Tissue Growth Research Articles

Multi-tissue metabolomic profiling reveals the crucial metabolites and pathways associated with scallop growth.

Bivalves represent a vital economic resource in aquaculture for their high productivity and extensive market demand. Growth is one of the most important and desired aquaculture traits for bivalves, regulated by multiple levels, notably intricate metabolic processes. However, the understanding of the metabolic profiles that influence bivalve growth is limited, particularly from a multi-tissue perspective. In this study, metabolic profiles of multiple tissues of Chlamys farreri with different growth performance were systematically investigated by ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Through comparing the metabolic variation between fast-growing (FG) scallops and slow-growing (SG) scallops, 613, 509, 105, and 192 significantly different metabolites (SDMs) were identified in the mantle, gill, adductor muscle, and digestive gland, respectively. Growth-related metabolic pathways including sphingolipid metabolism, fatty acid biosynthesis, and ABC transporter pathway, along with 11 SDMs associated with growth traits were identified in all four tissues, implying they were involved in the growth of multiple tissues in scallops. Tissue-specific metabolic profiling indicated that sulfur-containing amino acid metabolism in the mantle potentially contributed to shell growth, while the gill synergistically participated with the mantle through various metabolic processes, such as tyrosine metabolism, glycine, serine, and threonine metabolism and melanogenesis; energy metabolism was crucial for adductor muscle growth; and nutrients digestion and absorption in the digestive gland were linked to scallop growth. Our results represent the first comprehensive analysis of the crucial pathways and metabolites associated with the growth of C. farreri, offering valuable insights for future bivalve aquaculture production.

Contact area and tissue growth dynamics shape synthetic juxtacrine signaling patterns.

Cell-cell communication through direct contact, or juxtacrine signaling, is important in development, disease, and many areas of physiology. Synthetic forms of juxtacrine signaling can be precisely controlled and operate orthogonally to native processes, making them a powerful reductionist tool with which to address fundamental questions in cell-cell communication in vivo. Here we investigate how cell-cell contact length and tissue growth dynamics affect juxtacrine signal responses through implementing a custom synthetic gene circuit in Drosophila wing imaginal discs alongside mathematical modeling to determine synthetic Notch (synNotch) activation patterns. We find that the area of contact between cells largely determines the extent of synNotch activation, leading to the prediction that the shape of the interface between signal-sending and signal-receiving cells will impact the magnitude of the synNotch response. Notably, synNotch outputs form a graded spatial profile that extends several cell diameters from the signal source, providing evidence that the response to juxtacrine signals can persist in cells as they proliferate away from source cells, or that cells remain able to communicate directly over several cell diameters. Our model suggests the former mechanism may be sufficient, since it predicts graded outputs without diffusion or long-range cell-cell communication. Overall, we identify that cell-cell contact area together with output synthesis and decay rates likely govern the pattern of synNotch outputs in both space and time during tissue growth, insights that may have broader implications for juxtacrine signaling in general.

Pain and Fertility Outcomes in Patients Undergoing Cyst Excision Versus Cyst Aspiration in Moderate to Severe Endometriosis: A Case Series

Background: Endometriosis and ovarian cysts are prevalent gynecological disorders characterized by the presence of abnormal tissue growth in the pelvic cavity. Objective: To document the pain and fertility outcomes in patients undergoing cyst excision versus cyst aspiration in moderate to severe endometriosis presenting to a tertiary healthcare facility. Methods: This was a case series conducted in the Department of Obstetrics and Gynecology, Vinayaka Missions Medical College & Hospital, Vinayaka Missions Research Foundation (VMRF, Deemed to be University), Karaikal, Puducherry, India between June 2021 and May 2023 (n=14). Results: The study included 14 patients, divided evenly with 7 undergoing cyst excision and 7 undergoing cyst aspiration. Before surgery, both groups had comparable baseline characteristics in terms of age, symptom severity, and the nature of the ovarian cysts. After surgery, patients who underwent cyst excision showed a higher rate of pain relief compared to those who underwent cyst aspiration (61% versus 26%, respectively). In terms of fertility outcomes, 55% of patients in the cyst excision group achieved improved clinical pregnancy outcomes after surgery, whereas 35% of those in the cyst aspiration group had comparable results. Conclusion: Cyst excision appears to be associated with superior pain relief and faster recovery compared to cyst aspiration in patients with endometriosis or ovarian cysts.

