Collagen Formation Research Articles

The WIRS motifs in Fat2 are required for Drosophila egg chamber rotation but not for elongation.

The elongation of tissues and organs is important for proper morphogenesis in animal development. In Drosophila ovaries, the elongation of egg chambers involves aligned Collagen IV fiber-like structures, a gradient of extracellular matrix stiffness and actin-based protrusion-driven collective cell migration, leading to the rotation of the egg chamber. Egg chamber elongation and rotation depend on the atypical cadherin Fat2. Fat2 contains in its intracellular region three WRC interacting receptor sequence (WIRS) motifs, which previously had been shown to bind to the WAVE regulatory complex (WRC), a conserved actin regulator. Here, we show that in fat2 mutant flies lacking the WIRS motifs, egg chambers fail to rotate and Collagen IV fiber-like structures are impaired, yet a gradient of extracellular matrix stiffness is established and egg chambers properly elongate. We conclude that the WIRS motifs are required for egg chamber rotation and that egg chamber rotation might be a prerequisite for proper formation of Collagen IV fiber-like structures. Egg chamber rotation, however, is dispensable for extracellular matrix stiffness gradient formation and for egg chamber elongation.

Diabetic Wound Healing: Factors, Mechanisms, and Treatment Strategies Using Herbal Components.

Managing diabetic wounds is a significant challenge for healthcare professionals since severe complications and delayed recovery greatly impact the patients' quality of life. This article aimed to explore various factors affecting diabetic wound healing, the mechanism of wound healing, and potential natural products having wound healing capability. It focuses on mechanisms of action and the therapeutic effectiveness of the compounds employed in the management of diabetic wounds. The review discusses the function of nutrition in wound healing, emphasizing the significance of consuming adequate amounts of protein, energy, lipids, amino acids, vitamins, minerals, and water to promote healing. Several herbs, including Rosmarinus officinalis, Carica papaya, Aloe vera, Annona squamosa, and Punica granatum, are being tested for wound healing qualities in diabetes circumstances. These plants have a variety of modes of action, including antioxidant, anti-inflammatory, antibacterial, and immunomodulatory activities that help to speed up wound healing, stimulate collagen formation, and promote tissue regeneration. The variety of action mechanisms seen in natural products, especially in plants, offers hope for the treatment of diabetic wounds. It may also be possible to improve healing results and the quality of life of diabetes individuals with chronic wounds by including these herbal treatments in wound care programs.

Regulation of fibronectin and collagens type I, III and VI by TNF-α, TGF-β, IL-13, and tofacitinib

Understanding how inflammatory cytokines influence profibrogenic wound healing responses in fibroblasts is important for understanding the pathogenesis of fibrosis. TNF-α and IL-13 are key cytokines in Th1 and Th2 immune responses, respectively, while TGF-β1 is the principal pro-fibrotic mediator. We show that 12-day fibroblast culture with TNF-α or IL-13 induces fibrogenesis, marked by progressively increasing type III and VI collagen formation, and that TGF-β1 co-stimulation amplifies these effects. Tofacitinib substantially reduced the formation of ECM proteins in response to IL-13, while fibrogenesis in response to TNF-α or TGF-β1 was marginally inhibited. The in vitro findings were supported by clinical observations in patients with active rheumatoid arthritis, which had elevated serum type III collagen formation, indicating ongoing fibrogenesis during inflammation. After 48–60 weeks of tofacitinib treatment, type III collagen degradation, aswell as formation, were significantly decreased compared to baseline, highlighting dual anti-inflammatory and anti-fibrogenic effects of tofacitinib. In contrast, other anti-inflammatory treatments including methotrexate, adalimumab and tocilizumab demonstrated anti-inflammatory effects only. Our results highlight fibro-inflammatory profiles associated with TNF-α or IL-13 stimulation, both alone and in combination with TGF-β1, and support the use of tofacitinib as an anti-fibrogenic treatment in chronic inflammatory conditions.

Exploring the ncRNA landscape in exosomes: Insights into wound healing mechanisms and therapeutic applications.

