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This study was undertaken to develop a mathematical model of the long-term in vivo remodeling processes in postimplanted pulmonary artery (PA) conduits. Experimental results from two extant ovine in vivo studies, wherein polyglycolic-acid (PGA)/poly-L-lactic acid tubular conduits were constructed, cell seeded, incubated for 4 weeks, and then implanted in mature sheep to obtain the remodeling data for up to two years. Explanted conduit analysis included detailed novel structural and mechanical studies. Results in both studies indicated that the in vivo conduits remained dimensionally stable up to 80 weeks, so that the conduits maintained a constant in vivo stress and deformation state. In contrast, continued remodeling of the constituent collagen fiber network as evidenced by an increase in effective tissue uniaxial tangent modulus, which then stabilized by one year postimplant. A mesostructural constitute model was then applied to extant planar biaxial mechanical data and revealed several interesting features, including an initial pronounced increase in effective collagen fiber modulus, paralleled by a simultaneous shift toward longer, more uniformly length-distributed collagen fibers. Thus, while the conduit remained dimensionally stable, its internal collagen fibrous structure and resultant mechanical behaviors underwent continued remodeling that stabilized by one year. A time-evolving structural mixture-based mathematical model specialized for this unique form of tissue remodeling was developed, with a focus on time-evolving collagen fiber stiffness as the driver for tissue-level remodeling. The remodeling model was able to fully reproduce (1) the observed tissue-level increases in stiffness by time-evolving simultaneous increases in collagen fiber modulus and lengths, (2) maintenance of the constant collagen fiber angular dispersion, and (3) stabilization of the remodeling processes at one year. Collagen fiber remodeling geometry was directly verified experimentally by histological analysis of the time-evolving collagen fiber crimp, which matches model predictions very closely. Interestingly, the remodeling model indicated that the basis for tissue homeostasis was maintenance of the collagen fiber ensemble stress for all orientations, and not individual collagen fiber stresses. Unlike other growth and remodeling models that traditionally treat changes in the external boundary conditions (e.g., changes in blood pressure) as the primary input stimuli, the driver herein is changes to the internal constituent collagen fiber themselves due to cellular mediated cross-linking. [ABSTRACT FROM AUTHOR]

[Display omitted] Tissue expansion (TE) is the primary method for breast reconstruction after mastectomy. In many cases, mastectomy patients undergo radiation treatment (XR). Radiation is known to induce skin fibrosis and is one of the main causes for complications during post-mastectomy breast reconstruction. TE, on the other hand, induces a pro-regenerative response that culminates in growth of new skin. However, the combined effect of XR and TE on skin mechanics is unknown. Here we used the porcine model of TE to study the effect of radiation on skin fibrosis through biaxial testing, histological analysis, and kinematic analysis of skin deformation over time. We found that XR leads to stiffening of skin compared to control based on a shift in the transition stretch (transition between a low stiffness and an exponential stress-strain region characteristic of collagenous tissue) and an increase in the high modulus (modulus computed with stress-stretch data past the transition point). The change in transition stretch can be explained by thicker, more aligned collagen fiber bundles measured in histology images. Skin subjected to both XR+TE showed similar microstructure to controls as well as similar biaxial response, suggesting that physiological remodeling of collagen induced by TE partially counteracts pro-fibrotic XR effects. Skin growth was indirectly assessed with a kinematic approach that quantified increase in permanent area changes without reduction in thickness, suggesting production of new tissue driven by TE even in the presence of radiation treatment. Future work will focus on the detailed biological mechanisms by which TE counteracts radiation induced fibrosis. Breast cancer is the most prevalent in women and its treatment often results in total breast removal (mastectomy), followed by reconstruction using tissue expanders. Radiation, which is used in about a third of breast reconstruction cases, can lead to significant complications. The timing of radiation treatment remains controversial. Radiation is known to cause immediate skin damage and long-term fibrosis. Tissue expansion leads to a pro-regenerative response involving collagen remodeling. Here we show that tissue expansion immediately prior to radiation can reduce the level of radiation-induced fibrosis. Thus, we anticipate that this new evidence will open up new avenues of investigation into how the collagen remodeling and pro-regenerative effects of tissue expansion can be leverage to prevent radiation-induced fibrosis. [ABSTRACT FROM AUTHOR]

Abstract Background Chronic radiation dermatitis (CRD) is a late consequence of radiation with high incidence in patients receiving radiotherapy. Conventional therapies often yield unsatisfactory results. Therefore, this study aimed to explore the therapeutic potential and mechanism of adipose-derived stem cells (ADSCs) for CRD, paving the way for novel regenerative therapies in clinical practice. Methods Clinical CRD skin biopsies were analyzed to character the pathological changes of CRD skin and guided the animal modeling scheme. Subsequently, an in vivo analysisusing mouse CRD models was conducted to explore their effects of ADSCs on CRD, monitoring therapeutic impact for up to 8 weeks. Transcriptome sequencing and histologic sections analysis were performed to explore the potential therapeutic mechanism of ADSCs. Following observing extensive apoptosis of transplanted ADSCs, the therapeutic effect of ADSCs were compared with those of apoptosis-inhibited ADSCs. Multiphoton imaging and analysis of collagen morphologic features were employed to explain how translated ADSCs promote collagen remodeling at the microscopic level based on the contrast of morphology of collagen fibers. Results Following injection into CRD-afflicted skin, ADSCs therapy effectively mitigated symptoms of CRD, including acanthosis of the epidermis, fibrosis, and irregular collagen deposition, consistent with the possible therapeutic mechanism suggested by transcriptome sequencing. Notably, in vivo tracking revealed a significant reduction in ADSCs number due to extensive apoptosis. Inhibiting apoptosis in ADSCs partially tempered their therapeutic effects. Mechanically, analysis of collagen morphologic features indicated that translated ADSCs might promote dermal extracellular matrix remodeling through enlarging, lengthening, crimping, and evening collagen, counteracting the atrophy and rupture caused by irradiation. Conclusions This study demonstrated that ADSCs underwent substantial apoptosis upon local skin transplantation, and paradoxically, this apoptosis is essential for their efficacy in promoting the regeneration of late radiation-impaired skin. Mechanically, transplanted ADSCs could promote the remodeling and rearrangement of radiation-damaged dermal collagen matrix.

Abstract Degenerative mitral valve disease is a common valvular disease with two arguably distinct phenotypes: fibroelastic deficiency and Barlow’s disease. These phenotypes significantly alter the microstructures of the leaflets, particularly the collagen fibers, which are the main mechanical load carriers. The predominant method of investigation is histological sections. However, the sections are cut transmurally and provide a lateral view of the microstructure of the leaflet, while the mechanics and function are determined by the planar arrangement of the collagen fibers. This study, for the first time, quantitatively examined planar collagen distribution quantitatively in health and disease using second harmonic generation microscopy throughout the thickness of the mitral valve leaflets. Twenty diseased samples from eighteen patients and six control samples were included in this study. Healthy tissue had highly aligned collagen fibers. In fibroelastic deficiency they are less aligned and in Barlow’s disease they are completely dispersed. In both diseases, collagen fibers have two preferred orientations, which, in contrast to the almost constant one orientation in healthy tissues, also vary across the thickness. The results indicate altered in vivo mechanical stresses and strains on the mitral valve leaflets as a result of disease-related collagen remodeling, which in turn triggers further remodeling.

