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Cell Communication and Signaling : CCS Aug 2023Keloids are a fibroproliferative skin disorder that develops in people of all ages. Keloids exhibit some cancer-like behaviors, with similar genetic and epigenetic... (Review)
Review
Keloids are a fibroproliferative skin disorder that develops in people of all ages. Keloids exhibit some cancer-like behaviors, with similar genetic and epigenetic modifications in the keloid microenvironment. The keloid microenvironment is composed of keratinocytes, fibroblasts, myofibroblasts, vascular endothelial cells, immune cells, stem cells and collagen fibers. Recent advances in the study of keloids have led to novel insights into cellular communication among components of the keloid microenvironment as well as potential therapeutic targets for treating keloids. In this review, we summarized the nature of genetic and epigenetic regulation in keloid-derived fibroblasts, epithelial-to-mesenchymal transition of keratinocytes, immune cell infiltration into keloids, the differentiation of keloid-derived stem cells, endothelial-to-mesenchymal transition of vascular endothelial cells, extracellular matrix synthesis and remodeling, and uncontrolled angiogenesis in keloids with the aim of identifying new targets for therapeutic benefit. Video Abstract.
Topics: Humans; Keloid; Endothelial Cells; Epigenesis, Genetic; Skin; Keratinocytes
PubMed: 37587491
DOI: 10.1186/s12964-023-01214-0 -
Science (New York, N.Y.) Sep 2023After heart injury, dead heart muscle is replaced by scar tissue. Fibroblasts can electrically couple with myocytes, and changes in fibroblast membrane potential can...
After heart injury, dead heart muscle is replaced by scar tissue. Fibroblasts can electrically couple with myocytes, and changes in fibroblast membrane potential can lead to myocyte excitability, which suggests that fibroblast-myocyte coupling in scar tissue may be responsible for arrhythmogenesis. However, the physiologic relevance of electrical coupling of myocytes and fibroblasts and its impact on cardiac excitability in vivo have never been demonstrated. We genetically engineered a mouse that expresses the optogenetic cationic channel ChR2 (H134R) exclusively in cardiac fibroblasts. After myocardial infarction, optical stimulation of scar tissue elicited organ-wide cardiac excitation and induced arrhythmias in these animals. Complementing computational modeling with experimental approaches, we showed that gap junctional and ephaptic coupling, in a synergistic yet functionally redundant manner, excited myocytes coupled to fibroblasts.
Topics: Animals; Mice; Arrhythmias, Cardiac; Cicatrix; Fibroblasts; Myocytes, Cardiac; Channelrhodopsins; Optogenetics; Connexin 43; Gene Knockout Techniques
PubMed: 37769108
DOI: 10.1126/science.adh9925 -
Frontiers in Immunology 2023Injuries to our skin trigger a cascade of spatially- and temporally-synchronized healing processes. During such endogenous wound repair, the role of fibroblasts is... (Review)
Review
Injuries to our skin trigger a cascade of spatially- and temporally-synchronized healing processes. During such endogenous wound repair, the role of fibroblasts is multifaceted, ranging from the activation and recruitment of innate immune cells through the synthesis and deposition of scar tissue to the conveyor belt-like transport of fascial connective tissue into wounds. A comprehensive understanding of fibroblast diversity and versatility in the healing machinery may help to decipher wound pathologies whilst laying the foundation for novel treatment modalities. In this review, we portray the diversity of fibroblasts and delineate their unique wound healing functions. In addition, we discuss future directions through a clinical-translational lens.