Peripheral straightness leads to shape diversification during formations of entire leaves.

The ways to read out positional information are essential to determine final shapes in developmental processes. Relative shaping to different sizes of positional information enables robust morphogenesis; however, the same difference sometimes causes diversity. Different responses to a positional information will enable such switching of identical/diverse shapes, though detail mechanisms remain unknown. In this paper, we describe growing forms by constructing the contour of a two-dimensional object using propagating points and segments connecting them. In plant morphogenesis that lacks almost cell movements, tissue growth accompanied by cell divisions is central. We focused on peripheral cell composition in leaf formation as a frame. The growth with or without cell division on the periphery was analyzed with simple algorithms. We calculated the shapes of entire leaves with different ovality using combined growth algorithms as a model. Responces of the respective algorithms to simple positional information were explored to seek the origin of the shape diversification. The algorithm for "growth with cell divisions" maintained identical shapes; however, diverse shapes were generated by the algorithm "growth without cell division" with gradients. The simplified model allowed us to interpret the oval shape diversity due to slants on edges. We concluded that peripheral straightness can generate shape diversity, at least in leaf morphogenesis.

Epithelial Folding Through Local Degradation of an Elastic Basement Membrane Plate

AbstractEpithelia are polarized layers of cells that line the outer and inner surfaces of organs. At the basal side, the epithelial cell layer is supported by a basement membrane, which is a thin polymeric layer of self‐assembled extracellular matrix (ECM) that tightly adheres to the basal cell surface. Proper shaping of epithelial layers is an important prerequisite for the development of healthy organs during the morphogenesis of an organism. Experimental evidence suggests that local degradation of the basement membrane is one of the mechanisms that can drive epithelial folding. However, how folding emerges in the absence of tissue growth remains elusive. Here, we present a coarse‐grained plate theory model of the basement membrane that assumes force balance between i) cell‐transduced active forces and ii) deformation‐induced elastic forces. We verify key assumptions of this model through experiments in the Drosophila wing disc epithelium and demonstrate that the model can explain the emergence of outward epithelial folds upon local plate degradation. The model accounts for local degradation of the basement membrane as a mechanism for the generation of epithelial folds in the absence of epithelial growth.

Synthesis methods of Mg-based scaffolds and their applications in tissue engineering: A review.

Repair and regeneration of damaged tissues due to disease and accidents have become a severe challenge to tissue engineers and researchers. In recent years, biocompatible metal materials such as stainless steels, cobalt alloys, titanium alloys, tantalum alloys, nitinol, and Mg alloys have been studied for tissue engineering applications; as suitable candidates in orthopedic and dentistry implants. These materials and their alloys are used for load-bearing and physiological roles in biological applications. Due to the suitable conditions provided by a porous material, many studies have been performed on the porous implants, including Mg-based scaffolds. Mg alloy scaffolds are attractive due to some outstanding features and susceptibilities, such as providing a cell matrix for cell proliferation, migration, and regeneration, providing metabolic substances for bone tissue growth, biocompatibility, good biodegradability, elastic modulus comparable to the natural bone, etc. Accordingly, in the present study, a general classification of all the production methods of Mg-based scaffolds is provided. Strengths and weaknesses, the effect of the production approach on the final properties of scaffolds, including mechanical and biological capabilities, and the impact of alloying elements and process parameters have been reviewed, and discussed. Finally, the manufacturing methods have been compared and the upcoming challenges have been stated.