Exosomal non-coding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs, have emerged as crucial modulators in cellular signaling, influencing wound healing processes. Stem cell-derived exosomes, which serve as vehicles for these ncRNAs, show remarkable therapeutic potential due to their ability to modulate wound healing stages, from initial inflammation to collagen formation. These ncRNAs act as molecular signals, regulating gene expression and protein synthesis necessary for cellular responses in healing. Wound healing is a complex, staged process involving inflammation, hemostasis, fibroblast proliferation, angiogenesis, and tissue remodeling. Stem cell-derived exosomal ncRNAs enhance these stages by reducing excessive inflammation, promoting anti-inflammatory responses, guiding fibroblast and keratinocyte maturation, enhancing vascularization, and ensuring organized collagen deposition. Their molecular cargo, particularly ncRNAs, specifically targets pathways to aid chronic wound repair and support scarless regeneration. This review delves into the unique composition and signaling roles of Stem cell-derived exosomes and ncRNAs, highlighting their impact across wound healing stages and their potential as innovative therapeutics. Understanding the interaction between exosomal ncRNAs and cellular signaling pathways opens new avenues in regenerative medicine, positioning Stem cell-derived exosomes and their ncRNAs as promising molecular-level interventions in wound healing.

Antibacterial, Antifungal and Phytochemical Properties of Alcea rosea Leaves Extract and Evaluate its Contribution to Healing Wound that Infected by Staphylococcus aureus

Medicinal plants have been used to treat various infectious illnesses in humans, a significant component of traditional medicine. Medicinal plants are currently considered a promising alternative in treating diseases caused by antibiotic-resistant microorganisms, one of the most essential therapeutic problems. Alcea rosea is a medicinal plant used for multiple therapeutic properties. This study investigated the antibacterial, antifungal, antioxidant and phytochemical properties of A. rosea aqueous extract leaves. It evaluated its contribution to healing wounds Infected by Staphylococcus aureus to verify its ability to heal wounds scientifically. Aqueous extracts of the A. rosea leaves were tested using a rat dermal excision wound model. The antibacterial activity was assessed using the broth dilution test; the antioxidant activity was evaluated using the total antioxidant capacity, phenolic and flavonoid content, ferric reducing power, and DPPH free radical scavenging. Topical use of extract creams demonstrated significant wound healing. On the 10th day, the groups treated with conventional medication and blank cream, 10% stem bark and leaf creams, and 95.8%, 96.3%, and 73.9% total wound surface closure were noted, respectively. Significant collagen formation, sparse infiltrations of inflammatory cells and re-epithelialization were observed histopathologically in the sections of healed tissue. In contrast, isolated regions of dispersed inflammatory cells and an abscess were seen in the tissues from the blank cream treatment group. S. aureus was susceptible to the antibacterial properties of the methanol stem bark extract.

Green synthesis of magnesium oxide nanoparticles using the extract of Falcaria vulgaris to enhance the healing of burn wounds

Treating burn lesions has always been challenging because any product should be cheap, accessible, and have anti-bacterial commodities and tissue regeneration properties. The green synthesis of magnesium oxide nanoparticles (GS-MgONPs) can create an optimal prospect that is safe with low toxicity in biological tissue and better safety for application while including the antibacterial effect. This recent study aimed to evaluate the effectiveness of burn wound treatment using GS-MgONPs in rats. GS-MgONPs were synthesized for the first time using a Falcaria vulgaris extract (FVE) and characterized. Thirty male Wistar rats were divided into five groups: a 1. An untreated group 2. A conventional product treated group 3. GS-MgONPs at 1 wt% concentrate 4.3 GS-MgONPs at 3wt% concentrate 5.FVE (1 wt%). A second-degree burn wound model was established through contact with a heated object. Treatments commenced immediately following burn induction and were administered daily for a duration of 21 days. GS-MgONPs showed a spherical morphology with a diameter of less than 100 nm. The NPs (1% and 3wt%) and FVE demonstrated significant growth inhibition against Staphylococcus aureus while showing no cytotoxic effects on human fibroblast cells. The proposed subjects treated with 1 wt% and 3 wt% GS-MgONPs were able to significantly increase the rate of wound closure (p< 0.05). Histological observations revealed that collagen formation and epithelial regeneration were more pronounced in the groups receiving 1 wt% and 3 wt% MgONPs. These results indicate that GS-MgONPs effectively enhance the regeneration process.