Background: Chronic radiation dermatitis (CRD) is a late consequence of radiation with high incidence in patients receiving radiotherapy. Conventional therapies often yield unsatisfactory results. Therefore, this study aimed to explore the therapeutic potential and mechanism of adipose-derived stem cells (ADSCs) for CRD, paving the way for novel regenerative therapies in clinical practice. Methods: Clinical CRD skin biopsies were analyzed to character the pathological changes of CRD skin and guided the animal modeling scheme. Subsequently, an in vivo analysisusing mouse CRD models was conducted to explore their effects of ADSCs on CRD, monitoring therapeutic impact for up to 8 weeks. Transcriptome sequencing and histologic sections analysis were performed to explore the potential therapeutic mechanism of ADSCs. Following observing extensive apoptosis of transplanted ADSCs, the therapeutic effect of ADSCs were compared with those of apoptosis-inhibited ADSCs. Multiphoton imaging and analysis of collagen morphologic features were employed to explain how translated ADSCs promote collagen remodeling at the microscopic level based on the contrast of morphology of collagen fibers. Results: Following injection into CRD-afflicted skin, ADSCs therapy effectively mitigated symptoms of CRD, including acanthosis of the epidermis, fibrosis, and irregular collagen deposition, consistent with the possible therapeutic mechanism suggested by transcriptome sequencing. Notably, in vivo tracking revealed a significant reduction in ADSCs number due to extensive apoptosis. Inhibiting apoptosis in ADSCs partially tempered their therapeutic effects. Mechanically, analysis of collagen morphologic features indicated that translated ADSCs might promote dermal extracellular matrix remodeling through enlarging, lengthening, crimping, and evening collagen, counteracting the atrophy and rupture caused by irradiation. Conclusions: This study demonstrated that ADSCs underwent substantial apoptosis upon local skin transplantation, and paradoxically, this apoptosis is essential for their efficacy in promoting the regeneration of late radiation-impaired skin. Mechanically, transplanted ADSCs could promote the remodeling and rearrangement of radiation-damaged dermal collagen matrix. [ABSTRACT FROM AUTHOR]

Aortic stiffening is an inevitable manifestation of chronological aging, yet the mechano‐molecular programs that orchestrate region‐ and layer‐specific adaptations along the length and through the wall of the aorta are incompletely defined. Here, we show that the decline in passive cyclic distensibility is more pronounced in the ascending thoracic aorta (ATA) compared to distal segments of the aorta and that collagen content increases in both the medial and adventitial compartments of the ATA during aging. The single‐cell RNA sequencing of aged ATA tissues reveals altered cellular senescence, remodeling, and inflammatory responses accompanied by enrichment of T‐lymphocytes and rarefaction of vascular smooth muscle cells, compared to young samples. T lymphocyte clusters accumulate in the adventitia, while the activation of mechanosensitive Piezo‐1 enhances vasoconstriction and contributes to the overall functional decline of ATA tissues. These results portray the immuno‐mechanical aging of the ATA as a process that culminates in a stiffer conduit permissive to the accrual of multi‐gerogenic signals priming to disease development. [ABSTRACT FROM AUTHOR]

Degenerative mitral valve disease is a common valvular disease with two arguably distinct phenotypes: fibroelastic deficiency and Barlow’s disease. These phenotypes significantly alter the microstructures of the leaflets, particularly the collagen fibers, which are the main mechanical load carriers. The predominant method of investigation is histological sections. However, the sections are cut transmurally and provide a lateral view of the microstructure of the leaflet, while the mechanics and function are determined by the planar arrangement of the collagen fibers. This study, for the first time, quantitatively examined planar collagen distribution quantitatively in health and disease using second harmonic generation microscopy throughout the thickness of the mitral valve leaflets. Twenty diseased samples from eighteen patients and six control samples were included in this study. Healthy tissue had highly aligned collagen fibers. In fibroelastic deficiency they are less aligned and in Barlow’s disease they are completely dispersed. In both diseases, collagen fibers have two preferred orientations, which, in contrast to the almost constant one orientation in healthy tissues, also vary across the thickness. The results indicate altered in vivo mechanical stresses and strains on the mitral valve leaflets as a result of disease-related collagen remodeling, which in turn triggers further remodeling. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSCs), pivotal for tissue repair, utilize collagen to restore structural integrity in damaged tissue, preserving its organization through concomitant remodeling. The non-enzymatic glycation of collagen potentially compromises MSC communication, particularly upon advancing the process, underlying various pathologies such as late-stage diabetic complications and aging. However, an understanding of the impact of early-stage collagen glycation on MSC interaction is lacking. This study examines the fate of in vitro glycated rat tail collagen (RTC) upon exposure to glucose for 1 or 5 days in contact with MSCs. Utilizing human adipose tissue-derived MSCs (ADMSCs), we demonstrate their significantly altered interaction with glycated collagen, characterized morphologically by reduced cell spreading, diminished focal adhesions formation, and attenuated development of the actin cytoskeleton. The morphological findings were confirmed by ImageJ 1.54g morphometric analysis with the most significant drop in the cell spreading area (CSA), from 246.8 μm2 for the native collagen to 216.8 μm2 and 163.7 μm2 for glycated ones, for 1 day and 5 days, respectively, and a similar trend was observed for cell perimeter 112.9 μm vs. 95.1 μm and 86.2 μm, respectively. These data suggest impaired recognition of early glycated collagen by integrin receptors. Moreover, they coincide with the reduced fibril-like reorganization of adsorbed FITC-collagen (indicating impaired remodeling) and a presumed decreased sensitivity to proteases. Indeed, confirmatory assays reveal diminished FITC-collagen degradation for glycated samples at 1 day and 5 days by attached cells (22.8 and 30.4%) and reduced proteolysis upon exogenous collagenase addition (24.5 and 40.4%) in a cell-free system, respectively. The mechanisms behind these effects remain uncertain, although differential scanning calorimetry confirms subtle structural/thermodynamic changes in glycated collagen. [ABSTRACT FROM AUTHOR]

The molecular pathways involved in oviductal adenogenesis are highly conserved among vertebrates. In this work, we study the histomorphological changes and molecular pathways involved in Caiman latirostris oviductal adenogenesis and the effects of in ovo exposure to environmentally relevant doses of endosulfan (END) and atrazine (ATZ) on these processes. To this end, the histomorphological changes at epithelial and subepithelial compartments, the protein expressions of β-catenin and Wnt-7a, and the gene expression of metalloproteinases (MMPs) and its inhibitors (TIMPs) were evaluated as biomarkers of oviductal adenogenesis in prepubertal juvenile C. latirostris. Exposure to END altered adenogenesis-related epithelium characteristics and mRNA expression of MMP2, MMP9, and TIMP1. Exposure to ATZ increased the width of the subepithelial stroma with loosely arranged collagen fibers and increased β-catenin expression in buds (invaginated structures that precede glands). The results demonstrate that in ovo exposure to ATZ and END alters oviductal adenogenesis at tissue, cellular, and molecular levels. An altered oviductal adenogenesis could impair fertility, raising concern on the effects of pesticide pollution in wildlife and domestic animals. [ABSTRACT FROM AUTHOR]

