Cell-Type-Specific Differentiation and Molecular Profiles in Skin Transplantation: Implication of Medical Approach for Genetic Skin Diseases

Skin is highly accessible and valuable organ, which holds promise to accelerate the understanding of future medical innovation in association with skin transplantation, engineering, and wound healing. In skin transplantation biology, multistage and multifocal damages occur in both grafted donor and perilesional host skin and need to be repaired properly for the engraftment and maintenance of characteristic skin architecture. These local events are more unlikely to be regulated by the host immunity, because human skin transplantation has accomplished the donor skin engraftment onto the immunocompromised or immunosuppressive animals. Recent studies have emerged the importance of α-smooth muscle actin- (SMA-) positive myofibroblasts, via stage- and cell-specific contribution of TGFβ, PDGF, ET-1, CCN-2 signalling pathways, and mastocyte-derived mediators (e.g., histamine and tryptase), for the functional reorganisation of the grafted skin. Moreover, particular cell lineages from bone marrow (BM) cells have been shown to harbour the diferentiation capacity into multiple skin cell phenotypes, including epidermal keratinocytes and dermal endothelial cells and pericytes, undercontrolled by chemokines or cytokines. From a dermatological viewpoint, we review the recent update of cell-type- and molecular-specific action associated with reconstitution of the grafted skin and also focus on the novel application of BM transplantation medicine in genetic skin diseases.

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Ageing, Cellular Senescence and Neurodegenerative Disease

International Journal of Molecular Sciences ◽

10.3390/ijms19102937 ◽

2018 ◽

Vol 19 (10) ◽

pp. 2937 ◽

Cited By ~ 59

Author(s):

Marios Kritsilis ◽

Sophia V. Rizou ◽

Paraskevi Koutsoudaki ◽

Konstantinos Evangelou ◽

Vassilis Gorgoulis ◽

...

Keyword(s):

Multiple Sclerosis ◽

Neurodegenerative Disease ◽

Cellular Senescence ◽

Biological Process ◽

The Novel ◽

Cell Type ◽

Age Related ◽

Cell Type Specific ◽

First Time

Ageing is a major risk factor for developing many neurodegenerative diseases. Cellular senescence is a homeostatic biological process that has a key role in driving ageing. There is evidence that senescent cells accumulate in the nervous system with ageing and neurodegenerative disease and may predispose a person to the appearance of a neurodegenerative condition or may aggravate its course. Research into senescence has long been hindered by its variable and cell-type specific features and the lack of a universal marker to unequivocally detect senescent cells. Recent advances in senescence markers and genetically modified animal models have boosted our knowledge on the role of cellular senescence in ageing and age-related disease. The aim now is to fully elucidate its role in neurodegeneration in order to efficiently and safely exploit cellular senescence as a therapeutic target. Here, we review evidence of cellular senescence in neurons and glial cells and we discuss its putative role in Alzheimer’s disease, Parkinson’s disease and multiple sclerosis and we provide, for the first time, evidence of senescence in neurons and glia in multiple sclerosis, using the novel GL13 lipofuscin stain as a marker of cellular senescence.

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Cell Specific Consequences of Notch Signaling: PARP1/HES1 Interaction Reveals a Novel Tumor Suppressor Mechanism.

Blood ◽

10.1182/blood.v114.22.2388.2388 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2388-2388

Author(s):

Sankaranarayanan Kannan ◽

Patrick A. Zweidler-McKay

Keyword(s):