Transcriptomic integration and ligand-receptor crosstalk reveal the underlying molecular mechanisms between hip cartilage and subchondral bone in osteonecrosis of femoral head.

Osteonecrosis of femoral head (ONFH) is characterized not only by ischemic bone tissue necrosis but also by cartilage degeneration, which plays an essential role in the pathogenesis of ONFH. The molecular communication between tissues contributes to disease progression, however the communication between cartilage and subchondral bone in the progression of ONFH remains unclear. In this study, we integrated transcriptomic data from ONFH cartilage and subchondral bone, exploring common differentially expressed genes (DEGs), pathway and function enrichment analyses, the protein-protein interaction (PPI) network, and hub genes to comprehensively study molecular integration. Additionally, we explored the molecular crosstalk between and within cartilage and subchondral bone using ligand-receptor pairs and ONFH cartilage proteomic data. Finally, key genes and ligand-receptor pairs were validated by quantitative real-time PCR (qRT-PCR). There were 27 common DEGs and five hub genes in cartilage and subchondral bone. The defined hub genes included COL1A1, COLIA2, CTSK, SPARC, and MXRA5. Notably, pathways related to ossification, extracellular matrix, and collagen formation were significantly altered in ONFH. Ligand-receptor data combined with DEGs revealed 60 differentially expressed ligands and 51 differentially expressed receptors in cartilage and four ligands and three receptors in subchondral bone. In inter-tissue comparisons, ligands from chondrocytes predominantly paired with receptors on osteoblasts in the subchondral bone, such as FN1, MMP2, and FGF1. Conversely, ligands from osteoblasts and osteocytes in the subchondral bone frequently paired with chondrocyte receptors, including FN1, COL1A1, and SEMA7A. At the protein level, we identified thirteen ligands and one receptor, with COL3A1 being the most highly expressed ligand and CD82 the only differentially expressed receptor in ONFH. This study highlights common molecular mechanisms and ligand-receptor crosstalk between and within cartilage and subchondral bone in ONFH, offering new insights into the disease's pathophysiology and potential molecular targets for therapeutic intervention.

Quercetin-Loaded Melanin Nanoparticles Decorated with Collagenase Mediates Synergistic Immunomodulation and Restores Extracellular Matrix Homeostasis in Liver Fibrosis.

Liver fibrosis is a chronic disease that lacks effective drug treatment. Chronic damage and inflammation lead to the formation of collagen and fibrous scars. However, the excessive accumulation of collagen I significantly hinders the delivery of drugs into liver tissue. Therefore, this study developed a quercetin-loaded melanin nanoparticle codecorated collagenase (MNP-QUE-COL) for the treatment of liver fibrosis. These results showed that MNP-QUE-COL degraded excessive collagen I, thereby efficiently delivering melanin and quercetin into the liver tissue. MNP-QUE-COL exhibited optimal PA/MRI dual-mode imaging ability. In addition, the synergistic anti-inflammatory and reactive oxygen species scavenging function of quercetin and melanin was achieved by regulation of M1-M2 macrophage polarization and inhibition of pro-inflammatory cytokine release, reshaping the imbalanced extracellular interstitial inflammatory environment. The results of this research suggest that MNP-QUE-COL is a safe and efficient therapeutic nanoplatform for liver fibrosis, showing promise as a potential therapeutic strategy for liver fibrosis and associated diseases.