The role of histohematologic barriers and the possibility of using polarization biomedical optics methods in the diagnosis of autoimmune thyroiditis

Background. Violation of the integrity of the histohematologic barriers (blood-brain, blood-testis, blood-ocular, blood-labyrinth, blood-thyroid) leads to autoimmune damage to these organs. One of the manifestations of the latter is autoimmune thyroiditis, the structural and quantitative changes of which can be more informatively accurately assessed by polarization biomedical optics. The purpose of the study was to substantiate the possibility of using polarization biomedical optics methods in the diagnosis of autoimmune thyroiditis based on the use of pathophysiological analysis of blood-brain barrier integrity disorders. Materials and methods. Two groups of patients were studied: control group 1 — healthy donors (n = 51), study group 2 — people with autoimmune thyroiditis (n = 51) who underwent a puncture biopsy of the thyroid gland for diagnostic purposes. Instrumental laser methods were used: polarization, interference, multifractal. The statistical parameters of polarization ellipticity maps, polarization ellipticity of phase and multifractal spectra of digital microscopic images of native thyroid histological sections in patients with autoimmune thyroiditis were quantified: mean, dispersion, asymmetry, and kurtosis. The probability of differences compared to the controls, taken as 100 %, was evaluated using the Student’s parametric test (p < 0.05). Results. A significant increase in the mean and variance at inhibition of the asymmetry and kurtosis of polarization ellipticity, as well as in the mean and variance at reduction of the asymmetry and kurtosis of polarization ellipticity of phase digital microscopic images of thyroid native histological sections was revealed. There were a significant increase in dispersion and a decrease in the asymmetry and kurtosis of multifractal spectra of polarization ellipticity maps of digital microscopic images of native histological sections. Conclusions. A significant increase in the biophysical optical parameters of digital microscopic images of thyroid native histological sections from patients with autoimmune thyroiditis was found due to the growth of connective tissue in the interstitium as a result of an autoimmune inflammation. There was a significant inhibition of the asymmetry and kurtosis of the ellipticity of polarization of phase digital and multifractal spectra of polarization ellipticity maps of microscopic images of native histological sections in patients with autoimmune thyroiditis due to a decrease in the amount of colloids as a crystalline component caused by damage to the blood-thyroid barrier.

Anterior cruciate ligament reconstruction in a translational model in sheep using biointegrative mineral fiber reinforced screws

Anterior cruciate ligament reconstruction (ACLR) is one of the more common procedures performed worldwide and perhaps the most widely studied construct in orthopedic literature. Interference screws are reliable and frequently used for ligament reconstruction, providing rigid fixation and facilitates graft incorporation allowing for the physiologic loads of early rehabilitation. The purpose of this study was to determine the bio-integration profile and quality of soft tissue graft when using mineral fiber-reinforced screws in an ACLR interference model. Nine sheep underwent ACLR using harvested autologous tendon graft fixated with 4.75 mm screws made of continuous mineral fibers. Histopathology and imaging evaluation at 28, 52, 104, 132-weeks (W) demonstrated mesenchymal tissue ingrowth into implant wall at 28 W, which increased at 52 W and peaked at 104 W. At 132 W, implants fully replaced by newly remodeled bone. Graft cellularity was evident at 28 W and continued to increase through 132 W as the tendon ossified at sites of bone contact. Pro-healing M2-macrophages and giant cells remained infrequent, with minor increases between 52 W and 104 W, attributed to expected phagocytic response. Pro-inflammatory cells (i.e., M1-macrophages, polymorphonuclears) were absent through the entire study course. In conclusion, bio-integrative screws provide secure soft tissue fixation with replacement by bone demonstrating graft cellularization over time.

TEP in the ER: After Hours Tracheoesophageal Prosthesis Management for the Otolaryngologist.