Tumor Suppressor ◽

Notch Signaling ◽

Lymphoblastic Leukemia ◽

Growth Arrest ◽

Protein Sequencing ◽

The Novel ◽

Cell Type ◽

Adp Ribosylation ◽

Suppressor Mechanism ◽

Cell Type Specific

Abstract Abstract 2388 Poster Board II-365 The Notch signaling pathway is a critical regulator of cell fate determination and differentiation during development, which is highly cell type specific. Similarly, Notch signaling plays both oncogenic and tumor suppressor roles in a wide variety of malignancies, depending on cell type. In contrast to T cell acute lymphoblastic leukemia (T-ALL) where Notch activation promotes leukemogenesis, induction of Notch signaling in B-ALL leads to growth arrest and apoptosis. The Notch target gene Hairy/Enhancer of Split1 (HES1) is sufficient to reproduce this tumor suppressor phenotype in B-ALL, however the mechanism is not yet known. Here we report the novel finding that HES1 forms distinct complexes in B-ALL versus T-ALL. This suggests that HES1 interacting proteins may contribute to the cell-type specific consequences of Notch/HES1 signaling. During characterization of these complexes, we identified the novel interaction between HES1 and PARP1 through immunoprecipitation and MALDI-TOF protein sequencing. This interaction was dependent on the HES1 bHLH and Orange domains and PARP1 and HES1 co-localize to a genomic HES1 binding site by ChIP. This interaction both inhibits HES1 repressor function and induces PARP1 activation in B-ALL. HES1-induced PARP1 cleavage leads to enhanced poly ADP ribosylation of PARP1, consumption of NAD+, diminished ATP levels, and translocation of the Apoptosis Inducing Factor (AIF) from mitochondria to the nucleus, resulting in apoptosis in B-ALL, but not T-ALL. Importantly the potential therapeutic Notch agonist peptide “DSL” also induces cell-specific growth arrest and apoptosis (A+B), followed by poly-ADP ribosylation of PARP1 (C), and nuclear translocation of AIF in B-ALL but not T-ALL cells (D). These data reveal a novel interaction of HES1 and PARP1 in B-ALL which modulates the function of the HES1 transcriptional complex and signals through PARP1 to induce apoptosis. This novel tumor suppressor mechanism involving a Notch driven, cell-type specific pro-apoptotic pathway may lead to the development of Notch agonist-based cancer therapeutics. Disclosures: No relevant conflicts of interest to declare.

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Ectopic synthesis of epidermal cytokeratins in pancreatic islet cells of transgenic mice interferes with cytoskeletal order and insulin production.

The Journal of Cell Biology ◽

10.1083/jcb.120.3.743 ◽

1993 ◽

Vol 120 (3) ◽

pp. 743-755 ◽

Cited By ~ 48

Author(s):

M Blessing ◽

U Rüther ◽

W W Franke

Keyword(s):

Transgenic Mice ◽

Beta Cells ◽

Cell Function ◽

Cultured Cells ◽

Ectopic Expression ◽

Epidermal Keratinocytes ◽

Cell Type ◽

Cell Functions ◽

Insulin Promoter ◽

Cell Type Specific

The members of the multigene family of intermediate filament (IF) proteins are expressed in various combinations and amounts that are specific for a given pathway or state of differentiation. Previous experiments in which the cell type-specific IF cytoskeleton was altered by introducing foreign IF proteins into cultured cells or certain tissues of transgenic animals have shown a remarkable tolerance, without detectable interference with cell functions. To examine the importance of the cell type-specific cytokeratin (CK) IF pattern, we have studied the ectopic expression of CK genes in different epithelia of transgenic mice. Here we report changes observed in the beta cells of pancreatic islets expressing the genes for human epidermal CKs 1 and/or 10 brought under control of the rat insulin promoter. Both genes were efficiently expressed, resulting in the appearance of numerous and massive bundles of aggregated IFs, resembling those of epidermal keratinocytes. While the synthesis of epidermal CK 10 was readily accommodated and compatible with cell function, mice expressing CK 1 in their beta cells, alone or in combination with CK 10, developed a special form of diabetes characterized by a drastic reduction of insulin-secretory vesicles and of insulin-and CK 1-producing cells. In many CK 1-producing cells, accumulations of fibrous or granular material containing CK 1 were also seen in the nucleus. This demonstration of functional importance of the specific CK-complement in an epithelial cell indicates a contribution of cell type-specific factors to cytoplasmic IF compartmentalization and that the specific CK complement can be crucial for functions and longevity of a given kind of epithelium.

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Notch/HES1-mediated PARP1 activation: a cell type–specific mechanism for tumor suppression

Blood ◽

10.1182/blood-2009-12-253419 ◽

2011 ◽

Vol 117 (10) ◽

pp. 2891-2900 ◽

Cited By ~ 33

Author(s):

Sankaranarayanan Kannan ◽

Wendy Fang ◽

Guangchun Song ◽

Charles G. Mullighan ◽

Richard Hammitt ◽

...

Keyword(s):