Effectiveness of Gedong Gincu Mango Leaf Extract Gel (Mangifera indica L. var. Gedong gincu) on Cut Wound Healing in Male White Rats (Rattus norvegicus) of the Wistar Strain

Background: The Indonesia Basic Health Research data show the prevalence of wounds including incision/scratches/stab wounds reaches 20.1%. Natural herbal products play an important role in the wound healing process functioning as anti-inflammatories, antioxidants, antimicrobials, and collagen formation. Mango leaves are often considered waste even though they have many health benefits with the high content of coactive compounds, such as alkaloids, flavonoids, tannins, and saponins which are good for cut wound healing. The use of gel is more stable and controlled release compared to other topical preparations. Gedong Gincu mangoes originating from West Java have unique properties and they are marketed widely in some areas including Cirebon. Aims: This study aims to identify the most effective concentration of Gedong Gincu mango leaf extract on cut wound healing in male white rats (Rattus norvegicus) of the Wistar Strain. Methods: This study used a post-test-only control group design. The extract gel used three levels of concentration, namely 40%, 50%, and 60%. The positive control used 10% povidone iodine while the negative control used a gel base. The gel was applied to the cut wound twice a day for 14 days. Results: The average length of the cut wound was 0.916 cm, 0.912 cm, and 1.050 cm for concentration levels of 40%, 50%, and 60%. For the positive and negative controls, it reached 0.996 cm and 0.702 cm respectively. This indicates no significant difference in the length of the cut wound with a p-value of 0.121 (p&gt;0.05). The wound healing process was effective at a concentration level of 60% as indicated by the disappearance of erythema and edema. Conclusion: Mango leaf extract gel (Mangifera indica L.var. Gedong Gincu) is effective in healing cut wounds with the disappearance of erythema and edema in male white rats (Rattus norvegicus) Wistar strain with a concentration of 60%. Received: 25 September 2024 | Reviewed: 19 October 2024 | Revised: 30 November 2024 | Accepted: 15 December 2024.

Melatonin stabilizes atherosclerotic plaques: an association that should be clinically exploited.

Atherosclerosis is the underlying factor in the premature death of millions of humans annually. The cause of death is often a result of the rupture of an atherosclerotic plaque followed by the discharge of the associated molecular debris into the vessel lumen which occludes the artery leading to ischemia of downstream tissue and to morbidity or mortality of the individual. This is most serious when it occurs in the heart (heart attack) or brain (stroke). Atherosclerotic plaques are classified as either soft, rupture-prone, or hard, rupture resistant. Melatonin, the production of which diminishes with age, has major actions in converting soft to hard plaques. Experimentally, melatonin reduces the ingrowth of capillaries from the tunica media into the plaque relieving pressure on the plaque, reducing intraplaque hemorrhage and limiting the size of the necrotic core. Moreover, melatonin promotes the formation of collagen by invading vascular smooth muscle cells which strengthen the plaque crown making it resistant to rupture. Melatonin is also a powerful antioxidant and anti-inflammatory agent such that is reduces oxidative damage to tissues associated with the plaque and limits inflammation both of which contribute to plaque cap weakness. Additional benefits of melatonin relative to atherosclerosis is inhibition of adhesion molecules on the endothelial cell surface, limiting the invasion of monocytes into the arterial intima, and reducing the conversion of anti-inflammatory M2 macrophages to pro-inflammatory M1 macrophages. Given the high physiological and financial cost of cardiac and neural ischemic events, this information should be given high priority in the clinical setting.

Dysregulation of MMP2-dependent TGF-ß2 activation impairs fibrous cap formation in type 2 diabetes-associated atherosclerosis

Type 2 diabetes is associated with cardiovascular disease, possibly due to impaired vascular fibrous repair. Yet, the mechanisms are elusive. Here, we investigate alterations in the fibrous repair processes in type 2 diabetes atherosclerotic plaque extracellular matrix by combining multi-omics from the human Carotid Plaque Imaging Project cohort and functional studies. Plaques from type 2 diabetes patients have less collagen. Interestingly, lower levels of transforming growth factor-ß distinguish type 2 diabetes plaques and, in these patients, lower levels of fibrous repair markers are associated with cardiovascular events. Transforming growth factor-ß2 originates mostly from contractile vascular smooth muscle cells that interact with synthetic vascular smooth muscle cells in the cap, leading to collagen formation and vascular smooth muscle cell differentiation. This is regulated by free transforming growth factor-ß2 which is affected by hyperglycemia. Our findings underscore the importance of transforming growth factor-ß2-driven fibrous repair in type 2 diabetes as an area for future therapeutic strategies.

