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International Journal of Biological... Oct 2022Scars occur as a result of fibrosis after tissue damage or surgery and reports suggest that excessive Transforming growth factor-β (TGF-β) activity during the process...
Scars occur as a result of fibrosis after tissue damage or surgery and reports suggest that excessive Transforming growth factor-β (TGF-β) activity during the process of wound healing leads to progressive fibrosis. Decorin is an extracellular matrix (ECM) protein which regulates collagen fibrillogenesis. However, targeted delivery and effective protein therapy remains a challenge owing to degradation byproteases. Hence, we aimed to deliver Decorin in a sustainable mode for the reduction of TGF-β levels and subsequent scar formation. Herein, we have fabricated PCL-Gelatin bio-mimetic scaffolds to optimize the bio-activity and provide localized delivery of recombinant Decorin. The degradation and drug release patterns reveals that this biomaterial is biodegradable and offers sustained release of the recombinant Decorin. Decorin loaded nanofiber displayed lower adhesion and proliferation rates in in-vitro conditions. Moreover, Decorin loaded scaffolds demonstrated morphological changes in cells, specifically targeting the myofibroblast. The expression of TGF-β was also scrutinized to understand the effect of Decorin loaded nanofibers. Besides, in the in-vitro fibrotic model, Decorin loaded nanofibers efficiently reduced the expression of ECM related proteins. Therefore, we report the sustained delivery of the recombinant Decorin from nanofiber dressing to potentially obstruct scar formation during the process of wound healing.
Topics: Biocompatible Materials; Biomimetics; Cicatrix; Collagen; Decorin; Delayed-Action Preparations; Extracellular Matrix Proteins; Fibrosis; Gelatin; Humans; Transforming Growth Factor beta; Transforming Growth Factor beta1; Transforming Growth Factors
PubMed: 35952816
DOI: 10.1016/j.ijbiomac.2022.08.029 -
Journal of Gynecology Obstetrics and... Dec 2021Decorin is a leucine-rich proteoglycan, affects the proliferation, migration, and invasion of extravillous trophoblasts (EVTs). In this study, we aimed to determine the...
OBJECTIVE
Decorin is a leucine-rich proteoglycan, affects the proliferation, migration, and invasion of extravillous trophoblasts (EVTs). In this study, we aimed to determine the localization of decorin in the implantation site in human tubal ectopic pregnancy, to compare decorin expression levels in ectopic and intrauterine pregnancy, and to investigate the relationship between implantation depth of the tubal wall and expression levels of decorin.
METHODS
15 patients underwent salpingectomy for tubal ectopic pregnancy and 15 underwent curettage for voluntary interruption of pregnancy were included. All blocks were stained with decorin immunohistochemical staining. Trophoblastic cells of tubal Stage I-III and tubal epithelial and stromal cells were analyzed in terms of presence and intensity of decorin staining.
RESULTS
Decorin was expressed in both tubal and intrauterine trophoblasts, stroma, and surface epithelium during the first trimester of pregnancy. Decorin staining intensity was significantly lower in the villous cytotrophoblasts and syncytiotrophoblasts in tubal ectopic pregnancies, compared to intrauterine pregnancies (p = 0.001 for both). Decorin staining intensity also significantly lower in the extravillous cytotrophoblasts and syncytiotrophoblasts in the tubal ectopic pregnancies (p = 0.002 and p = 0.001, respectively). There was no significant difference in the staining intensity of the trophoblasts and surface epithelial between Stage II and Stage III tubal invasion; however, the decorin expression was lower in the stroma in Stage III (p = 0.094).
CONCLUSION
Decorin expression is significantly lower in trophoblastic cells of tubal ectopic pregnancies than the intrauterine pregnancies. Although it remains limited to explain the underlying cellular mechanisms, decorin seems to play a role in the development of tubal pregnancy.
Topics: Adult; Case-Control Studies; Decorin; Female; Gene Expression; Humans; Pregnancy; Pregnancy, Ectopic; Trophoblasts
PubMed: 34469778
DOI: 10.1016/j.jogoh.2021.102213 -
Plastic and Reconstructive Surgery.... Apr 2022Variations in skin healing capacities are observed during different murine embryonic developmental stages. Through embryonic day 16 (E16), embryos are able to regenerate...
