Elastin in Diseases.

Human skin undergoes morphological, biochemical and functional modifications during the ageing process. This study was designed to produce a 3-dimensional (3D) skin equivalent in vitro reflecting some aspects of in vivo aged skin. Reconstructed skin was generated by co-culturing skin fibroblasts and keratinocytes on a collagen-glycosaminoglycan-chitosan scaffold, and ageing was induced by the exposition of fibroblasts to Mitomycin-C (MMC). Recently published data showed that MMC treatment resulted in a drug-induced accelerated senescence (DIAS) in human dermal fibroblast cultures. Next to established ageing markers, histological changes were analysed in comparison with in vivo aged skin. In aged epidermis, the filaggrin expression is reduced in vivo and in vitro. Furthermore, in dermal tissue, the amount of elastin and collagen is lowered in aged skin in vivo as well as after the treatment of 3D skin equivalents with MMC in vitro. Our results show histological signs and some aspects of ageing in a 3D skin equivalent in vitro, which mimics aged skin in vivo.

Section: Histological Changes In Aged Skin In Vivo and In Vitromentioning

confidence: 99%

A three‐dimensional skin equivalent reflecting some aspects of in vivo aged skin

Diekmann

Alili

Scholz

et al. 2015

“…Similar to humans, several naturally occuring disease-causing mutations that lead to blistering have been identified in animals, such as dogs, horses and sheep. These models have enhanced our understanding of disease pathogenesis (reviewed in [23][24][25]. In addition, genetically engineered mouse models have been generated for the major forms of keratinopathic genodermatoses and have significantly contributed to our current understanding of the pathomechanisms of their different forms and also provided insights into the complex secondary effects mediated by signalling pathways and other systems that modify disease phenotypes (reviewed in 22,23,26).…”

Section: Animal Models For Cutaneous Keratin Disordersmentioning

confidence: 99%

“…These models have enhanced our understanding of disease pathogenesis (reviewed in [23][24][25]. In addition, genetically engineered mouse models have been generated for the major forms of keratinopathic genodermatoses and have significantly contributed to our current understanding of the pathomechanisms of their different forms and also provided insights into the complex secondary effects mediated by signalling pathways and other systems that modify disease phenotypes (reviewed in 22,23,26). Despite the fact that murine models for human diseases often recapitulate the human phenotype, limitations are there that they are time-consuming, labour intensive, less cost-effective, have lack of corresponding human genes in their genome and are often associated with embryonic lethality, which in concert have led to the quest for alternative strategies (23).…”

Section: Animal Models For Cutaneous Keratin Disordersmentioning

confidence: 99%

“…The patient-specific iPSCs (PS-iPSCs) have now been generated from several human diseases including heritable skin disorders (reviewed in 23), It has been demonstrated that both normal and patient-specific (PS) iPSCs can be differentiated directly into functional keratinocytes, with specific surface markers being used to purify iPSC-derived keratinocytes and allowing for enrichment of keratinocyte lineage cells (135). Further availability of reliable and mutation free non-viral integration of transcription factors will provide relevance prior to clinical application (23). Therefore, there is great promise that iPSCs may provide unprecedented sources of cells for heritable skin keratinopathies as well.…”

Section: Induced Pluripotent Stem Cells (Ipscs) and Revertant Mosaicimentioning

confidence: 99%

See 1 more Smart Citation

Progress towards genetic and pharmacological therapies for keratin genodermatoses: current perspective and future promise

Chamcheu

Wood

Siddiqui

et al. 2012

Hereditary keratin disorders of the skin and its appendages comprise a large group of clinically heterogeneous disfiguring blistering and ichthyotic diseases, primarily characterized by the loss of tissue integrity, blistering and hyperkeratosis in severely affected tissues. Pathogenic mutations in keratins cause these afflictions. Typically, these mutations in concert with characteristic features have formed the basis for improved disease diagnosis, prognosis and most recently therapy development. Examples include epidermolysis bullosa simplex, keratinopathic ichthyosis, pachyonychia congenita and several other tissue-specific hereditary keratinopathies. Understanding the molecular and genetic events underlying skin dysfunction has initiated alternative treatment approaches that may provide novel therapeutic opportunities for affected patients. Animal and in vitro disease modelling studies have shed more light on molecular pathogenesis, further defining the role of keratins in disease processes and promoting the translational development of new gene and pharmacological therapeutic strategies. Given that the molecular basis for these monogenic disorders is well established, gene therapy and drug discovery targeting pharmacological compounds with the ability to reinforce the compromised cytoskeleton may lead to promising new therapeutic strategies for treating hereditary keratinopathies. In this review, we will summarize and discuss recent advances in the preclinical and clinical modelling and development of gene, natural product, pharmacological and protein-based therapies for these disorders, highlighting the feasibility of new approaches for translational clinical therapy.

“…These KO mice were examined with respect to tissue mineralization up to 8 months of age. The Samd9l tm1Homy mice, as well as their heterozygous or wild-type counterparts, were also crossed with Abcc6 tm1JfK mice, an animal model for another ectopic mineralization disorder, pseudoxanthoma elasticum (PXE) (6), to examine whether the absence of Samd9l functional protein may accelerate the mineralization noted in Abcc6 tm1JfK mice.…”

Section: Questions Addressedmentioning

confidence: 99%

Mouse Samd9l is not a functional paralogue of the human SAMD9, the gene mutated in normophosphataemic familial tumoral calcinosis

Guo

Matsui

et al. 2012

Self Cite

Normophosphatemic familial tumoral calcinosis, characterized by ectopic mineralization of skin, is caused by mutations in the SAMD9 gene located on human chromosome 7q21, next to a paralogous gene, SAMD9-like (SAMD9L). Mouse does not have a SAMD9 orthologue, Samd9, because it has been deleted during evolution due to genomic rearrangements. It has been suggested that the mouse Samd9l gene serves as a functional paralogue of human SAMD9. In this study we examined Samd9l knockout mice with respect to ectopic mineralization. We also crossed these mice with Abcc6tm1JfK mice, a model system to study pseudoxanthoma elasticum, to see if the absence of the Samd9l gene modifies the mineralization process. Necropsy analysis of Samd9ltm1Homy mice revealed no evidence of ectopic mineralization, and deletion of the Samd9l gene in mice failed to modify the mineralization process on the Abcc6tm1JfK background. Collectively, the results suggest that mouse Samd9l is not a functional paralogue of human SAMD9.