Metabolic modelling links Warburg effect to collagen formation, angiogenesis and inflammation in the tumoral stroma.

Cancer cells are known to express the Warburg effect-increased glycolysis and formation of lactic acid even in the presence of oxygen-as well as high glutamine uptake. In tumors, cancer cells are surrounded by collagen, immune cells, and neoangiogenesis. Whether collagen formation, neoangiogenesis, and inflammation in cancer are associated with the Warburg effect needs to be established. Metabolic modelling has proven to be a tool of choice to understand biological reality better and make in silico predictions. Elementary Flux Modes (EFMs) are essential for conducting an unbiased decomposition of a metabolic model into its minimal functional units. EFMs can be investigated using our tool, aspefm, an innovative approach based on logic programming where biological constraints can be incorporated. These constraints allow networks to be characterized regardless of their size. Using a metabolic model of the human cell containing collagen, neoangiogenesis, and inflammation markers, we derived a subset of EFMs of biological relevance to the Warburg effect. Within this model, EFMs analysis provided more adequate results than parsimonious flux balance analysis and flux sampling. Upon further inspection, the EFM with the best linear regression fit to cancer cell lines exometabolomics data was selected. The minimal pathway, presenting the Warburg effect, collagen synthesis, angiogenesis, and release of inflammation markers, showed that collagen production was possible directly de novo from glutamine uptake and without extracellular import of glycine and proline, collagen's main constituents.

Investigating the Relationship Between the Emulsification Parameters and Physical-Chemical Properties of Poly(D,L-lactic acid) Particles for Dermal Fillers.

Poly(L-lactic acid) (PLLA) and poly(D,L-lactic acid) (PDLLA) particles have been applied as dermal fillers for soft-tissue augmentation because they can induce foreign-body reactions, resulting in fibroblast proliferation and collagen formation. Although PLLA and PDLLA fillers are safe and biocompatible, clinical complications such as nodules and granulomas have been reported, possibly due to incomplete reconstitution. PDLLA particles were prepared via emulsification in this study, and three stirring speeds were investigated when adding PDLLA into carboxymethyl cellulose solution. The particle size, molecular weight of PDLLA, optical rotation, pH value, osmotic pressure, and reconstitution time were analyzed. A rabbit dorsal ear model was established to evaluate the soft-tissue augmentation of a commercial PDLLA filler. The results demonstrated that the stirring speed affected the particle size, but not other physical-chemical properties of the PDLLA particles. All the PDLLA particles were reconstituted in less than 7 min, which is faster than the process for the other commercial PDLLA dermal filler products. In addition, the PDLLA particles could induce inflammation and fibroblast proliferation. Although the PDLLA particles generated in this study have not yet been investigated in vivo, the results demonstrated here suggest their potential for application as dermal fillers.

Single‐Cell RNA‐Seq Reveals Injuries in Aortic Dissection and Identifies PDGF Signalling Pathway as a Potential Therapeutic Target