Topics: Humans; Fibroblasts; Wound Healing; Cicatrix; Skin
PubMed: 37646029
DOI: 10.3389/fimmu.2023.1233800 -
The Journal of Dermatological Treatment Dec 2023Platelet-rich plasma (PRP) offers anti-inflammatory and regenerative properties through angiogenesis, cell differentiation, and proliferation. Although studied in many... (Review)
Review
Platelet-rich plasma (PRP) offers anti-inflammatory and regenerative properties through angiogenesis, cell differentiation, and proliferation. Although studied in many dermatologic conditions, its efficacy is not well-understood. Our objective is to review the use and effectiveness of PRP for dermatologic conditions. A literature search was performed through PubMed and yielded 54 articles published between January 2000 and November 2021; articles written in English were reviewed. Intradermal injections were associated with increased hair density in androgenic alopecia. Successful treatment of inflammatory nail diseases with PRP has been reported. Improvement in psoriasis was described, but only two studies were available. PRP was associated with higher patient self-assessment scores of photoaging and fine lines. Treatment with PRP in melasma has been associated with improved subjective satisfaction, but not with objective measures of disease improvement. PRP can serve as a safe and potentially effective adjunct for hair loss, vitiligo, nonhealing wounds, photoaging, and acne scars. An important barrier to interpreting PRP research is lack of standardization of PRP preparation protocols, inconsistent clinical endpoints, and frequent combination treatments. However, PRP is relatively noninvasive, has a well-established safety profile, and patient satisfaction is often high as patients perceive great benefit from treatment with PRP.
Topics: Humans; Alopecia; Cicatrix; Patient Satisfaction; Injections, Intradermal; Platelet-Rich Plasma; Treatment Outcome
PubMed: 36318219
DOI: 10.1080/09546634.2022.2142035 -
European Journal of Obstetrics,... Sep 2023A Cesarean Scar Pregnancy (CSP) is a variant of uterine ectopic pregnancy defined by full or partial implantation of the gestational sac in the scar of a previous... (Review)
Review
A Cesarean Scar Pregnancy (CSP) is a variant of uterine ectopic pregnancy defined by full or partial implantation of the gestational sac in the scar of a previous cesarean section. The continuous increase of Cesarean Deliveries is causing a parallel increase in CSP and its complications. Considering its high morbidity, the most usual recommendation has been termination of pregnancy in the first trimester; however, several cases progress to viable births. The aim of this systematic review is to evaluate the outcome of CSP managed expectantly and understand whether sonographic signs could correlate to the outcomes. An online-based search of PubMed and Cochrane Library Databases was used to gather studies including women diagnosed with a CSP who were managed expectantly. The description of all cases was analysed by the authors in order to obtain information for each outcome. 47 studies of different types were retrieved, and the gestational outcome was available in 194 patients. Out of these, 39 patients (20,1%) had a miscarriage and 16 (8,3%) suffered foetal death. 50 patients (25,8%) had a term delivery and 81 (41,8%) patients had a preterm birth, out of which 27 (13,9%) delivered before 34 weeks of gestation. In 102 (52,6%) patients, a hysterectomy was performed. Placenta Accreta Spectrum (PAS) was a common disorder among CSP and was linked to a higher rate of complications such as foetal death, preterm birth, hysterectomy, haemorrhagic morbidity and surgical complications. Some of the analysed articles showed that sonographic signs with specific characteristics, such as type II and III CSP classification, Crossover Sign - 1, "In the niche" implantation and lower myometrial thickness could be related to worse outcomes of CSP. This article provides a good understanding of CSP as an entity that, although rare, presents with a high rate of relevant morbidity. It is also understood that pregnancies with confirmed PAS had an even higher rate of morbidity. Some sonographic signs were shown to predict the prognosis of these pregnancies and further investigation is necessary to validate one or more signs so they can be used for a more reliable counselling of women with CSP.
Topics: Pregnancy; Infant, Newborn; Humans; Female; Cesarean Section; Premature Birth; Cicatrix; Watchful Waiting; Pregnancy, Ectopic; Pregnancy Outcome; Placenta Accreta; Fetal Death; Retrospective Studies
PubMed: 37421745
DOI: 10.1016/j.ejogrb.2023.06.030 -
The Journal of Clinical Investigation Sep 2023Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with poor survival. The incidence and mortality of IPF are rising, but treatment... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung with poor survival. The incidence and mortality of IPF are rising, but treatment remains limited. Currently, two drugs can slow the scarring process but often at the expense of intolerable side effects, and without substantially changing overall survival. A better understanding of mechanisms underlying IPF is likely to lead to improved therapies. The current paradigm proposes that repetitive alveolar epithelial injury from noxious stimuli in a genetically primed individual is followed by abnormal wound healing, including aberrant activity of extracellular matrix-secreting cells, with resultant tissue fibrosis and parenchymal damage. However, this may underplay the importance of the vascular contribution to fibrogenesis. The lungs receive 100% of the cardiac output, and vascular abnormalities in IPF include (a) heterogeneous vessel formation throughout fibrotic lung, including the development of abnormal dilated vessels and anastomoses; (b) abnormal spatially distributed populations of endothelial cells (ECs); (c) dysregulation of endothelial protective pathways such as prostacyclin signaling; and (d) an increased frequency of common vascular and metabolic comorbidities. Here, we propose that vascular and EC abnormalities are both causal and consequential in the pathobiology of IPF and that fuller evaluation of dysregulated pathways may lead to effective therapies and a cure for this devastating disease.