• Discoidin domain receptors (DDRs), including DDR1 and DDR2, are a unique class of receptor tyrosine kinases (RTKs) that interact directly with the native collagen triple helix. • Through its ability to sense collagen-related ECM changes, DDR2 is co-opted by tumor cells to alter cell-matrix communication and support pro-migratory and pro-invasive programs. • DDR2 acts in several cancer-associated stromal cells, fostering the establishment of a pre-metastatic niche and supporting the metastatic spread of cancer cells, thereby providing a novel therapeutic target for clinical strategies. Discoidin domain receptors (DDRs), including DDR1 and DDR2, are a unique class of receptor tyrosine kinases (RTKs) activated by collagens at the cell-matrix boundary interface. The peculiar mode of activation makes DDRs as key cellular sensors of microenvironmental changes, with a critical role in all physiological and pathological processes governed by collagen remodeling. DDRs are widely expressed in fetal and adult tissues, and experimental and clinical evidence has shown that their expression is deregulated in cancer. Strong findings supporting the role of collagens in tumor progression and metastasis have led to renewed interest in DDRs. However, despite an increasing number of studies, DDR biology remains poorly understood, particularly the less studied DDR2, whose involvement in cancer progression mechanisms is undoubted. Thus, the understanding of a wider range of DDR2 functions and related molecular mechanisms is expected. To date, several lines of evidence support DDR2 as a promising target in cancer therapy. Its involvement in key functions in the tumor microenvironment makes DDR2 inhibition particularly attractive to achieve simultaneous targeting of tumor and stromal cells, and tumor regression, which is beneficial for improving the response to different types of anti-cancer therapies, including chemo- and immunotherapy. This review summarizes current research on DDR2, focusing on its role in cancer progression through its involvement in tumor and stromal cell functions, and discusses findings that support the rationale for future development of direct clinical strategies targeting DDR2. [ABSTRACT FROM AUTHOR]

Considering difficulties of achieving vertical incidence of beam in different positions of skin, it is significant to study potential effects of incidence angles of laser on incisions. Surgical platform with a 1064 nm continuous fiber laser was established. Incident angle was adopted and real‐time temperature fluctuations in laser operating area could be monitored. The rats were treated with laser at day 0 and day 3 after incision modeling, and H&E, Masson, Sirius Red, and Immuno‐histochemical staining and enzyme‐linked immunosorbent assay were adopted at day 3, 7, 14 to analyze the performance of healing. Laser with energy density of 67.54 J/mm2 can effectively accelerate wound healing in vivo, in which a laser with incident angle around 60° can effectively avoid scar hyperplasia. Therefore, the use of low energy laser with a small deflection angle has a good clinical application prospect in promoting wound healing. [ABSTRACT FROM AUTHOR]

Abstract Background Eosinophilic esophagitis (EoE) is a chronic progressive inflammatory disease of the esophagus, characterized by extracellular matrix remodeling and fibrotic stricture formation. Disease monitoring requires multiple re-endoscopies with esophageal biopsies. Hence non-invasive methods for determining tissue fibrosis and treatment efficacy are warranted. Aims To investigate the ability of extracellular matrix proteins in serum as potential biomarkers of tissue remodeling and clinical, endoscopic, and histological disease outcomes in adult EoE patients. Methods Protein-fingerprint assays were used to measure neo-epitope specific fragments of collagen remodeling, human-neutrophil elastase degraded calprotectin, and citrullinated or non-citrullinated vimentin in the serum of an adult EoE-cohort. Biomarker analysis, symptoms, endoscopic features and histological disease activity (eosinophils(eos) per high-power-field(hpf)) were evaluated at baseline and after six weeks of dietary intervention. Results Patients with a baseline (Endoscopic Reference score) EREFS fibrosis subscore ≥ 2 presented with increased fibrolysis of cross-linked type III collagen (CTX-III) (p

In the rapidly advancing field of modern medicine, despite the availability of sophisticated techniques, suturing remains a fundamental procedure in both surgical and internal medicine operations. However, this traditional method inevitably gives rise to issues such as inflammation, fibrosis, or secondary damage. Laser tissue welding and soldering technologies offer a non-contact approach to surgical suturing with advantages including simplicity of operation, reduced fibrosis tendency, and ensured wound closure strength. Nevertheless, its applications have been attempts at clinical trials but no actual implementation. The development and implementation of this technique have the potential to revolutionize both internal and external surgery by enabling automated suture placement. This holds significant importance for ensuring suture quality and postoperative performance. This article provides a detailed summary and discussion on the current applications of this biotechnologies in various organ systems within the human body, as well as an exploration into the interaction mechanisms between tissues and lasers. Additionally, it presents a comprehensive analysis and discussion on laser types suitable for bio tissue laser soldering. Prospects for addressing tissue fibrosis resulting from laser contactless suturing are also explored. These insights will serve as valuable references and guidance for future advancements in utilizing lasers as viable alternatives in human surgical suturing.

Q-switched lasers have undeniably revolutionized the field of laser dermatology since four decades ago. Just as the first-generation laser emits its photonic signal in a few nanoseconds, the picosecond laser delivers pulse widths of at least ten times shorter. These devices offer a powerful tool for treating a wide range of skin conditions with a minimal downtime for visible improvement. For the current study, a literature research was performed on the dermatological applications of picosecond laser. The literature searched on this topic between 1999 and 2023 accessible through various platforms produce a result of 62 articles. The included studies have discussed the application of picosecond laser technology in tattoo removal, treatment of epidermal and dermal pigmentation, and collagen remodeling. After sifting the data from the articles into tables, the results were discussed in detail. The study shows a lot of evidence towards the efficacy of picosecond laser, yet it draws attention to its downsides. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic esophagitis (EoE) is a chronic progressive inflammatory disease of the esophagus, characterized by extracellular matrix remodeling and fibrotic stricture formation. Disease monitoring requires multiple re-endoscopies with esophageal biopsies. Hence non-invasive methods for determining tissue fibrosis and treatment efficacy are warranted. Aims: To investigate the ability of extracellular matrix proteins in serum as potential biomarkers of tissue remodeling and clinical, endoscopic, and histological disease outcomes in adult EoE patients. Methods: Protein-fingerprint assays were used to measure neo-epitope specific fragments of collagen remodeling, human-neutrophil elastase degraded calprotectin, and citrullinated or non-citrullinated vimentin in the serum of an adult EoE-cohort. Biomarker analysis, symptoms, endoscopic features and histological disease activity (eosinophils(eos) per high-power-field(hpf)) were evaluated at baseline and after six weeks of dietary intervention. Results: Patients with a baseline (Endoscopic Reference score) EREFS fibrosis subscore ≥ 2 presented with increased fibrolysis of cross-linked type III collagen (CTX-III) (p < 0.01), whereas low CTX-III levels were observed in patients achieving histological remission (< 15 eos/hpf) (vs. no histological remission (p < 0.05). Progression of endoscopic fibrosis after intervention was associated with increased levels of type-III (PRO-C3) and -VI collagen (PRO-C6) formation (all; p < 0.05). A baseline EREFS inflammatory subscore ≥ 2 correlated with higher neutrophilic activity (Cpa9-HNE) at week 6 (p < 0.05). Moreover, increased degradation of type-III (C3M) and -IV (C4M/PRO-C4) collagens were associated with remission of food impaction after intervention (all; p < 0.05). Conclusion: Serum extracellular matrix remodeling proteins demonstrated potential as surrogate biomarkers for assessing histological disease remission, endoscopic fibrosis, and remission of symptoms of food impaction after diet intervention in adult EoE patients. [ABSTRACT FROM AUTHOR]