ABSTRACTAortic dissection (AD) represents a critical condition characterised by a tear in the inner lining of the aorta, leading to the leakage of blood into the layers of the aortic wall, posing a significant risk to life. However, the pathogenesis is unclear. In this study, scRNA‐seq was applied to cells derived from aortas of both AD and non‐AD donors (control) to unveil the cellular landscape. ScRNA‐seq data uncover significant cellular heterogeneity in AD aortas. Specifically, we observed an accumulation of CD4+ T cells, which contributed to inflammation and cell death, and abnormal collagen formation mediated by fibroblast cells in AD. Moreover, we revealed a greater prevalence of cell death, oxidative stress and senescence in AD aorta cells. Furthermore, we found a decrease in the percentage of vascular stem cells (VSCs), along with a repression in their ability to differentiate into contractile vascular smooth muscle cells (VSMCs). Finally, our data demonstrated that the PDGF signalling pathway was activated in AD. We found that PDGF activation could lead to VSMCs aberrant switch from contractile to synthetic phenotype, which could be ameliorated by PDGF inhibitor. This underscores the potential of the PDGF as a therapeutic target for AD. In summary, our study highlights the cellular heterogeneity and associated injuries within aortas affected by AD, including cell death, oxidative stress, senescence and dysregulation of signalling pathways influencing the aberrant phenotypic switch of VSMCs. These insights offer valuable contributions to understanding the molecular mechanisms underlying AD and present new avenues for therapeutic intervention in this condition.

Aberrant basement membrane production by HSCs in MASLD is attenuated by the bile acid analog INT-767.

The farnesoid X receptor (FXR) is a leading therapeutic target for metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis. INT-767, a potent FXR agonist, has shown promise in preclinical models. We aimed to define the mechanisms of INT-767 activity in experimental MASH and dissect cellular and molecular targets of FXR agonism in human disease. Leptin-deficient ob/ob mice were fed a MASH-inducing diet for 15 weeks before the study started. After baseline liver biopsy and stratification, mice were allocated to INT-767 (10mg/kg/d) or vehicle treatment for 8 weeks, either alongside an ongoing MASH diet (progression) or following conversion to normal chow (reversal). Effects on extracellular matrix remodeling were analyzed histologically and by RNA-sequencing. Serum fibrosis biomarkers were measured longitudinally. Human liver samples were investigated using bulk and single-cell RNA-sequencing, histology, and cell culture assays. INT-767 treatment was antifibrotic during MASH progression but not reversal, attenuating the accumulation of type I collagen and basement membrane proteins (type IV collagen and laminin). Circulating levels of PRO-C4, a type IV collagen formation marker, were reduced by INT-767 treatment and correlated with fibrosis. Expression of basement membrane constituents also correlated with fibrosis severity and adverse clinical outcomes in human MASH. Single-cell RNA-sequencing analysis of mouse and human livers, and immunofluorescence staining colocalized FXR and basement membrane expression to myofibroblasts within the fibrotic niche. Treatment of culture-activated primary human HSCs with INT-767 decreased expression of basement membrane components. These findings highlight the importance of basement membrane remodeling in MASH pathobiology and as a source of circulating biomarkers. Basement membrane deposition by activated HSCs is abrogated by INT-767 treatment and measurement of basement membrane molecules should be included when determining the therapeutic efficacy of FXR agonists.

559 Activated macrophages induce a pro-fibrotic response in dermal fibroblasts with increased type III and VI collagen formation

559 Activated macrophages induce a pro-fibrotic response in dermal fibroblasts with increased type III and VI collagen formation

Genetic diagnosis of the Ehlers-Danlos syndromes.

The Ehlers-Danlos syndromes (EDS) represent a group of genetically diverse disorders characterized by the variable combination of joint hypermobility, hyperextensibility of the skin, and connective tissue fragility affecting the skin and other organs. Based on clinical features, 13 different types of EDS have been delineated, 12 of which represent monogenic conditions caused by pathogenic variants in 21 confirmed genes. Pathogenesis is related to disturbances of collagen formation and/or stability. No monogenic cause has been identified for hypermobile EDS (hEDS), a more common EDS type, which is unlikely to represent a single gene disorder in the majority of affected individuals and at present cannot be diagnosed by genetic investigations. Here we summarize the clinical features and the molecular bases of the monogenic EDS types, highlight diagnostic challenges, and provide guidance for the molecular work-up of affected individuals. In general, genetic tests are indicated if clinical features suggest a monogenic EDS type but are usually unrewarding for other cases of hypermobility.