Tracheoesophageal voice puncture and prosthesis (TEP) is a common method of voice restoration following total laryngectomy. A variety of complications, both minor and major, can be associated with the TEP and require timely intervention/management. Some of those complications include premature leakage, periprosthetic leakage, granulation tissue growth, TEP dislodgement, or embedding of the TEP. Patients may present with problems and/or complications with the voice prosthesis in an emergency setting or after clinic hours when a trained speech pathologist is not present or readily available for evaluation and management. This manuscript aims to provide guidance for management of acute TEP complications to otolaryngology responders, especially those who may be less familiar with TEP troubleshooting. Experiential and literature review was undertaken by a group of head and neck specialized Speech Language Professionals in high volume Head & Neck Oncology practices, to develop consensus guidelines for emergency TEP management. TEP emergencies were categorized as (1) leakage through, (2) leakage around, (3) sudden loss of voicing, (4) loss of prosthesis, still in tract, (5) loss of prosthesis, not in tract. Management strategies for each form of emergency were developed to achieve patient safety and stability until definitive measures could be performed by the patient's Speech Language Professional. The goals of emergency management of TEP problems focused on minimizing risk of aspiration pneumonia, risk of foreign body aspiration, risk of wound complications at the puncture site. A simple management algorithm was developed for emergency or on-call otolaryngology responders.

EFFICACY OF HORMONAL METHODS AS ONE OF THE PILLARS IN THE TREATMENT OF ENDOMETRIOSIS

Endometriosis is a gynecological manifestation of a systemic inflammatory disease that causes chronic pelvic pain and can lead to infertility, characterized by the growth of endometrial tissue outside the uterus. This occurs due to retrograde menstruation, which consists of the leakage of part of the menstrual flow into the pelvis, and is common in 90% of women and eliminated by the immune system. However, in a portion of this population, the endometrial tissue proliferates and enters organs such as the intestine and bladder, growing during the menstrual period, which results in complications, intense pain and incapacity in daily life. It is estimated that between 5% and 10% of women of reproductive age worldwide are affected by this pathology, in addition to being the second most common pelvic disorder and the most frequent cause of female pelvic pain. Endometriosis is believed to be caused by the dysregulation of the female hormones estrogen and progesterone. Thus, the regulation of these hormonal agents through the use of hormonal methods has proven efficacy, as it reduces or even eliminates estrogenic stimulation and consequently improves the quality of life of patients; since this stimulus is the main agent responsible for the growth and permanence of the foci of this disease, which highlights the efficacy of this method as an important pillar in the treatment of endometriosis.

STEM CELL APPROACHES IN ORGAN REGENERATION AND REPAIR

Recent advances in stem cell research have provided new hope for treating a variety of diseases and conditions that currently have no effective cure. Stem cells have the unique ability to differentiate into various cell types, enabling them to support tissue growth and replace damaged or specialized cells throughout the lifespan. Among the most promising types of stem cells are mesenchymal stem cells (MSCs), which are easily harvested from adipose tissue and can be cultured and expanded in the lab. Due to their versatility, MSCs have become a focal point in tissue regeneration and have been widely used in animal studies and clinical trials involving humans. This review aims to summarize the current understanding of MSCs, focusing on the various types of stem cells isolated from different animal models such as horses, pigs, goats, dogs, rabbits, cats, rats, and mice. Given the growing interest in MSCs, we will also discuss their applications in veterinary and regenerative medicine. Current research highlights the potential of MSCs in treating conditions like heart failure, wound healing, and tooth regeneration, demonstrating their broad therapeutic potential. KEYWORDS: Mesenchymal stem cells (MSCs), animal models, cell-based therapy, regenerative medicine

Buckling by disordered growth

Buckling instabilities driven by tissue growth underpin key developmental events such as the folding of the brain. Tissue growth is disordered due to cell-to-cell variability, but the effects of this variability on buckling are unknown. Here, we analyze what is perhaps the simplest setup of this problem: the buckling of an elastic rod with fixed ends driven by spatially varying, yet highly symmetric growth. Combining analytical calculations for simple growth fields and numerical sampling of random growth fields, we show that variability can increase as well as decrease the growth threshold for buckling, even when growth variability does not cause any residual stresses. For random growth, we find numerically that the shift of the buckling threshold correlates with spatial moments of the growth field. Our results imply that biological systems can either trigger or avoid buckling by exploiting the spatial arrangement of growth variability. Published by the American Physical Society 2024

Conjunctival squamous metaplasia on amniotic membrane in Stevens-Johnson syndrome: a case report