Background: Cancers aggressively reorganize collagen in their microenvironment, leading to the evasion of tumor cells from immune surveillance. However, the biological significance and molecular mechanism of collagen alignment in breast cancer (BC) have not been well established. Methods: In this study, BC-related RNA-Seq data were obtained from the TCGA database to analyze the correlation between DDR1 and immune cells. Mouse BC cells EO771 were selected for in vitro validation, and dual-luciferase experiments were conducted to examine the effect of TFAP2A on DDR1 promoter transcription activity. ChIP experiments were performed to assess TFAP2A enrichment on the DDR1 promoter, while Me-RIP experiments were conducted to detect TFAP2A mRNA m6A modification levels, and PAR-CLIP experiments were conducted to determine VIRMA's binding to TFAP2A mRNA and RIP experiments to investigate HNRNPC's recognition of m6A modification on TFAP2A mRNA. Additionally, an in vivo mouse BC transplant model and the micro-physiological system was constructed for validation, and Masson staining was used to assess collagen fiber arrangement. Immunohistochemistry was conducted to identify the number of CD8-positive cells in mouse BC tumors and Collagen IV content in ECM, while CD8 + T cell migration experiments were performed to measure CD8 + T cell migration. Results: Bioinformatics analysis showed that DDR1 was highly expressed in BC and negatively correlated with the proportion of anti-tumor immune cell infiltration. In vitro cell experiments indicated that VIRMA, HNRNPC, TFAP2A, and DDR1 were highly expressed in BC cells. In addition, HNRNPC promoted TFAP2A expression and, therefore, DDR1 transcription by recognizing the m6A modification of TFAP2A mRNA by VIRMA. In vivo animal experiments further confirmed that VIRMA and HNRNPC enhanced the TFAP2A/DDR1 axis, promoting collagen fiber alignment, reducing anti-tumor immune cell infiltration, and promoting immune escape in BC. Conclusion: This study demonstrated that HNRNPC promoted DDR1 transcription by recognizing VIRMA-unveiled m6A modification of TFAP2A mRNA, which enhanced collagen fiber alignment and ultimately resulted in the reduction of anti-tumor immune cell infiltration and promotion of immune escape in BC. [ABSTRACT FROM AUTHOR]

Remodeling of extracellular matrix proteins underlies the development of cardiovascular disease. Herein, we utilized a novel molecular probe, collagen hybridizing peptide (CHP), to target collagen molecular damage during atherogenesis. The thoracic aorta was dissected from ApoE−/− mice that had been on a high-fat diet for 0–18 weeks. Using an optimized protocol, tissues were stained with Cy3-CHP and digested to quantify CHP with a microplate assay. Results demonstrated collagen molecular damage, inferred from Cy3-CHP fluorescence, was a function of location and time on the high-fat diet. Tissue from the aortic arch showed a significant increase in collagen molecular damage after 18 weeks, while no change was observed in tissue from the descending aorta. No spatial differences in fluorescence were observed between the superior and inferior arch tissue. Our results provide insight into the early changes in collagen during atherogenesis and present a new opportunity in the subclinical diagnosis of atherosclerosis. [ABSTRACT FROM AUTHOR]

Background/Aims: Hyaluronan (HA) oligosaccharides are involved in several biological processes, primarily collagen remodeling and wound healing. Collagen remodeling is retarded in aging skin and causes wrinkles. The aim of this study was to evaluate the effect of 2‐kDa HA oligosaccharides (HA2k) on wrinkles by permeation through the stratum corneum and promotion of collagen remodeling. Methods: A 3D skin model and excised human skin were used to evaluate the permeation of fluorescein‐labeled HA2k. The effect of HA2k on collagen metabolism was evaluated by measuring the protein level of type 1 pro‐collagen (COL1A1) and matrix metalloproteinase‐1 (MMP‐1) in the 3D skin model. 0.1% HA2k solution and vehicle control was applied to the human forearm for 8 weeks to evaluate dermal collagen density. To evaluate the effect of HA2k on depth of facial wrinkles, a randomized controlled trial was conducted with 0.1% HA2k lotion and vehicle lotion for 8 weeks. Results: HA2k was confirmed to permeate through the stratum corneum by fluorescent microscopy. Both COL1A1 and MMP‐1 were upregulated by HA2k application in a 3D skin model culture. The collagen density was higher for the HA2k‐treated forearm than for the vehicle control‐treated forearm after 4 weeks. The maximum wrinkle depths in the nasolabial fold and crow's feet area were significantly shallower in the HA2k lotion group than in the control group. Conclusion: HA2k permeated the stratum corneum, activated collagen synthesis and degradation simultaneously, and ameliorated wrinkles. [ABSTRACT FROM AUTHOR]

Introduction: Atrial Fibrillation (AF) is the most prevalent cardiac arrhythmia worldwide. Inflammation and structural remodeling of the left atrium are thought to be involved in the pathogenesis of AF. This study explores collagen remodeling and inflammatory biomarkers in AF patients compared to healthy controls to discern their role in AF. Materials and Methods: Plasma samples were collected from AF patients undergoing first AF ablation (n = 72) and compared with commercially available human plasma samples from healthy subjects (n = 62). The collagen remodeling biomarkers and inflammatory biomarkers in the AF patients and control population were quantified using sandwich ELISA kits. GraphPad prism was used to perform statistical analyses. Results: There was a statistically significant elevation in all the collagen remodeling biomarkers and inflammatory biomarkers in the AF patients compared to healthy controls. Spearman correlation analysis demonstrated significant correlations between inflammatory and collagen remodeling biomarkers, and among the collagen biomarkers. Of note, CRP was found to be correlated with TIMP-1, ICTP and PIIINP. IL6 and TIMP-1 were also found to be intercorrelated. Furthermore, correlations were noted among the different collagen remodeling peptides, and between TNFa and IL6, two of the inflammatory markers explored in this study. Conclusions: The elevation of the inflammatory biomarkers and collagen remodeling proteins in AF patients is suggestive of inflammation and increased collagen turnover. The association between inflammatory biomarkers and collagen remodeling proteins may contribute to their regulation and role in the remodeling process. [ABSTRACT FROM AUTHOR]

Glioma is the most common brain tumor in the central nervous system and characterized by diffuse invasion into adjacent brain tissue. The extracellular matrix (ECM) is an essential component of the tumor microenvironment and it contributes to tumor progression through close interactions with glioma cells. Accumulated evidence has indicated that collagen levels, which are the most critical components of the ECM, are elevated in gliomas and collagen contributes to glioma progression. In this review, we provide a comprehensive summary of the roles of various collagens in glioma. A better understanding of the interactions of various collagens with glioma cells may provide new therapeutic strategies for gliomas.

Professional peeling using chemicals (chemical peeling) is a popular non‐surgical procedure commonly used for the treatment for photoaging, pigmentary disorders, scarring, fine lines, and wrinkles. The objective of our case study was to elucidate the mechanism of action of professional peels/peeling. For proof‐of‐concept, we used a commercial blended peel containing trichloroacetic acid and lactic acid. The facial peeling was performed by a physician on four subjects. These subjects were followed over time in the clinic to take clinical pictures and monitor surface and anatomical changes in inflammation, melanin, and collagen at regular intervals post‐peel (5 min, 48 h, and day 9). Dermoscope and Vivascope® were used to image surface and subsurface anatomical changes, respectively, and ConfoScan® was used to quantify aforementioned anatomical changes. Based on Vivascope and ConfoScan analysis, we could see clear visual clinical evidence of controlled injury‐healing mechanism of peel's action: immediate but transient onset of inflammation within 5 min (indicate injury response by skin), followed by melanin redistribution evident at 48 h (indicate activation of skin's defense system), and remodeled fibrous collagen network without any inflammatory cells on day 9 (healing response). To our knowledge, this is the first ever clinical study to deconvolute the mysterious mechanism of action of peels, in‐vivo. [ABSTRACT FROM AUTHOR]