Synthesis, evaluation and mechanism study of novel pyrazole enamides to alleviate lung injury

Particulate matter with diameter ≤2.5 μm particles (PM2.5) can trigger pulmonary inflammation and lung injury. However, there is still no specific and effective treatment. Lansiumamide B (LB) is a natural cis-enamide compound isolated from wampee seeds, and has potential anti-inflammatory effect. Herein, two series of pyrazole enamide analogues were designed and synthesized based on the scaffold hopping strategy. The inhibition rates of inflammatory cytokines on compound 11a were superior to other compounds and exhibited good dose-dependent manner and safety. Mechanism studies shown that 11a activated the Keap1/Nrf2/HO-1 signaling pathway and promoted Nrf2 entering into nucleus. Further, 11a alleviated pulmonary inflammation, collagen formation and mucus secretion in PM2.5 induced lung injury mice. Besides, 11a administration inhibited M1 macrophage polarization and neutrophil infiltration. Overall, 11a is an effective anti-inflammatory agent which might be a potent candidate to treat lung injury.

Collagen formation, function and role in kidney disease.

Highly abundant in mammals,collagens define the organization of tissues and participate in cell signalling. Most of the 28 vertebrate collagens, with the exception of collagens VI, VII, XXVI and XXVIII, can be categorized into five subgroups: fibrillar collagens, network-forming collagens, fibril-associated collagens with interrupted triple helices, membrane-associated collagens with interrupted triple helices and multiple triple-helix domains with interruptions. Collagen peptides are synthesized from the ribosome and enter the rough endoplasmic reticulum, where they undergo numerous post-translational modifications. The collagen chains form triple helices that can be secreted to form a diverse array of supramolecular structures in the extracellular matrix. Collagens are ubiquitously expressed and have been linked to a broad spectrum of disorders, including genetic disorders with kidney phenotypes. They also have an important role in kidney fibrosis and mass spectrometry-based proteomic studies have improved understanding of the composition of fibrosis in kidney disease. A wide range of therapeutics are in development for collagen and kidneydisorders, including genetic approaches, chaperone therapies, proteindegradation strategies and anti-fibrotic therapies. Improved understanding of collagens and their role in disease is needed to facilitate the development of more specific treatments for collagen and kidney disorders.

Microfocused Ultrasound With Visualization Induces Remodeling of Collagen and Elastin Within the Skin.

Microfocused ultrasound with real-time visualization (MFU-V) is often used for noninvasive skin lifting, by precisely targeting dermal and subcutaneous tissues to create thermal coagulation points (TCPs). These TCPs denature collagen and initiate a transient inflammatory response, ultimately attracting dermal fibroblasts and inducing efficient neocollagenesis and extracellular matrix (ECM) remodeling, yielding to MFU-V's desired skin-lifting effects. The current study investigates MFU-V's underlying mode of action based on the histological progression of TCPs in the skin, providing new insight into the technology's regenerative effect. Following standard triple-depth MFU-V treatment, invivo skin samples were assessed using histology and immunohistochemistry to evaluate TCPs, heat shock protein (HSP47), and elastin expression in fibroblasts. MFU-V treatment induced elongated, flame-like TCPs with denatured collagen at focal depths of 1.5, 3.0, and 4.5 mm within the skin-each corresponding to its respective transducer depth. Time-dependent progression of TCPs showed significantly increased scores of fibroblasts and mature collagen along with recruitment of HSP47-positive fibroblasts to TCP areas on Day 90. Collagen formation and later maturation were visualized. Newly synthesized elastin significantly increased in the TCP area on Day 90 compared to Day 14. This work provides histological evidence of stimulation and regeneration of newly synthesized elastin fibers after TCP induction. MFU-V-generated TCPs triggered the body's own healing cascade of collagen denaturation, transient inflammation, proliferation, and tissue remodeling, resulting in attraction of HSP47-positive fibroblasts to the TCP sites, and new collagen and elastin fiber regeneration by fibroblasts. Besides the well-described neocollagenesis, this study demonstrates that MFU-V treatment induces elastin neogenesis that may result not only in skin lifting but also in improved skin elasticity, providing an overall regenerative effect.