mimics greatly enhances the reprogramming of human primary fibroblasts into iPSCs. This synergistic activity is dependent upon an optimal RNA transfection regimen and culturing conditions tailored specifically to human primary fibroblasts. As a result, we can now generate up to 4,019 iPSC colonies from only 500 starting human primary neonatal fibroblasts and reprogram up to 90.7% of individually plated cells, producing multiple sister colonies. This methodology consistently generates clinically relevant, integration-free iPSCs from a variety of human patient's fibroblasts under feeder-free conditions and can be applicable for the clinical translation of iPSCs and studying the biology of reprogramming.
Although the concept of cancer stem cells (CSCs) is well‐accepted for many tumors, the existence of such cells in human melanoma has been the subject of debate. In this study, we demonstrate the ...existence of human melanoma cells that fulfill the criteria for CSCs (self‐renewal and differentiation) by serially xenotransplanting cells into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice. These cells possess high aldehyde dehydrogenase (ALDH) activity with ALDH1A1 and ALDH1A3 being the predominant ALDH isozymes. ALDH‐positive melanoma cells are more tumorigenic than ALDH‐negative cells in both NOD/SCID mice and NSG mice. Biological analyses of the ALDH‐positive melanoma cells reveal the ALDH isozymes to be key molecules regulating the function of these cells. Silencing ALDH1A by siRNA or shRNA leads to cell cycle arrest, apoptosis, decreased cell viability in vitro, and reduced tumorigenesis in vivo. ALDH‐positive melanoma cells are more resistant to chemotherapeutic agents and silencing ALDH1A by siRNA sensitizes melanoma cells to drug‐induced cell death. Furthermore, we, for the first time, examined the molecular signatures of ALDH‐positive CSCs from patient‐derived tumor specimens. The signatures of melanoma CSCs include retinoic acid (RA)‐driven target genes with RA response elements and genes associated with stem cell function. These findings implicate that ALDH isozymes are not only biomarkers of CSCs but also attractive therapeutic targets for human melanoma. Further investigation of these isozymes and genes will enhance our understanding of the molecular mechanisms governing CSCs and reveal new molecular targets for therapeutic intervention of cancer. STEM Cells2012;30:2100–2113
Harlequin Ichthyosis is a severe skin disease caused by mutations in the human gene encoding ABCA12. Here, we characterize a novel mutation in intron 29 of the mouse Abca12 gene that leads to the ...loss of a 5' splice donor site and truncation of the Abca12 RNA transcript. Homozygous mutants of this smooth skin or smsk allele die perinatally with shiny translucent skin, typical of animal models of Harlequin Ichthyosis. Characterization of smsk mutant skin showed that the delivery of glucosylceramides and CORNEODESMOSIN was defective, while ultrastructural analysis revealed abnormal lamellar bodies and the absence of lipid lamellae in smsk epidermis. Unexpectedly, mutant stratum corneum remained intact when subjected to harsh chemical dissociation procedures. Moreover, both KALLIKREIN 5 and -7 were drastically decreased, with retention of desmoplakin in mutant SC. In cultured wild type keratinocytes, both KALLIKREIN 5 and -7 colocalized with ceramide metabolites following calcium-induced differentiation. Reducing the intracellular levels of glucosylceramide with a glucosylceramide synthase inhibitor resulted in decreased secretion of KALLIKREIN proteases by wild type keratinocytes, but not by smsk mutant keratinocytes. Together, these findings suggest an essential role for ABCA12 in transferring not only lipids, which are required for the formation of multilamellar structures in the stratum corneum, but also proteolytic enzymes that are required for normal desquamation. Smsk mutant mice recapitulate many of the pathological features of HI and can be used to explore novel topical therapies against a potentially lethal and debilitating neonatal disease.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cornification is a specialized mode of the cell-death program exclusively allowed for terrestrial amniotes. Recent investigations suggest that loricrin (LOR) is an important cornification effector. ...As the connotation of its name ("lorica" meaning an armor in Latin) suggests, the keratin-associated protein LOR promotes the maturation of the epidermal structure through organizing covalent cross-linkages, endowing the epidermis with the protection against oxidative injuries. By reviewing cornification mechanisms, we seek to classify ichthyosiform dermatoses based on their function, rather than clinical manifestations. We also reviewed recent mechanistic insights into the Kelch-like erythroid cell-derived protein with the cap "n" collar homology-associated protein 1/nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway in skin health and diseases, as LOR and NRF2 coordinate the epidermis-intrinsic xenobiotic metabolism. Finally, we refine the theoretical framework of cross-talking between keratinocytes and epidermal resident leukocytes, dissecting an LOR immunomodulatory function.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Development of stratified epithelia, such as the epidermis, requires p63 expression. The p63 gene encodes isoforms that contain (TA) or lack (DeltaN) a transactivation domain. We demonstrate that ...TAp63 isoforms are the first to be expressed during embryogenesis and are required for initiation of epithelial stratification. In addition, TAp63 isoforms inhibit terminal differentiation, suggesting that TAp63 isoforms must be counterbalanced by DeltaNp63 isoforms to allow cells to respond to signals required for maturation of embryonic epidermis. Our data demonstrate that p63 plays a dual role: initiating epithelial stratification during development and maintaining proliferative potential of basal keratinocytes in mature epidermis.
The mammalian olfactory neuroepithelium provides a unique system for understanding the regulation of neurogenesis by adult neural stem cells. Recently, mouse horizontal basal cells (HBCs) were ...identified as stem cells that regenerate olfactory receptor neurons (ORNs) and non‐neuronal cell types only after extensive injury of the olfactory epithelium (OE). Here we report a broader spectrum of action for these cells. We show that even during normal neuronal turnover, HBCs actively generate neuronal and non‐neuronal cells throughout adulthood. This occurs in a temporally controlled manner: an initial wave of HBC‐derived neurogenesis was observed soon after birth, and a second wave of neurogenesis was observed at 4 months of age. Moreover, upon selective depletion of mature ORNs by olfactory bulbectomy, HBCs give rise to more neurons. Our findings demonstrate a crucial role for HBCs as multipotent progenitors in the adult OE, acting during normal neuronal turnover as well as in acute regeneration upon injury.
Disclosure of potential conflicts of interest is found at the end of this article.
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