Demand for facial contouring procedures has increased dramatically in recent years. Common regions of concern for patients seeking a rejuvenated, more youthful appearance include the cheeks, jawline, submental area, and neck. Radiofrequency technology offers a non‐invasive and effective method of improving skin laxity and subcutaneous fat in these areas. The Evoke system from InMode Aesthetics is a radiofrequency modality designed to address the lower face and neck that stimulates collagen remodeling for skin tightening and thermal lipolysis for improved facial contour. While alternate technologies for radiofrequency facial remodeling are commercially available, Evoke is the first of its kind in introducing a reliable, operator‐independent hands‐free device developed based on InMode's proprietary Acquire, Control, and Extend technology targeting the deep fibro‐septal network to provide optimal and consistent outcomes. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) is a significant factor in cancer progression. Collagens, as the main component of the ECM, are greatly remodeled alongside cancer development. More and more studies have confirmed that collagens changed from a barrier to providing assistance in cancer development. In this course, collagens cause remodeling alongside cancer progression, which in turn, promotes cancer development. The interaction between collagens and tumor cells is complex with biochemical and mechanical signals intervention through activating diverse signal pathways. As the mechanism gradually clears, it becomes a new target to find opportunities to diagnose and treat cancer. In this review, we investigated the process of collagen remodeling in cancer progression and discussed the interaction between collagens and cancer cells. Several typical effects associated with collagens were highlighted in the review, such as fibrillation in precancerous lesions, enhancing ECM stiffness, promoting angiogenesis, and guiding invasion. Then, the values of cancer diagnosis and prognosis were focused on. It is worth noting that several generated fragments in serum were reported to be able to be biomarkers for cancer diagnosis and prognosis, which is beneficial for clinic detection. At a glance, a variety of reported biomarkers were summarized. Many collagen-associated targets and drugs have been reported for cancer treatment in recent years. The new targets and related drugs were discussed in the review. The mass data were collected and classified by mechanism. Overall, the interaction of collagens and tumor cells is complicated, in which the mechanisms are not completely clear. A lot of collagen-associated biomarkers are excavated for cancer diagnosis. However, new therapeutic targets and related drugs are almost in clinical trials, with merely a few in clinical applications. So, more efforts are needed in collagens-associated studies and drug development for cancer research and treatment. [ABSTRACT FROM AUTHOR]

Tissue fibrosis manifests as excessive deposition of compacted, highly aligned collagen fibrils, which interfere with organ structure and function. Cells in collagen‐rich lesions often exhibit marked overexpression of discoidin domain receptor 1 (DDR1), which is linked to increased collagen compaction through the association of DDR1 with the Ca2+‐dependent nonmuscle myosin IIA (NMIIA). We examined the functional relationship between DDR1 and the transient receptor potential vanilloid type 4 (TRPV4) channel, a Ca2+‐permeable ion channel that is implicated in collagen compaction. Fibroblasts expressing high levels of DDR1 were used to model cells in lesions with collagen compaction. In these cells, the expression of the β1 integrin was deleted to simplify studies of DDR1 function. Compared with DDR1 wild‐type cells, high DDR1 expression was associated with increased Ca2+ influx through TRPV4, enrichment of TRPV4 in collagen adhesions, and enhanced contractile activity mediated by NMIIA. At cell adhesion sites to collagen, DDR1 associated with TRPV4, which enhanced DDR1‐mediated collagen alignment and compaction. We conclude that DDR1 regulates Ca2+ influx through the TRPV4 channel to promote critical, DDR1‐mediated processes that are important in lesions with collagen compaction and alignment. [ABSTRACT FROM AUTHOR]

Liver kinase B1 (LKB1) is a potent tumor suppressor that regulates cellular energy balance and metabolism as an upstream kinase of the AMP-activated protein kinase (AMPK) pathway. LKB1 regulates cancer cell invasion and metastasis in multiple cancer types, including breast cancer. In this study, we evaluated LKB1’s role as a regulator of the tumor microenvironment (TME). This was achieved by seeding the MDA-MB-231-LKB1 overexpressing cell line onto adipose and tumor scaffolds, followed by the evaluation of tumor matrix-induced tumorigenesis and metastasis. Results demonstrated that the presence of tumor matrix enhanced tumorigenesis in both MDA-MB-231 and MDA-MB-231-LKB1 cell lines. Metastasis was increased in both MDA-MB-231 and -LKB1 cells seeded on the tumor scaffold. Endpoint analysis of tumor and adipose scaffolds revealed LKB1-mediated tumor microenvironment remodeling as evident through altered matrix protein production. The proteomic analysis determined that LKB1 overexpression preferentially decreased all major and minor fibril collagens (collagens I, III, V, and XI). In addition, proteins observed to be absent in tumor scaffolds in the LKB1 overexpressing cell line included those associated with the adipose matrix (COL6A2) and regulators of adipogenesis (IL17RB and IGFBP4), suggesting a role for LKB1 in tumor-mediated adipogenesis. Histological analysis of MDA-MB-231-LKB1-seeded tumors demonstrated decreased total fibril collagen and indicated decreased stromal cell presence. In accordance with this, in vitro condition medium studies demonstrated that the MDA-MB-231-LKB1 secretome inhibited adipogenesis of adipose-derived stem cells. Taken together, these data demonstrate a role for LKB1 in regulating the tumor microenvironment through fibril matrix remodeling and suppression of adipogenesis.

Collagen has an essential role in aortic biomechanics, and collagen remodeling has been associated with the development and progression of aortic aneurysm. However, the exact mechanisms behind collagen remodeling and the biomechanical implications are not well understood. This study presents an investigation of the relationship between collagen remodeling in the aortic wall and biomechanics, by means of collagen assays, smooth muscle cell gene expression, and mechanical testing on human aortic specimens collected from patients with bicuspid aortic valve. Collagen assay analysis was employed to determine collagen-I and total collagen content; quantitative real-time PCR was used to determine amounts COL1A1 and COL3A1 expression in the tissue. These parameters were compared with the local biomechanical properties determined from biaxial and uniaxial tensile testing. Collagen-I content was found to relate to improved mechanical properties, while total collagen content did not exhibit a relationship with biomechanics. COL1A1 and COL3A1 expression were found to relate to the collagen-I content of the tissue, but not the total collagen content or biomechanical performance. Relationships between variables appeared to be dependent on the collagen content in specific layers of the aortic wall. The effect of age is also noted, as total collagen content and biomechanics were found to have significant associations with increasing age, while collagen-I content and collagen gene expression did not exhibit any correlation. Varying relationships were observed when looking at younger versus older patients. Findings highlight the importance of type and location in determining the influence of collagen on aortic biomechanics, as well as the role of gene expression in the onset and progression of collagen remodeling in aortic aneurysm.

Oral tolerance blocks the development of specific immune responses to proteins ingested by the oral route. One of the first registries of oral tolerance showed that guinea pigs fed corn became refractory to hypersensitivity to corn proteins. Mice fed with chow containing corn are tolerant to zein, and parenteral injection of zein plus adjuvant blocks immunization to unrelated proteins injected concomitantly and reduces unspecific inflammation. Extensive and prolonged inflammatory infiltrate in the wound bed is one of the causes of pathological wound healing. Previous research shows that intraperitoneal injection of zein concomitant with skin injuries reduces the inflammatory infiltrate in the wound bed and improves wound healing. Herein, we tested if one subcutaneous injection of zein before skin injury improves wound healing. We also investigated how long the effects triggered by zein could improve skin wound healing. Mice fed zein received two excisional wounds on the interscapular skin under anesthesia. Zein plus Al(OH)3 was injected at the tail base at 10 min, or 3, 5, or 7 days before skin injuries. Wound healing was analyzed at days 7 and 40 after injury. Our results showed that a zein injection up to 5 days before skin injury reduced the inflammatory infiltrate, increased the number of T-cells in the wound bed, and improved the pattern of collagen deposition in the neodermis. These findings could promote the development of new strategies for the treatment and prevention of pathological healing using proteins normally found in the common diet.