BackgroundTo present a case of conjunctival growth on the amniotic membrane and subsequent pathology revealing conjunctival squamous metaplasia in a patient with Stevens-Johnson syndrome.Case presentationA 21-year-old female presented with painful, blurred vision in both eyes for two weeks. She was diagnosed with Stevens-Johnson syndrome 5 weeks before. Due to bilateral corneal epithelial defects, ProKera®, an amniotic membrane corneal bandage with a polycarbonate ring, was placed in both eyes. However, three weeks later, a slit-lamp examination revealed vascularized tissue growth from the palpebral conjunctiva to the amniotic membrane, along with symblepharon formation in the left eye. The patient underwent conjunctival biopsy, amniotic membrane removal, and symblepharon release. Pathology report showed the growth of squamous epithelium on the acellular amniotic membrane. Immunohistochemistry further supported the diagnosis, revealing squamous markers through p40 staining and highlighting the presence of the amniotic membrane using trichrome stain. Three months later, the patient’s visual acuity had improved to 20/25 and no symblepharon was noted.ConclusionsThis is the first case of conjunctival squamous metaplasia on amniotic membrane associated with Stevens-Johnson syndrome. Our case indicates that, despite the anti-inflammatory properties of amniotic membrane, conjunctival squamous metaplasia may arise after amniotic membrane grafting due to intense inflammation in Stevens-Johnson syndrome. Clinicians should conduct regular monitoring before amniotic membrane dissolution to preclude the development of conjunctival squamous metaplasia on the membrane and potential invasion into the cornea.

NEDD4 Knockdown Suppresses Human Endometrial Stromal Cell Growth and Invasion by Regulating PTGS2-Mediated Ferroptosis in Endometriosis.

Endometriosis (EM) is a gynecological disease characterized by the benign growth of endometrial tissue outside the uterus. Upregulation of neuronally expressed developmentally downregulated 4 (NEDD4) has been reported to accelerate endometrial cancer progression. We explored whether abnormal expression of NEDD4 is correlated with EM. Endometrial tissue in patients without endometriosis was used to develop the original generation of endometrial stromal cells (ESCs). Different types of endometrial tissue of patients with endometriosis were used to measure the expression of NEDD4 by immunohistochemistry (IHC) and western blotting. Its biological functions in ESCs were investigated using a cell counting kit-8 assay, fluorescein diacetate (FDA) staining, and Transwell invasion assays. Additionally, its involvement in ferroptosis was assessed by measuring Fe2+, malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) levels and the expression of ferroptosis markers. Compared with normal controls, NEDD4 levels were significantly elevated in the endometrial tissue of patients with EM. Furthermore, NEDD4 expression was higher in the ectopic endometrium than in the eutopic endometrium. NEDD4 knockdown reduced the viability and invasive capacity of ESCs, increased Fe2+, MDA, and ROS levels, and decreased GSH content. Further analysis revealed that NEDD4 knockdown promoted ferroptosis in ESCs by increasing the expression of prostaglandin-endoperoxide synthase 2 (PTGS2). As an E3 ubiquitin ligase, NEDD4 reduced PTGS2 protein levels by accelerating its ubiquitination and subsequent proteasomal degradation. These findings suggest that inhibiting NEDD4 reduces ESC growth and invasion in EM by regulating PTGS2-dependent ferroptosis.

KRAS G12C mutation in NSCLC in a small genetic center: insights into sotorasib therapy response potential

Lung cancer remains a significant health challenge, characterized by aberrant tissue growth within the pulmonary system. Early carcinogenic events often involve genomic instability and the emergence of a mutator phenotype. In this study, we aimed to explore the mutator phenotype in 89 patients diagnosed with non-small-cell lung cancer (NSCLC). RNA isolation from formalin-fixed paraffin-embedded (FFPE) tissue samples was performed using the Promega ReliaPrep RNA Miniprep System, facilitating gene amplification relevant to cancer through the Archer® FusionPlexComprehensiveThyroid and Lung (CTL) kit. Next-generation sequencing (NGS) on the Illumina NextSeq platform enabled comprehensive analysis of target areas. Utilizing Archer Analysis software, secondary analyses involving data cleansing, alignment, and variant/fusion identification were executed against the human reference genome hg19 (GRCh37). Expression patterns were visualized using HeatMap graphics. Our findings revealed a notable presence of KRAS gene mutations in approximately 20% of NSCLC patients. Among these mutations, the G12C variant was predominant at 50%, followed by G12V and G12D variants at 11.2% each. Notably, patients harboring the G12C variant responded favorably to sotorasib medication. These results underscore the importance of mutational profiling and targeted therapeutic approaches in managing NSCLC, particularly highlighting the promising efficacy of sotorasib in G12C-mutated cases.