T Cell ◽

Tumor Suppressor ◽

Notch Signaling ◽

Lymphoblastic Leukemia ◽

Cancer Therapeutics ◽

The Novel ◽

Cell Type ◽

Interacting Protein ◽

A Cell ◽

Cell Type Specific

Abstract Notch signaling plays both oncogenic and tumor suppressor roles, depending on cell type. In contrast to T-cell acute lymphoblastic leukemia (ALL), where Notch activation promotes leukemogenesis, induction of Notch signaling in B-cell ALL (B-ALL) leads to growth arrest and apoptosis. The Notch target Hairy/Enhancer of Split1 (HES1) is sufficient to reproduce this tumor suppressor phenotype in B-ALL; however, the mechanism is not yet known. We report that HES1 regulates proapoptotic signals by the novel interacting protein Poly ADP-Ribose Polymerase1 (PARP1) in a cell type–specific manner. Interaction of HES1 with PARP1 inhibits HES1 function, induces PARP1 activation, and results in PARP1 cleavage in B-ALL. HES1-induced PARP1 activation leads to self-ADP ribosylation of PARP1, consumption of nicotinamide adenine dinucleotide+, diminished adenosine triphosphate levels, and translocation of apoptosis-inducing factor from mitochondria to the nucleus, resulting in apoptosis in B-ALL but not T-cell ALL. Importantly, induction of Notch signaling by the Notch agonist peptide Delta/Serrate/Lag-2 can reproduce these events and leads to B-ALL apoptosis. The novel interaction of HES1 and PARP1 in B-ALL modulates the function of the HES1 transcriptional complex and signals through PARP1 to induce apoptosis. This mechanism shows a cell type–specific proapoptotic pathway that may lead to Notch agonist–based cancer therapeutics.

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Cell-Type-Specific Activation of p38 Protein Kinase Cascades by the Novel Tumor Promoter Palytoxin

Toxicology and Applied Pharmacology ◽

10.1006/taap.1999.8754 ◽

1999 ◽

Vol 160 (2) ◽

pp. 109-119 ◽

Cited By ~ 16

Author(s):

Shunan Li ◽

Elizabeth V. Wattenberg

Keyword(s):

Protein Kinase ◽

Tumor Promoter ◽

The Novel ◽

Cell Type ◽

Cell Type Specific

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ECLIPSER: identifying causal cell types and genes for complex traits through single cell enrichment of e/sQTL-mapped genes in GWAS loci

10.1101/2021.11.24.469720 ◽

2021 ◽

Author(s):

John M Rouhana ◽

Jiali Wang ◽

Gokcen Eraslan ◽

Shankara Anand ◽

Andrew R Hamel ◽

...

Keyword(s):

Single Cell ◽

Complex Traits ◽

Complex Disease ◽

Skin Diseases ◽

Source Code ◽

Data Access ◽

Cell Types ◽

Cell Type ◽

Healthy Human ◽

Cell Type Specific

Summary: ECLIPSER was developed to identify pathogenic cell types and cell type-specific genes that may affect complex disease susceptibility and trait variation by integrating single cell data with known GWAS loci. ECLIPSER maps genes to GWAS loci for a given complex trait based on expression and splicing quantitative trait loci (e/sQTLs) and other functional data, and tests whether the mapped genes are enriched for cell type-specific expression in particular cell types using single-cell/nucleus RNA-seq data from one or more tissues of interest. A Bayesian Fisher's exact test is used to compute fold-enrichment significance. We demonstrate the application of ECLIPSER on various skin diseases and traits using snRNA-seq of healthy human skin samples. Availability and Implementation: The python source code and documentation for ECLIPSER and a Jupyter notebook for generating output tables and figures are available at https://github.com/segrelabgenomics/ECLIPSER. The source code for GWASvar2gene that maps genes to GWAS loci based on e/sQTLs is available at https://github.com/segrelabgenomics/GWASvar2gene. The analysis presented here used data from GTEx (https://gtexportal.org/home/datasets) and Open Targets Genetics (https://genetics-docs.opentargets.org/data-access/graphql-api), but can also be applied to other GWAS variant lists and QTL studies. Data used to reproduce the results of the paper are available in Supplementary data.

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Epidermal Lamellar Body Biogenesis: Insight Into the Roles of Golgi and Lysosomes

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.701950 ◽

2021 ◽

Vol 9 ◽

Author(s):

Sarmistha Mahanty ◽

Subba Rao Gangi Setty

Keyword(s):

Skin Diseases ◽

Lamellar Body ◽

Current Evidence ◽

Future Research ◽

Cell Type ◽

Cargo Transport ◽

Cell Type Specific ◽

Lysosome Related Organelles ◽

Golgi Network ◽

Insight Into

Epidermal lamellar bodies (eLBs) are secretory organelles that carry a wide variety of secretory cargo required for skin homeostasis. eLBs belong to the class of lysosome-related organelles (LROs), which are cell-type-specific organelles that perform diverse functions. The formation of eLBs is thought to be related to that of other LROs, which are formed either through the gradual maturation of Golgi/endosomal precursors or by the conversion of conventional lysosomes. Current evidence suggests that eLB biogenesis presumably initiate from trans-Golgi network and receive cargo from endosomes, and also acquire lysosome characteristics during maturation. These multistep biogenesis processes are frequently disrupted in human skin disorders. However, many gaps remain in our understanding of eLB biogenesis and their relationship to skin diseases. Here, we describe our current understanding on eLB biogenesis with a focus on cargo transport to this LRO and highlight key areas where future research is needed.

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