The current therapeutic approach to asthma focuses exclusively on targeting inflammation and reducing airway smooth muscle force to prevent the recurrence of symptoms. However, even when inflammation is brought under control, airways in an asthmatic can still hyperconstrict when exposed to a low dose of agonist. This suggests that there are mechanisms at play that are likely triggered by inflammation and eventually become self-sustaining so that even when airway inflammation is brought back under control, these alternative mechanisms continue to drive airway hyperreactivity in asthmatics. In this study, we hypothesized that stiffening of the airway extracellular matrix is a core pathological change sufficient to support excessive bronchoconstriction even in the absence of inflammation. To test this hypothesis, we increased the stiffness of the airway extracellular matrix by photo-crosslinking collagen fibers within the airway wall of freshly dissected bovine rings using riboflavin (vitamin B2) and Ultraviolet-A radiation. In our experiments, collagen crosslinking led to a twofold increase in the stiffness of the airway extracellular matrix. This change was sufficient to cause airways to constrict to a greater degree, and at a faster rate when they were exposed to 10-5 M acetylcholine for 5 min. Our results show that stiffening of the extracellular matrix is sufficient to drive excessive airway constriction even in the absence of inflammatory signals. [ABSTRACT FROM AUTHOR]

Poly-L-lactic acid is presented as freeze-dried preparation of 150 mg per vial and, according to consensus, the recommendation on your preparation is hydrate in sterile water for injection (SWFI) or bacteriostatic water at room temperature for ≥24 hours. (J Drugs Dermatol; 2014;13:s44) However, in these long periods of hydration, it is time-consuming and costly for the physicians. To demonstrate the safeness of immediate reconstitution of facial biostimulation treatment with PLLA. A clinical prospective study with 26 Latin American female patients, aged between 27 and 80 years, complaining of facial laxity of treated with immediate PLLA reconstitution. One PLLA vial was injected per session in 12 mL total dilution. All patients had their pictures taken before and after the treatment in Photo Analysis Program Vectra 3D (Canfield®). A follow-up 90 days was performed. The total of 58 facial applications of PLLA was reported in female patients with a mean age 52.62 (±13.46) years. Pain was reported in 17 injections (29.31%) and ecchymosis in 6 (10.34%). Also, 2 patients (3.44%) developed a nodule. None of the patients presented significant bruising, edema, or papules formation. Despite the literature declare that a longer hydration times (up to 48 hours) have been shown to reduce the risk of nodule formation (Aesthet Surg J; 2011;31:95), our study demonstrated the safeness of injection with immediate reconstitution and a very low adverse events rate. Immediate PLLA reconstitution is a great asset for physicians, injections in account of being less laborious, less time-consuming, and reducing product loss for the injector. [ABSTRACT FROM AUTHOR]

Fibrosis has also been recorded as a prominent pathological feature within wooden breast (WB) myopathy of broiler chickens. This study was conducted to evaluate the accumulation of fibril collagen, deposition of the extracellular matrix (ECM) components, and the underlying mechanism mediating the pathogenic fibrotic process in the pectoralis major (PM) muscle of WB-affected birds. Broiler chickens were categorized into the control and WB groups based on the evaluation of myopathic lesions. Results indicated that the total content and area of collagen in cross-sections of the PM muscle, as well as the augmented expression of collagen-I and fibronectin in the ECM, were greatly increased in birds with WB. Wooden breast myopathy upregulated expressions of transforming growth factor-beta (TGF-β) and the phosphorylation of Smad 2 and 3, thereby activating TGF-β-mediated Smad signaling pathway, which further enhanced the transcription of profibrotic mediators. In addition, regulators involved in collagen biosynthesis and cross-linking including prolyl 4-hydroxylase, lysyl oxidase, lysyl hydroxylase, and decorin were increased in the WB muscle. Finally, the expressions of both matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) were increased in the WB muscle, which might be related with reduced ECM remodeling. Overall, WB myopathy induces severe fibrosis by enhancing ECM deposition and collagen cross-linking in the PM muscle of broiler chickens, possibly via the activation of TGF-β signaling and the dysregulation of the MMP and TIMP system.

Background: Myocardial infarction (MI) induces an intense injury response that ultimately generates a collagen-dominated scar. Although required to prevent ventricular rupture, the fibrotic process is often sustained in a manner detrimental to optimal recovery. Cardiac myofibroblasts are the cells tasked with depositing and remodeling collagen and are a prime target to limit the fibrotic process after MI. Serotonin 2B receptor (5-HT2B) signaling has been shown to be harmful in a variety of cardiopulmonary pathologies and could play an important role in mediating scar formation after MI.Methods: We used 2 pharmacological antagonists to explore the effect of 5-HT2B inhibition on outcomes after MI and characterized the histological and microstructural changes involved in tissue remodeling. Inducible 5-HT2B ablation driven by Tcf21MCM and PostnMCM was used to evaluate resident cardiac fibroblast- and myofibroblast-specific contributions of 5-HT2B, respectively. RNA sequencing was used to motivate subsequent in vitro analyses to explore cardiac fibroblast phenotype.Results: 5-HT2B antagonism preserved cardiac structure and function by facilitating a less fibrotic scar, indicated by decreased scar thickness and decreased border zone area. 5-HT2B antagonism resulted in collagen fiber redistribution to thinner collagen fibers that were more anisotropic, enhancing left ventricular contractility, whereas fibrotic tissue stiffness was decreased, limiting the hypertrophic response of uninjured cardiomyocytes. Using a tamoxifen-inducible Cre, we ablated 5-HT2B from Tcf21-lineage resident cardiac fibroblasts and saw similar improvements to the pharmacological approach. Tamoxifen-inducible Cre-mediated ablation of 5-HT2B after onset of injury in Postn-lineage myofibroblasts also improved cardiac outcomes. RNA sequencing and subsequent in vitro analyses corroborate a decrease in fibroblast proliferation, migration, and remodeling capabilities through alterations in Dnajb4 expression and Src phosphorylation.Conclusions: Together, our findings illustrate that 5-HT2B expression in either cardiac fibroblasts or activated myofibroblasts directly contributes to excessive scar formation, resulting in adverse remodeling and impaired cardiac function after MI. [ABSTRACT FROM AUTHOR]

Background: Rupture of brain aneurysms is associated with high fatality and morbidity rates. Through remodeling of the collagen matrix, many aneurysms can remain unruptured for decades, despite an enlarging and evolving geometry. Objective: Our objective was to explore this adaptive remodeling for the first time in an elastase induced aneurysm model in rabbits. Methods: Saccular aneurysms were created in 22 New Zealand white rabbits and remodeling was assessed in tissue harvested 2, 4, 8 and 12 weeks after creation. Results: The intramural principal stress ratio doubled after aneurysm creation due to increased longitudinal loads, triggering a remodeling response. A distinct wall layer with multi-directional collagen fibers developed between the media and adventitia as early as 2 weeks, and in all cases by 4 weeks with an average thickness of 50.6 ± 14.3 μm. Collagen fibers in this layer were multi-directional (AI = 0.56 ± 0.15) with low tortuosity (1.08 ± 0.02) compared with adjacent circumferentially aligned medial fibers (AI = 0.78 ± 0.12) and highly tortuous adventitial fibers (1.22 ± 0.03). A second phase of remodeling replaced circumferentially aligned fibers in the inner media with longitudinal fibers. A structurally motivated constitutive model with both remodeling modes was introduced along with methodology for determining material parameters from mechanical testing and multiphoton imaging. Conclusions: A new mechanism was identified by which aneurysm walls can rapidly adapt to changes in load, ensuring the structural integrity of the aneurysm until a slower process of medial reorganization occurs. The rabbit model can be used to evaluate therapies to increase aneurysm wall stability. [ABSTRACT FROM AUTHOR]