BACKGROUND
Variations in skin healing capacities are observed during different murine embryonic developmental stages. Through embryonic day 16 (E16), embryos are able to regenerate dermal architecture following flank skin wounding; however, after E17, wounds heal incompletely, inducing scar formation. The regenerative ability of the E16 fetal dermis depends on the migration of dermal mesenchymal cells. Decorin is a small molecule known to affect tissue tensile strength, cell phenotype, and tissue repair, including skin wound healing. In the current study, we evaluated the expression and roles of decorin in wound healing.
METHODS
Surgical injury was induced at E16 and E17 in ICR mouse embryos. Decorin expression was evaluated in tissue samples from these embryos using immunohistochemistry and reverse transcription quantitative polymerase chain reaction. Cell migration assays were used to evaluate wound healing capability of separated dermal and fascial tissues.
RESULTS
Our results showed that decorin exhibited distinct expression patterns during wound healing at E16 versus E17. Additionally, decorin expression altered cell migration in vitro. Dermal and fascial mesenchymal cells were found to exhibit distinct migration patterns concomitant with altered decorin expression. Specifically, decorin inhibited migration and favored scar formation.
CONCLUSION
Decorin expression may contribute to scar formation in the late stage of mouse embryos by inhibiting the migration of dermal mesenchymal cells.
PubMed: 35425688
DOI: 10.1097/GOX.0000000000004245 -
Reproductive Sciences (Thousand Oaks,... Jan 2021Preterm birth is a leading cause of infant morbidity and mortality. Decorin and biglycan are proteoglycans that play key roles in maintaining the connective tissue...
Preterm birth is a leading cause of infant morbidity and mortality. Decorin and biglycan are proteoglycans that play key roles in maintaining the connective tissue matrix and tensile strength of human fetal membranes and have been previously linked to PPROM. Extracellular matrix proteins, such as matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), TIMP metallopeptidase inhibitor 1 (TIMP-1), TIMP metallopeptidase inhibitor 2 (TIMP-2), and collagen VI (COL-6), have also been linked to PPROM and may have utility in a serum-based screening model for this condition. To define the natural course of serum decorin and biglycan expression throughout the duration of healthy pregnancy, to explore patterns of serum decorin and biglycan expression in serum of asymptomatic women who go on to develop spontaneous preterm labor, and to investigate the potential role for matrix metalloproteinases, their inhibitors, and collagen VI in a serum-based screening model to predict PPROM. Serum decorin level decreases less than 1% per week, and serum biglycan decreases by 2.9% per week over the duration of healthy pregnancy. Serum decorin and biglycan concentrations do not differ in spontaneous preterm labor cases compared with those in controls. Mean concentrations of MMP-2, MMP-9, TIMP-1, TIMP-2, and COL-6 do not differ in PPROM cases compared with those in controls. We have demonstrated that serum decorin and biglycan concentrations remain stable throughout the duration of normal pregnancy and are not early indicators of preterm labor, while common MMPs, TIMPs, and collagen VI are not early indicators of PPROM.
Topics: Biglycan; Biomarkers; Collagen Type VI; Decorin; Enzyme-Linked Immunosorbent Assay; Extracellular Matrix Proteins; Female; Fetal Membranes, Premature Rupture; Humans; Matrix Metalloproteinases; Predictive Value of Tests; Pregnancy; Premature Birth; Retrospective Studies; Tissue Inhibitor of Metalloproteinases
PubMed: 32804350
DOI: 10.1007/s43032-020-00251-1 -
Journal of Orthopaedic Research :... Oct 2023The small leucine-rich proteoglycans, decorin and biglycan, are minor components of the tendon extracellular matrix that regulate fibrillogenesis and matrix assembly....