Topics: Humans; Endothelial Cells; Cicatrix; Idiopathic Pulmonary Fibrosis; Drug-Related Side Effects and Adverse Reactions; Epoprostenol
PubMed: 37712420
DOI: 10.1172/JCI172058 -
International Journal of Cardiology Jan 2024Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by prominent "non-ischemic" myocardial scarring predisposing to ventricular electrical...
Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by prominent "non-ischemic" myocardial scarring predisposing to ventricular electrical instability. Diagnostic criteria for the original phenotype, arrhythmogenic right ventricular cardiomyopathy (ARVC), were first proposed in 1994 and revised in 2010 by an international Task Force (TF). A 2019 International Expert report appraised these previous criteria, finding good accuracy for diagnosis of ARVC but a lack of sensitivity for identification of the expanding phenotypic disease spectrum, which includes left-sided variants, i.e., biventricular (ABVC) and arrhythmogenic left ventricular cardiomyopathy (ALVC). The ARVC phenotype together with these left-sided variants are now more appropriately named ACM. The lack of diagnostic criteria for the left ventricular (LV) phenotype has resulted in clinical under-recognition of ACM patients over the 4 decades since the disease discovery. In 2020, the "Padua criteria" were proposed for both right- and left-sided ACM phenotypes. The presently proposed criteria represent a refinement of the 2020 Padua criteria and have been developed by an expert European TF to improve the diagnosis of ACM with upgraded and internationally recognized criteria. The growing recognition of the diagnostic role of CMR has led to the incorporation of myocardial tissue characterization findings for detection of myocardial scar using the late‑gadolinium enhancement (LGE) technique to more fully characterize right, biventricular and left disease variants, whether genetic or acquired (phenocopies), and to exclude other "non-scarring" myocardial disease. The "ring-like' pattern of myocardial LGE/scar is now a recognized diagnostic hallmark of ALVC. Additional diagnostic criteria regarding LV depolarization and repolarization ECG abnormalities and ventricular arrhythmias of LV origin are also provided. These proposed upgrading of diagnostic criteria represents a working framework to improve management of ACM patients.
Topics: Humans; Cicatrix; Consensus; Contrast Media; Gadolinium; Arrhythmogenic Right Ventricular Dysplasia; Cardiomyopathies; Arrhythmias, Cardiac
PubMed: 37844667
DOI: 10.1016/j.ijcard.2023.131447 -
Nature Communications Sep 2023Asherman's Syndrome is characterized by intrauterine adhesions or scarring, which cause infertility, menstrual abnormalities, and recurrent pregnancy loss. The...
Asherman's Syndrome is characterized by intrauterine adhesions or scarring, which cause infertility, menstrual abnormalities, and recurrent pregnancy loss. The pathophysiology of this syndrome remains unknown, with treatment restricted to recurrent surgical removal of intrauterine scarring, which has limited success. Here, we decode the Asherman's Syndrome endometrial cell niche by analyzing data from over 200,000 cells with single-cell RNA-sequencing in patients with this condition and through in vitro analyses of Asherman's Syndrome patient-derived endometrial organoids. Our endometrial atlas highlights the loss of the endometrial epithelium, alterations to epithelial differentiation signaling pathways such as Wnt and Notch, and the appearance of characteristic epithelium expressing secretory leukocyte protease inhibitor during the window of implantation. We describe syndrome-associated alterations in cell-to-cell communication and gene expression profiles that support a dysfunctional pro-fibrotic, pro-inflammatory, and anti-angiogenic environment.
Topics: Female; Pregnancy; Humans; Cicatrix; Gynatresia; Uterine Diseases; Cell Communication; Embryo Implantation
PubMed: 37735465
DOI: 10.1038/s41467-023-41656-1 -
Journal of Hepatology May 2024Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which there is an unmet need to understand the cellular composition of the...