Tony Melcher, a highly influential and forward‐thinking scientist and teacher, focussed on the origins, behaviour and regulation of cells in periodontal tissues. His recent death in April 2020, has motivated us to highlight his multi‐level contributions to research in biology and the dental sciences. Tony was particularly adept at recognizing the inherent instructive power of the periodontium, most notably as a model system for studying the inter‐relationships between the structure, development and functions of connective tissues. Further, his mentoring of dozens of students who subsequently went on to develop their own careers in research, and his leadership in promoting collaborations in dental sciences world‐wide, engendered important advances in the importance and utility of research relating to oral tissues. Here, we reflect upon his development of a large, multi‐disciplinary research enterprise, the MRC Group in Periodontal Physiology at the University of Toronto and brief commentaries of those who worked with him there. We examine his early career development and then go on to consider some of his most highly cited publications and their impact on subsequent research trends. [ABSTRACT FROM AUTHOR]

In this study, the application of a recently introduced device based on electromagnetic energy transfer by microwaves for fat reduction, permitted to study specifically the modifications of thick fibrous collagen interlobular septa in the subcutaneous adipose tissue, related to the formation of large clusters of adipocytes. The use of Picrosirius red staining associated with circularly polarized microscopy gave evidence of appreciable modifications of the fibrous connective tissue forming septa. Compact fibrotic bundles of collagen I forming interlobular septa appeared reduced or dissolved, in part substituted by the increase of more diffuse and finely reticular collagen III. Remodeling of fibrous collagen, which formed bridles involved in the appearance at the surface of the skin of dimpling/orange peer pattern typical of cellulite, was observed. [ABSTRACT FROM AUTHOR]

The interplay between vitamin D, the renin–angiotensin system (RAS), and collagen remodeling has been implicated in the pathogenesis of various cardiovascular diseases. This study sought to explore this relationship in atrial fibrillation (AF) by profiling plasma levels of 25-hydroxyvitamin D, RAS biomarkers, and collagen remodeling biomarkers using the enzyme-linked immunosorbent assay method. We hypothesized that 25-hydroxyvitamin D levels would inversely correlate with RAS biomarkers and that levels of RAS and collagen remodeling biomarkers would positively correlate with each other. Although our AF cohort (n = 37) did not exhibit decreased 25-hydroxyvitamin D levels compared to normal controls (n = 26), these levels inversely correlated with renin (Spearman r = −0.57, P = 0.005). Renin levels were elevated in patients with AF compared to normal controls (1233 ± 238 ng/mL vs 401 ± 27 ng/mL, P = 0.0002) and positively correlated with levels of matrix metalloproteinase 1 (MMP-1; Spearman r = 0.89, P = 0.01) and MMP-2 (Spearman r = 0.82, P = 0.03). These data suggest that 25-hydroxyvitamin D may influence RAS activation, and renin may help mediate the collagen remodeling process in AF. Understanding mediators of RAS dysregulation in AF may elucidate targets for therapeutic intervention to prevent collagen remodeling. [ABSTRACT FROM AUTHOR]

César Arroyo HM Montepríncipe University Hospital Laser Unit, Madrid, Spain Background: This study investigated a novel fractional carbon dioxide (CO2) laser for treatment of symptoms associated with vulvovaginal atrophy (VVA) in perimenopausal women.Methods: The study included 21 perimenopausal women (mean age 45±7 years) treated three times by CO2 laser resurfacing and coagulation of the vaginal canal tissue and mucosal tissue of the introitus. Vaginal health index (VHI) scores were computed by the investigator at baseline and follow-ups. Subjects reported on sexual function, satisfaction, and improvement with treatment. A visual analog scale was used to measure discomfort with treatment.Results: Vaginal health and subject assessment of vaginal symptoms improved with successive treatments. At 12 weeks following the third treatment, 82% of the patients showed a statistically significant improvement in VHI (P

Discoidin domain receptor 1 (DDR1) is a tyrosine kinase collagen adhesion receptor that mediates cell migration through association with non-muscle myosin IIA (NMIIA). Because DDR1 is implicated in cancer fibrosis, we hypothesized that DDR1 interacts with NMIIA to enable collagen compaction by traction forces. Mechanical splinting of rat dermal wounds increased DDR1 expression and collagen alignment. In periodontal ligament of DDR1 knockout mice, collagen mechanical reorganization was reduced >30%. Similarly, cultured cells with DDR1 knockdown or expressing kinase-deficient DDR1d showed 50% reduction of aligned collagen. Tractional remodeling of collagen was dependent on DDR1 clustering, activation, and interaction of the DDR1 C-terminal kinase domain with NMIIA filaments. Collagen remodeling by traction forces, DDR1 tyrosine phosphorylation, and myosin light chain phosphorylation were increased on stiff versus soft substrates. Thus, DDR1 clustering, activation, and interaction with NMIIA filaments enhance the collagen tractional remodeling that is important for collagen compaction in fibrosis.

Periodontal ligament (PDL), as a mechanical connection between the alveolar bone and tooth, plays a pivotal role in force-induced orthodontic tooth movement (OTM). However, how mechanical force controls remodeling of PDL collagenous extracellular matrix (ECM) is largely unknown. Here, we aimed to evaluate the stress distribution and ECM fiber remodeling of PDL during the process of OTM. An experimental tooth movement model was built by ligating a coil spring between the left maxillary first molar and the central incisors. After activating the coil spring for 7 days, the distance of tooth movement was 0.324 ± 0.021 mm. The 3D finite element modeling showed that the PDL stress obviously concentrated at cervical margin of five roots and apical area of the mesial root, and the compression region was distributed at whole apical root and cervical margin of the medial side (normal stress < −0.05 MPa). After force induction, the ECM fibers were disordered and immature collagen III fibers significantly increased, especially in the apical region, which corresponds to the stress concentration and compression area. Furthermore, the osteoclasts and interleukin-1β expression were dramatically increased in the apical region of the force group. Taken together, orthodontic loading could change the stress distribution of PDL and induce a disordered arrangement and remodeling of ECM fibers. These findings provide orthodontists both mechanical and biological evidences that root resorption is prone to occur in the apical area during the process of OTM.

Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as “desmoplastic reaction”. This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors.

Periodontal ligament (PDL), as a mechanical connection between the alveolar bone and tooth, plays a pivotal role in force-induced orthodontic tooth movement (OTM). However, how mechanical force controls remodeling of PDL collagenous extracellular matrix (ECM) is largely unknown. Here, we aimed to evaluate the stress distribution and ECM fiber remodeling of PDL during the process of OTM. An experimental tooth movement model was built by ligating a coil spring between the left maxillary first molar and the central incisors. After activating the coil spring for 7 days, the distance of tooth movement was 0.324 ± 0.021 mm. The 3D finite element modeling showed that the PDL stress obviously concentrated at cervical margin of five roots and apical area of the mesial root, and the compression region was distributed at whole apical root and cervical margin of the medial side (normal stress < −0.05 MPa). After force induction, the ECM fibers were disordered and immature collagen III fibers significantly increased, especially in the apical region, which corresponds to the stress concentration and compression area. Furthermore, the osteoclasts and interleukin-1β expression were dramatically increased in the apical region of the force group. Taken together, orthodontic loading could change the stress distribution of PDL and induce a disordered arrangement and remodeling of ECM fibers. These findings provide orthodontists both mechanical and biological evidences that root resorption is prone to occur in the apical area during the process of OTM. [ABSTRACT FROM AUTHOR]

In the present paper we propose and study a simple model of collagen remodeling occurring in latter stage of tendon healing process. The model is an integro-differential equation describing the possibility of an alignment of collagen fibers in a finite time. We show that the solutions may either exist globally in time or blow-up in a finite time depending on initial data. The latter behavior can be related to the healing of injury without the scar formation in a finite time: a full alignment of collagen fibers. We believe that the present model is an essential ingredient of the full description of collagen remodeling. [ABSTRACT FROM AUTHOR]