3D Bioprinting Tissues: Revolutionizing Organ Transplants

The shortage of organ donors presents a critical challenge in modern healthcare, with demand for organ transplants far outstripping supply. 3D bioprinting, a transformative innovation leveraging biological materials and cells to create tissues and organs, offers a promising solution. This review examines the evolution of 3D bioprinting from early tissue engineering methods to its current role in regenerative medicine and organ transplant applications. It discussed key bioprinting techniques, bio-inks, and scaffold materials that support tissue growth, as well as the technical challenges and ethical considerations faced by researchers. With potential applications ranging from cartilage and skin grafts to fully functional organs, 3D bioprinting stands at the forefront of a new era in organ transplantation. However, barriers such as vascularization, biocompatibility, and regulatory hurdles remain before this technology can be fully integrated into clinical practice. Keywords: 3D bioprinting, organ transplantation, bioink, regenerative medicine, tissue engineering.

Sodium alginate hydrogels co-encapsulated with cell free fat extract-loaded core-shell nanofibers and menstrual blood stem cells derived exosomes for acceleration of articular cartilage regeneration

This study presents a novel scaffold system comprising sodium alginate hydrogels (SAh) co-encapsulated with cell-free fat extract (CEFFE)-loaded core-shell nanofibers (NFs) and menstrual blood stem cell-derived exosomes (EXOs). The scaffold integrates the regenerative potential of EXOs and CFFFE, offering a multifaceted strategy for promoting articular cartilage repair. Coaxially electrospun core-shell NFs exhibited successful encapsulation of CEFFE and seamless integration into the SAh matrix. Structural modifications induced by the incorporation of CEFFE-NFs enhanced hydrogel porosity, mechanical strength, and degradation kinetics, facilitating cell adhesion, proliferation, and tissue ingrowth. The release kinetics of growth factors from the composite scaffold demonstrated sustained and controlled release profiles, essential for optimal tissue regeneration. In vitro studies revealed high cell viability, enhanced chondrocyte proliferation, and migration in the presence of EXOs/CEFFE-NFs@SAh composite scaffolds. Additionally, in vivo experiments demonstrated significant cartilage regeneration, with the composite scaffold outperforming controls in promoting hyaline cartilage formation and defect bridging. Overall, this study underscores the potential of EXOs and CEFFE-NFs integrated into SAh matrices for enhancing chondrocyte viability, proliferation, migration, and ultimately, articular cartilage regeneration. Future research directions may focus on elucidating underlying mechanisms and conducting long-term in vivo studies to validate clinical applicability and scalability.

Design and preparation of biomimetic "Hard-soft" functional scaffold with gradient irregular pore structure for bone repair

To treat critical-sized defects in long bones, a novel structure was proposed by introducing a Haversian biomimetic structure and trabecular-like irregular pore morphology (IPM) structure into functional gradient porous scaffolds (FGPS). The outer shell structure is a "hard" structure providing mechanical support, and the inner core is a "soft" structure with radial gradient distribution IPM structure to promote the ingrowth of bone tissue. In this study, different inner core continuous gradient FGPS (GIPM) and layered FGPS (IPM, and BCC structure), with different outer shell pore sizes (300, 500, and 700 μm) were designed and fabricated by selective laser melting. The results show the stiffness of those FGPS was between 20.0-28.7 kN/mm, which is similar to the native femur (with a stiffness ranging from 7.2-11.7 kN/mm) of similar size. The GIPM-500 has more uniform stress distribution and stress transfer, resulting in superior load-bearing efficiency. Moreover, GIPM-500 exhibited excellent fatigue durability, achieving excellent fatigue cycles of more than 1×106 cycles. Cell immunofluorescence shows that the GIPM-500 and IPM-500 are more suitable for cell attachment and growth due to the flexibility of the local porosity and curvature. Bone defect repair simulations showed that GIPM-500 can meet normal load-bearing requirements while having little impact on the normal stress-strain trajectory. This work provides a novel biomimetic scaffold design containing both cortical and trabecular bone components for repairing critical-size defects in long bones.