The small leucine-rich proteoglycans, decorin and biglycan, are minor components of the tendon extracellular matrix that regulate fibrillogenesis and matrix assembly. Our study objective was to define the temporal roles of decorin and biglycan during tendon healing using inducible knockout mice to include genetic knockdown at specific phases of healing: time of injury, the proliferative phase, and the remodeling phase. We hypothesized that knockdown of decorin or biglycan would adversely affect tendon healing, and that by prescribing the timing of knockdown, we could elucidate the temporal roles of these proteins during healing. Contrary to our hypothesis, decorin knockdown did not affect tendon healing. However, when biglycan was knocked down, either alone or coupled with decorin, tendon modulus was increased relative to wild-type mice, and this finding was consistent among all induction timepoints. At 6 weeks postinjury, we observed increased expression of genes associated with the extracellular matrix and growth factor signaling in the biglycan knockdown and compound decorin-biglycan knockdown tendons. Interestingly, these groups demonstrated opposing trends in gene expression as a function of knockdown-induction timepoint, highlighting distinct temporal roles for decorin and biglycan. In summary, this study finds that biglycan plays multiple functions throughout tendon healing, with the most impactful, detrimental role likely occurring during late-stage healing. Statement of clinical importance: This study helps to define the molecular factors that regulate tendon healing, which may aid in the development of new clinical therapies.
Topics: Animals; Mice; Biglycan; Decorin; Extracellular Matrix Proteins; Mice, Knockout; Tendons; Wound Healing
PubMed: 37132501
DOI: 10.1002/jor.25590 -
American Journal of Physiology. Cell... Nov 2022Decorin, a small leucine-rich proteoglycan with multiple biological functions, is known to evoke autophagy and mitophagy in both endothelial and cancer cells. Here, we...
Decorin, a small leucine-rich proteoglycan with multiple biological functions, is known to evoke autophagy and mitophagy in both endothelial and cancer cells. Here, we investigated the effects of soluble decorin on mitochondrial homeostasis using live cell imaging and ex vivo angiogenic assays. We discovered that decorin triggers mitochondrial depolarization in triple-negative breast carcinoma, HeLa, and endothelial cells. This bioactivity was mediated by the protein core in a time- and dose-dependent manner and was specific for decorin insofar as biglycan, the closest homolog, failed to trigger depolarization. Mechanistically, we found that the bioactivity of decorin to promote depolarization required the MET receptor and its tyrosine kinase. Moreover, two mitochondrial interacting proteins, mitostatin and mitofusin 2, were essential for downstream decorin effects. Finally, we found that decorin relied on the canonical mitochondrial permeability transition pore to trigger tumor cell mitochondrial depolarization. Collectively, our study implicates decorin as a soluble outside-in regulator of mitochondrial dynamics.
Topics: Humans; Biglycan; Carcinoma; Decorin; Endothelial Cells; Extracellular Matrix Proteins; Mitochondrial Permeability Transition Pore; Protein-Tyrosine Kinases; Signal Transduction
PubMed: 36036446
DOI: 10.1152/ajpcell.00325.2022 -
Cellular Signalling Aug 2020Glioblastoma (GBM) is an aggressive and devastating primary brain cancer which responds very poorly to treatment. The average survival time of patients is only... (Review)
Review
Glioblastoma (GBM) is an aggressive and devastating primary brain cancer which responds very poorly to treatment. The average survival time of patients is only 14-15 months from diagnosis so there is a clear and unmet need for the development of novel targeted therapies to improve patient outcomes. The multifunctional cytokine TGFβ plays fundamental roles in development, adult tissue homeostasis, tissue wound repair and immune responses. Dysfunction of TGFβ signalling has been implicated in both the development and progression of many tumour types including GBM, thereby potentially providing an actionable target for its treatment. This review will examine TGFβ signalling mechanisms and their role in the development and progression of GBM. The targeting of TGFβ signalling using a variety of approaches including the TGFβ binding protein Decorin will be highlighted as attractive therapeutic strategies.
Topics: Animals; Brain Neoplasms; Decorin; Glioblastoma; Humans; Signal Transduction; Transforming Growth Factor beta; Tumor Microenvironment
PubMed: 32320860
DOI: 10.1016/j.cellsig.2020.109638 -
International Journal of Cosmetic... Dec 2020This work analyses the role of proteoglycans on skin ageing, influenced by the presence of glycosylated proteins, which exercise diverse functions on the skin. They are... (Review)
Review
This work analyses the role of proteoglycans on skin ageing, influenced by the presence of glycosylated proteins, which exercise diverse functions on the skin. They are essential components that restore the cells, providing hydration, maintaining hydration of the extracellular matrix, preventing the formation of wrinkles thanks to their ability to combine to other molecules such as collagen or hyaluronic acid and favouring the smoothness of the skin texture. The use of these proteins is a very recent and promising topic, since their application may revolutionize skin ageing therapies. Of the existing proteoglycans, decorin, versican and perlecan are of special note, playing a fundamental role on skin.