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer death; identifying PDAC enablers may reveal potential therapeutic targets. Expression of the actomyosin regulatory ROCK1 and ROCK2 kinases increased with tumor progression in human and mouse pancreatic tumors, while elevated ROCK1/ROCK2 expression in human patients, or conditional ROCK2 activation in a KrasG12D/p53R172H mouse PDAC model, was associated with reduced survival. Conditional ROCK1 or ROCK2 activation promoted invasive growth of mouse PDAC cells into three‐dimensional collagen matrices by increasing matrix remodeling activities. RNA sequencing revealed a coordinated program of ROCK‐induced genes that facilitate extracellular matrix remodeling, with greatest fold‐changes for matrix metalloproteinases (MMPs) Mmp10 and Mmp13. MMP inhibition not only decreased collagen degradation and invasion, but also reduced proliferation in three‐dimensional contexts. Treatment of KrasG12D/p53R172H PDAC mice with a ROCK inhibitor prolonged survival, which was associated with increased tumor‐associated collagen. These findings reveal an ancillary role for increased ROCK signaling in pancreatic cancer progression to promote extracellular matrix remodeling that facilitates proliferation and invasive tumor growth.

DDR1 is a collagen adhesion-mechanoreceptor expressed in fibrotic lesions. DDR1 mediates non-muscle myosin IIA (NMIIA)-dependent collagen remodeling. We discovered that the myosin phosphatase Rho-interacting protein (MRIP), is enriched in DDR1-NMIIA adhesions on collagen. MRIP regulates RhoA- and myosin phosphatase-dependent myosin activity. We hypothesized that MRIP regulates DDR1-NMIIA interactions to enable cell migration and collagen tractional remodeling. After deletion of MRIP in β1-integrin null cells expressing DDR1, in vitro wound closure, collagen realignment, and contraction were reduced. Cells expressing DDR1 and MRIP formed larger and more abundant DDR1 clusters on collagen than cells cultured on fibronectin or cells expressing DDR1 but null for MRIP or cells expressing a non-activating DDR1 mutant. Deletion of MRIP reduced DDR1 autophosphorylation and blocked myosin light chain-dependent contraction. Deletion of MRIP did not disrupt the association of DDR1 with NMIIA. We conclude that MRIP regulates NMIIA-dependent DDR1 cluster growth and activation. Accordingly, MRIP may provide a novel drug target for dysfunctional DDR1-related collagen tractional remodeling in fibrosis.

Graphical abstract Abstract The hemodynamic functionality of heart valves strongly depends on the distribution of collagen fibers, which are their main load-bearing constituents. It is known that collagen networks remodel in response to mechanical stimuli. Yet, the complex interplay between external load and collagen remodeling is poorly understood. In this study, we adopted a computational approach to simulate collagen remodeling occurring in native fetal and pediatric heart valves. The computational model accounted for several biological phenomena: cellular (re)orientation in response to both mechanical stimuli and topographical cues provided by collagen fibers; collagen deposition and traction forces along the main cellular direction; collagen degradation decreasing with stretch; and cell-mediated collagen prestretch. Importantly, the computational results were well in agreement with previous experimental data for all simulated heart valves. Simulations performed by varying some of the computational parameters suggest that cellular forces and (re)orientation in response to mechanical stimuli may be fundamental mechanisms for the emergence of the circumferential collagen alignment usually observed in native heart valves. On the other hand, the tendency of cells to coalign with collagen fibers is essential to maintain and reinforce that circumferential alignment during development. Statement of Significance The hemodynamic functionality of heart valves is strongly influenced by the alignment of load-bearing collagen fibers. Currently, the mechanisms that are responsible for the development of the circumferential collagen alignment in native heart valves are not fully understood. In the present study, cell-mediated remodeling of native human heart valves during early development was computationally simulated to understand the impact of individual mechanisms on collagen alignment. Our simulations successfully predicted the degree of collagen alignment observed in native fetal and pediatric semilunar valves. The computational results suggest that the circumferential collagen alignment arises from cell traction and cellular (re)orientation in response to mechanical stimuli, and with increasing age is reinforced by the tendency of cells to co-align with pre-existing collagen fibers. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Renin-angiotensin axis plays a pivotal role in the cardiovascular system, and Angiotensin II (Ang II) is of great importance in the progression of hypertension. Vasoactive peptide intermedin (IMD) belongs to calcitonin gene-related peptide (CGRP) family, which is involved in the regulation of the cardiovascular function. This study aims to determine the effect of vasoactive peptide intermedin on vascular collagen remodeling caused by angiotensin II-induced hypertension. MATERIALS AND METHODS: 12-week old rats were randomly assigned into three groups, and each group consisted of 12 rats. Rats were administered with Ang II or Ang II+IMD, respectively. Control group received saline administration. Blood pressure of caudal artery was examined two weeks after administration. Serum procollagen I and III were detected by enzyme-linked immunosorbent assay (ELISA). The vascular microstructure was examined via hematoxylin-eosin (HE) staining to evaluate vascular collagen remodeling. Expressions of protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) were tested by using Western-blot and RT-PCR. RESULTS: Compared with the control group (92.2±9.1 mmHg), blood pressure of group Ang II was increased by 88% (173.1±11.2 mmHg) (p<0.01). Moreover, blood pressure level in group Ang II+IMD (131.0±10.9 mmHg) was reduced compared to that in group Ang II (p<0.05). Compared with that in control group, higher level of serum procollagen, with significantly increasing vascular W/C ratio and collagen area percentage, was found in group Ang II, while all testing indexes above in group Ang II+IMD were lower than that in group Ang II. No differences were detected in the levels of Akt and MAPK mRNA among all three groups. However, highest expressions of phosphorylation Akt and MAPK protein were shown in group Ang II, and the levels were gradually lower in groups of Ang II+IMD and control. CONCLUSIONS: IMD could attenuate the vascular collagen remodeling caused by angiotensin II-induced hypertension via inhibiting phosphorylation of Akt and MAPK. [ABSTRACT FROM AUTHOR]

this study investigated a novel fractional carbon dioxide (co2) laser for treatment of symptoms associated with vulvovaginal atrophy (VVa) in perimenopausal women. methods: the study included 21 perimenopausal women (mean age 45 ± 7 years) treated three times by co2 laser resurfacing and coagulation of the vaginal canal tissue and mucosal tissue of the introitus. Vaginal health index (VhI) scores were computed by the investigator at baseline and follow-ups. subjects reported on sexual function, satisfaction, and improvement with treatment. a visual analog scale was used to measure discomfort with treatment. results: Vaginal health and subject assessment of vaginal symptoms improved with successive treatments. at 12 weeks following the third treatment, 82 % of the patients showed a statistically significant improvement in VhI (P < 0.05). additionally, 81 % of subjects reported improvement in sexual gratification, 94 % reported improvement in vaginal rejuvenation, and 100 % reported satisfaction with treatment. VhI improvement remained significant at 6--8 months after treatments (P < 0.01). most patients (97 %) reported no to mild discomfort with treatment. responses were mild and transient following treatment, with itching being the most commonly reported (20 %) side effect. conclusion: In this study, fractional co2 laser treatment was associated with improvement of vaginal health and amelioration of symptoms of VVa, resulting in improved sexual function in perimenopausal women. treatment time was quick, and there was minimal discomfort associated with treatment. Investigation of clinical outcome in a larger study population is warranted. [ABSTRACT FROM AUTHOR]