Fibrosis signaling in endometrial cells and endometriosis development

In endometriosis, the tissues similar to the endometrial tissue attaches outside the uterine cavity, causing inflammation and fibrosis. The retrograde menstruation theory is the most plausible mechanism, though the detailed pathogenesis remains unclear. Our observations suggest that endometriosis-like lesions occur more often at sites of ovarian excision causing bleeding in mouse models. Additionally, prostaglandin E2 (PGE2) and thrombin, a protease-activated receptor (PAR) agonist in menstrual blood exacerbate inflammation in these lesions. Focusing on the hypoxic conditions of menstrual blood, we investigated the effects of PGE2/thrombin on inflammation and fibrosis using primary cultured endometrial stromal cells (ESCs) and glandular epithelial cells (EECs) under low oxygen conditions. Chemokine CXCL12 secreted by endometrial stromal cells under hypoxia acts on CXCR4 receptors on glandular epithelial cells, inducing epithelial-mesenchymal transition (EMT), suggesting a possible role in endometriosis progression. RNA-seq analysis of PGE2/thrombin effects on endometrial stromal cells revealed activation of the transforming growth factor (TGF)-β pathway, particularly increased production and secretion of activin A, a member of the TGFβ family. Activin A, via increased connective tissue growth factor (CTGF) expression, promotes differentiation of endometrial stromal cells from fibroblast-like to myofibroblast transdifferentiation (FMT) of ESCs. In conclusion, targeting the CXCL12/CXCR4 and activin A/CTGF signaling pathways holds promise for improving fibrosis in endometriosis lesions.

Extracellular matrix protein 1 binds to connective tissue growth factor against liver fibrosis and ductular reaction.

Extracellular matrix protein 1 (ECM1) can inhibit TGFβ activation, but its antifibrotic action remains largely unknown. This study aims to investigate ECM1 function and its physical interaction with the profibrotic connective tissue growth factor (CTGF) in fibrosis and ductular reaction (DR). Ecm1 knockouts or animals that ectopically expressed this gene were subjected to induction of liver fibrosis and DR by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) or α-naphthyl-isothiocyanate (ANIT). ECM1 and CTGF were also examined in the livers of patients with alcohol-associated liver disease (ALD) or ethanol-exposed animals that were fed the western diet for 4 months in the WDA model with liver pathology resembing ALD in patients. ECM1 bound to CTGF in yeast two-hybrid systems, cultured liver cells, and cholestatic livers damaged by DDC or α-naphthyl-isothiocyanate. This interaction blocked integrin αvβ6-mediated TGFβ activation, thereby reducing fibrotic responses in vitro. ECM1 downregulation was associated with biliary CTGF induction during human ALD progression. In experimental models, Ecm1 loss enhanced susceptibility to DDC-induced cholestasis with upregulation of Ctgf, αvβ6, alpha-smooth muscle actin, procollagen type I, serum transaminase, and total bilirubin levels in germline knockouts, whereas forced expression of this gene significantly attenuated DR and biliary fibrosis after the feeding of DDC or α-naphthyl-isothiocyanate containing diets. Moreover, ectopic Ecm1 inhibited not only alcohol-associated fibrosis but also TGFβ-mediated deregulation of hepatocyte nuclear factor 4α, preventing the production of the fetal p2 promoter-driven isoforms in the WDA model. We uncover a novel antifibrotic action by ECM1 that binds CTGF and inhibits integrin αvβ6-mediated TGFβ activation. Targeting its loss has therapeutic potential for the treatment of DR and liver fibrosis in chronic conditions, such as cholangiopathy and ALD.