Topics: Humans; Proteoglycans; Skin Aging
PubMed: 32895982
DOI: 10.1111/ics.12660 -
PloS One 2021Effective patient prognosis necessitates identification of novel tumor promoting drivers of gastric cancer (GC) which contribute to worsened conditions by analysing...
Effective patient prognosis necessitates identification of novel tumor promoting drivers of gastric cancer (GC) which contribute to worsened conditions by analysing TCGA-gastric adenocarcinoma dataset. Small leucine-rich proteoglycans, asporin (ASPN) and decorin (DCN), play overlapping roles in development and diseases; however, the mechanisms underlying their interplay remain elusive. Here, we investigated the complex interplay of asporin, decorin and their interaction with TGFβ in GC tumor and corresponding normal tissues. The mRNA levels, protein expressions and cellular localizations of ASPN and DCN were analyzed using real-time PCR, western blot and immunohistochemistry, respectively. The protein-protein interaction was predicted by in-silico interaction analysis and validated by co-immunoprecipitation assay. The correlations between ASPN and EMT proteins, VEGF and collagen were achieved using western blot analysis. A significant increase in expression of ASPN in tumor tissue vs. normal tissue was observed in both TCGA and our patient cohort. DCN, an effective inhibitor of the TGFβ pathway, was negatively correlated with stages of GC. Co-immunoprecipitation demonstrated that DCN binds with TGFβ, in normal gastric epithelium, whereas in GC, ASPN preferentially binds TGFβ. Possible activation of the canonical TGFβ pathway by phosphorylation of SMAD2 in tumor tissues suggests its role as an intracellular tumor promoter. Furthermore, tissues expressing ASPN showed unregulated EMT signalling. Our study uncovers ASPN as a GC-promoting gene and DCN as tumor suppressor, suggesting that ASPN can act as a prognostic marker in GC. For the first time, we describe the physical interaction of TGFβ with ASPN in GC and DCN with TGFβ in GC and normal gastric epithelium respectively. This study suggests that prevention of ASPN-TGFβ interaction or overexpression of DCN could serve as promising therapeutic strategies for GC patients.
Topics: Decorin; Extracellular Matrix Proteins; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Staging; Phosphorylation; Prognosis; Protein Binding; RNA, Messenger; Smad2 Protein; Stomach Neoplasms; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A
PubMed: 34379688
DOI: 10.1371/journal.pone.0255915 -
Nature Communications Oct 2023Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in humans and other mammals, whereas it facilitates axon...
Extracellular matrix (ECM) deposition after central nervous system (CNS) injury leads to inhibitory scarring in humans and other mammals, whereas it facilitates axon regeneration in the zebrafish. However, the molecular basis of these different fates is not understood. Here, we identify small leucine-rich proteoglycans (SLRPs) as a contributing factor to regeneration failure in mammals. We demonstrate that the SLRPs chondroadherin, fibromodulin, lumican, and prolargin are enriched in rodent and human but not zebrafish CNS lesions. Targeting SLRPs to the zebrafish injury ECM inhibits axon regeneration and functional recovery. Mechanistically, we find that SLRPs confer mechano-structural properties to the lesion environment that are adverse to axon growth. Our study reveals SLRPs as inhibitory ECM factors that impair axon regeneration by modifying tissue mechanics and structure, and identifies their enrichment as a feature of human brain and spinal cord lesions. These findings imply that SLRPs may be targets for therapeutic strategies to promote CNS regeneration.
Topics: Animals; Humans; Small Leucine-Rich Proteoglycans; Proteoglycans; Chondroitin Sulfate Proteoglycans; Zebrafish; Decorin; Axons; Nerve Regeneration; Extracellular Matrix Proteins; Central Nervous System; Mammals
PubMed: 37884489
DOI: 10.1038/s41467-023-42339-7