Extracellular Matrix Stiffness and Composition Regulate the Myofibroblast Differentiation of Vaginal Fibroblasts

Fibroblast to myofibroblast differentiation is a key feature of wound-healing in soft tissues, including the vagina. Vaginal fibroblasts maintain the integrity of the vaginal wall tissues, essential to keep pelvic organs in place and avoid pelvic organ prolapse (POP). The micro-environment of vaginal tissues in POP patients is stiffer and has different extracellular matrix (ECM) composition than healthy vaginal tissues. In this study, we employed a series of matrices with known stiffnesses, as well as vaginal ECMs, in combination with vaginal fibroblasts from POP and healthy tissues to investigate how matrix stiffness and composition regulate myofibroblast differentiation in vaginal fibroblasts. Stiffness was positively correlated to production of α-smooth muscle actin (α-SMA). Vaginal ECMs induced myofibroblast differentiation as both α-SMA and collagen gene expressions were increased. This differentiation was more pronounced in cells seeded on POP-ECMs that were stiffer than those derived from healthy tissues and had higher collagen and elastin protein content. We showed that stiffness and ECM content regulate vaginal myofibroblast differentiation. We provide preliminary evidence that vaginal fibroblasts might recognize POP-ECMs as scar tissues that need to be remodeled. This is fundamentally important for tissue repair, and provides a rational basis for POP disease modelling and therapeutic innovations in vaginal reconstruction

Wound healing of the pelvic floor concerning pelvic organ prolapse – What do we know?

Pelvic organ prolapse (POP) is a result of the pelvic’s floor supportive tissues weakening, including levator ani muscles, endopelvic fascia, ligaments, and the vaginal wall. The objective of this review is to describe the wound healing physiology in tissues that might be injured in the pelvic floor and to discuss the factors that affect wound healing. Since the most important risk factors for POP, such as pregnancy, vaginal delivery, and increased intra-abdominal pressure, trigger tissue damage, i.e. a wound in the pelvic floor tissues, we hypothesize that a frustrated wound healing process could affect the tissue homeostasis and promote POP. MEDLINE database was searched to review the literature up to 2017. As with skin, the wound healing in the pelvic floor tissues takes place in four phases (hemostasis, inflammation, proliferation and remodeling), however the duration of each phase is longer in the different structures of the pelvic floor compared to skin. Mechanical loading in the pelvic floor negatively affects healing and is associated with increased collagenase activity, whilst estrogen seems to improve the mechanical properties of the stretched tissue and could be beneficial for vaginal wound healing. Neither damaged muscle, nerves, ligaments nor vaginal wall will fully recover their pre-wounding characteristics. We postulate that a frustrated wound healing of the tissues of the pelvic floor generates tissues with altered composition and mechanical properties which could lead to the incidence or progression of POP.O prolapso de órgão pélvico (POP) é resultado do enfraquecimento dos tecidos de sustentação e de suspensão dessa região, incluindo os músculos levantadores do ânus, a fáscia endopélvica, os ligamentos e a parede vaginal. Sabe-se que os fatores de risco mais importantes para o POP, como gravidez, parto vaginal e aumento da pressão intra-abdominal, causam lesão nos tecidos do assoalho pélvico. Assim, é possível que um processo de cicatrização imperfeito desses tecidos possa afetar sua homeostase e contribuir para o desenvolvimento do POP. Dessa forma, o objetivo deste artigo é revisar a fisiologia da cicatrização de tecidos do assoalho pélvico e discutir os fatores que interferem nesse processo. Para isso, foi feita uma revisão da literatura na base de dados do MEDLINE até 2017. Percebeu-se que, assim como na pele, a cicatrização das lesões do assoalho pélvico ocorre em quatro fases (hemostasia, inflamação, proliferação e remodelação), porém a duração de cada fase é maior nas diferentes estruturas do assoalho pélvico. Além disso, a pressão constante no assoalho pélvico está associada ao aumento da atividade da colagenase, afetando negativamente a cicatrização, enquanto o estrogênio melhora as propriedades mecânicas do tecido estirado e parece ser benéfico para a cicatrização das lesões na parede vaginal. De acordo com a literatura, os músculos, nervos, ligamentos ou parede vaginal danificados não recuperam totalmente suas características prévias. Desse modo, conclui-se que uma cicatrização imperfeita no assoalho pélvico resulta em tecidos com composição e propriedades mecânicas alteradas, o que pode levar à incidência ou progressão do POP

Management of post-midurethral sling voiding dysfunction. International Urogynecological Association research and development committee opinion