BACKGROUND & AIMS
Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which there is an unmet need to understand the cellular composition of the affected liver and how it underlies disease pathogenesis. We aimed to generate a comprehensive atlas of the PSC liver using multi-omic modalities and protein-based functional validation.
METHODS
We employed single-cell and single-nucleus RNA sequencing (47,156 cells and 23,000 nuclei) and spatial transcriptomics (one sample by 10x Visium and five samples with Nanostring GeoMx DSP) to profile the cellular ecosystem in 10 PSC livers. Transcriptomic profiles were compared to 24 neurologically deceased donor livers (107,542 cells) and spatial transcriptomics controls, as well as 18,240 cells and 20,202 nuclei from three PBC livers. Flow cytometry was performed to validate PSC-specific differences in immune cell phenotype and function.
RESULTS
PSC explants with parenchymal cirrhosis and prominent periductal fibrosis contained a population of cholangiocyte-like hepatocytes that were surrounded by diverse immune cell populations. PSC-associated biliary, mesenchymal, and endothelial populations expressed chemokine and cytokine transcripts involved in immune cell recruitment. Additionally, expanded CD4 T cells and recruited myeloid populations in the PSC liver expressed the corresponding receptors to these chemokines and cytokines, suggesting potential recruitment. Tissue-resident macrophages, by contrast, were reduced in number and exhibited a dysfunctional and downregulated inflammatory response to lipopolysaccharide and interferon-γ stimulation.
CONCLUSIONS
We present a comprehensive atlas of the PSC liver and demonstrate an exhaustion-like phenotype of myeloid cells and markers of chronic cytokine expression in late-stage PSC lesions. This atlas expands our understanding of the cellular complexity of PSC and has potential to guide the development of novel treatments.
IMPACT AND IMPLICATIONS
Primary sclerosing cholangitis (PSC) is a rare liver disease characterized by chronic inflammation and irreparable damage to the bile ducts, which eventually results in liver failure. Due to a limited understanding of the underlying pathogenesis of disease, treatment options are limited. To address this, we sequenced healthy and diseased livers to compare the activity, interactions, and localization of immune and non-immune cells. This revealed that hepatocytes lining PSC scar regions co-express cholangiocyte markers, whereas immune cells infiltrate the scar lesions. Of these cells, macrophages, which typically contribute to tissue repair, were enriched in immunoregulatory genes and demonstrated a lack of responsiveness to stimulation. These cells may be involved in maintaining hepatic inflammation and could be a target for novel therapies.
Topics: Humans; Cholangitis, Sclerosing; Cicatrix; Ecosystem; Liver; Liver Cirrhosis; Cytokines; Inflammation; Gene Expression Profiling
PubMed: 38199298
DOI: 10.1016/j.jhep.2023.12.023 -
Tracing immune cells around biomaterials with spatial anchors during large-scale wound regeneration.Nature Communications Sep 2023Skin scarring devoid of dermal appendages after severe trauma has unfavorable effects on aesthetic and physiological functions. Here we present a method for large-area...
Skin scarring devoid of dermal appendages after severe trauma has unfavorable effects on aesthetic and physiological functions. Here we present a method for large-area wound regeneration using biodegradable aligned extracellular matrix scaffolds. We show that the implantation of these scaffolds accelerates wound coverage and enhances hair follicle neogenesis. We perform multimodal analysis, in combination with single-cell RNA sequencing and spatial transcriptomics, to explore the immune responses around biomaterials, highlighting the potential role of regulatory T cells in mitigating tissue fibrous by suppressing excessive type 2 inflammation. We find that immunodeficient mice lacking mature T lymphocytes show the typical characteristic of tissue fibrous driven by type 2 macrophage inflammation, validating the potential therapeutic effect of the adaptive immune system activated by biomaterials. These findings contribute to our understanding of the coordination of immune systems in wound regeneration and facilitate the design of immunoregulatory biomaterials in the future.
Topics: Mice; Animals; Biocompatible Materials; Wound Healing; Cicatrix; Hair Follicle; Inflammation; Skin
PubMed: 37752124
DOI: 10.1038/s41467-023-41608-9