Peer reviewedPostprin

Fibroblasts from women with pelvic organ prolapse show differential mechanoresponses depending on surface substrates

INTRODUCTION AND HYPOTHESIS: Little is known about dynamic cell-matrix interactions in the context of pathophysiology and treatments for pelvic organ prolapse (POP). This study sought to identify differences between fibroblasts from women with varying degrees of prolapse in reaction to mechanical stimuli and matrix substrates in vitro. METHODS: Fibroblasts from the vaginal wall of three patients with POP Quantification (POP-Q) system stages 0, II, and IV were stretched on artificial polymer substrates either coated or not coated with collagen I. Changes in morphology and anabolic/catabolic compounds that affect matrix remodelling were evaluated at protein- and gene-expression levels. Statistical analysis was performed using one-way analysis of variance (ANOVA), followed by Tukey-Kramer’s post hoc test. RESULTS: POP fibroblasts show delayed cell alignment and lower responses to extracellular matrix remodelling factors at both enzymatic- and gene-expression levels compared with healthy fibroblasts. CONCLUSION: POP fibroblasts, when compared with healthy cells, show differential mechanoresponses on two artificial polymer substrates. This should be taken into account when designing or improving implants for treating POP

Variation in the practice of laparoscopic sacrohysteropexy and laparoscopic sacrocolpopexy for the treatment of pelvic organ prolapse: a Dutch survey

INTRODUCTION AND HYPOTHESIS: Laparoscopic techniques for pelvic organ prolapse surgery using mesh are gaining interest. A standard approach or published guideline for the laparoscopic sacrohysteropexy (LSH) or laparoscopic sacrocolpopexy (LSC) is lacking. The purpose of this study is to assess the variation between Dutch gynecologists in executing LSH and LSC. METHODS: A questionnaire was developed to evaluate the technique of LSH and LSC. All members of the Dutch Society for Gynecological Endoscopy and Minimally Invasive Surgery and the Dutch Society for Urogynecology were invited by email to participate in a web-based survey. RESULTS: With 357 respondents, the response rate was 71%. Of the respondents, a total of 49 gynecologists (13.7%) perform LSH and/or LSC. Gynecologists who perform both procedures use the same surgical technique for LSH and LSC. There are variations among gynecologists on several key points such as the level of dissection along the anterior and posterior walls of the vagina, the type of mesh used, the type of sutures used, the tension of the implanted mesh and reperitonealization of the mesh. CONCLUSIONS: There is a high practice variation in LSH and LSC performed by a selected group of Dutch gynecologists. Different methods have been described in the literature and there is no consensus on how to perform these procedures. A well-designed prospective study or randomized controlled trial with regard to the specific parts of these procedures is needed to provide evidence for the best surgical technique. The outcomes of these studies will help to establish evidence-based guidelines

Extracellular Matrix Stiffness and Composition Regulate the Myofibroblast Differentiation of Vaginal Fibroblasts

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Severe retinopathy of prematurity is associated with reduced cerebellar and brainstem volumes at term and neurodevelopmental deficits at 2 years

BackgroundTo evaluate the association between severe retinopathy of prematurity (ROP), measures of brain morphology at term-equivalent age (TEA), and neurodevelopmental outcome.MethodsEighteen infants with severe ROP (median gestational age (GA) 25.3 (range 24.6-25.9 weeks) were included in this retrospective case-control study. Each infant was matched to two extremely preterm control infants (n=36) by GA, birth weight, sex, and brain injury. T2-weighted images were obtained on a 3 T magnetic resonance imaging (MRI) at TEA. Brain volumes were computed using an automatic segmentation method. In addition, cortical folding metrics were extracted. Neurodevelopment was formally assessed at the ages of 15 and 24 months.ResultsInfants with severe ROP had smaller cerebellar volumes (21.4±3.2 vs. 23.1±2.6 ml; P=0.04) and brainstem volumes (5.4±0.5 ml vs. 5.8±0.5 ml; P=0.01) compared with matched control infants. Furthermore, ROP patients showed a significantly lower development quotient (Griffiths Mental Development Scales) at the age of 15 months (93±15 vs. 102±10; P=0.01) and lower fine motor scores (10±3 vs. 12±2; P=0.02) on Bayley Scales (Third Edition) at the age of 24 months.ConclusionSevere ROP was associated with smaller volumes of the cerebellum and brainstem and with poorer early neurodevelopmental outcome. Follow-up through childhood is needed to evaluate the long-term consequences of our findings