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ABSTRACT Background Aims Methods Results Conclusions Anti‐freeze Glycoproteins (AFGPs) were described to preserve biological materials and protect them from different stresses.The effects of a synthetic anti‐freeze glycoprotein‐based compound, TFC‐1326, on human skin quality and its biological actions were studied.The effects of various concentrations of TFC‐1326 on the biology of human preadipocytes, differentiated in the proinflammatory microenvironment, and on human fibroblasts grown in coculture with human mature adipocytes or monocultured in stress conditions were investigated in, in vitro studies. Additionally, the efficacy of a 1% TFC‐1326 topical cream was evaluated in a clinical investigation on the skin biology and appearance of 20 women aged between 40 and 65 years throughout 84 days of application.The in vitro studies revealed that TFC‐1326 mitigated the deleterious effects of a proinflammatory cytokine cocktail produced by human macrophages, by restoring preadipocyte adipogenic capacity and by reducing their fibroinflammatory state. TFC‐1326 also stimulated the proliferative capacity of dermal fibroblasts co‐cultured with mature adipocytes as well as their production of hyaluronic acid and procollagen type I, while decreasing IL6 secretion and increasing fibroblast viability. Furthermore, daily 1% TFC‐1326 topical cream application, measurably improved skin radiance and laxity, as well as skin density. Finally, significant reductions of the volume and depth of the crow's feet wrinkles were also observed.The compound TFC‐1326 significantly improved the physiological appearance and cellular functions of aging skin. [ABSTRACT FROM AUTHOR]

Endometriosis is a common chronic disorder characterized by the growth of endometrium-like tissue outside the uterine cavity. The disease is associated with chronic inflammation and pelvic pain and may have an impact on the patient's fertility. The causative factors and pathophysiology of the disease are still poorly recognized. The dysregulation of the immune system, aberrant tissue remodeling, and angiogenesis contribute to the disease progression. In endometriosis patients, the proteins regulating the breakdown and reorganization of the connective tissue, e.g., collagenases, and other proteases, as well as their inhibitors, show an incorrect pattern of expression. Here, we report that the expression of reversion-inducing cysteine-rich protein with Kazal motifs (RECK), one of the inhibitors of connective tissue proteases, is elevated in endometrioma cysts as compared to normal endometrium from unaffected women. We also demonstrate a reduced level of miR200b in endometriotic tissue that correlates with RECK mRNA levels. Furthermore, we employ the 12Z cell line, derived from a peritoneal endometriotic lesion, and the Ishikawa cell line, originating from endometrial adenocarcinoma to identify RECK as a direct target of miR200b. The described effect of miR200b on RECK, together with the aberrant expression of both genes in endometrioma, may help to understand the role played by the tissue remodeling system in the pathogenesis of endometriosis. [ABSTRACT FROM AUTHOR]

Cell migration through 3D environments is essential to development, disease, and regeneration processes. Conceptual models of migration have been developed primarily on the basis of 2D cell behaviors, but a general understanding of 3D cell migration is still lacking due to the added complexity of the extracellular matrix. Here, using a multiplexed biophysical imaging approach for single-cell analysis of human cell lines, we show how the subprocesses of adhesion, contractility, actin cytoskeletal dynamics, and matrix remodeling integrate to produce heterogeneous migration behaviors. This single-cell analysis identifies three modes of cell speed and persistence coupling, driven by distinct modes of coordination between matrix remodeling and protrusive activity. The framework that emerges establishes a predictive model linking cell trajectories to distinct subprocess coordination states.

• Syndecan 4 null mice show vertebral osteopenia, reduced bone stiffness, and functionally altered bone biomechanics. • Osteopenic phenotype in Sdc4 null mice is driven by elevated osteoclast numbers. • Syndecan 4 fine-tunes collagen maturity and ECM composition in the intervertebral disc during early adult life. • Transcriptomic analysis shows dysregulation in heparan sulfate biosynthesis, UPR, and degradation along with decreased mitochondria metabolism. Syndecan 4 (SDC4), a cell surface heparan sulfate proteoglycan, is known to regulate matrix catabolism by nucleus pulposus cells in an inflammatory milieu. However, the role of SDC4 in the aging spine has never been explored. Here we analyzed the spinal phenotype of Sdc4 global knockout (KO) mice as a function of age. Micro-computed tomography showed that Sdc4 deletion severely reduced vertebral trabecular and cortical bone mass, and biomechanical properties of vertebrae were significantly altered in Sdc4 KO mice. These changes in vertebral bone were likely due to elevated osteoclastic activity. The histological assessment showed subtle phenotypic changes in the intervertebral disc. Imaging-Fourier transform-infrared analyses showed a reduced relative ratio of mature collagen crosslinks in young adult nucleus pulposus (NP) and annulus fibrosus (AF) of KO compared to wildtype discs. Additionally, relative chondroitin sulfate levels increased in the NP compartment of the KO mice. Transcriptomic analysis of NP tissue using CompBio, an AI-based tool showed biological themes associated with prominent dysregulation of heparan sulfate GAG degradation, mitochondria metabolism, autophagy, endoplasmic reticulum (ER)-associated misfolded protein processes and ER to Golgi protein processing. Overall, this study highlights the important role of SDC4 in fine-tuning vertebral bone homeostasis and extracellular matrix homeostasis in the mouse intervertebral disc. [ABSTRACT FROM AUTHOR]

Matrix remodeling plays central roles in a range of physiological and pathological processes and is driven predominantly by the activity of matrix metalloproteinases (MMPs), which degrade extracellular matrix (ECM) proteins. How MMPs regulate cell and tissue dynamics is not well understood as in vivo approaches are lacking and many in vitro strategies cannot provide high‐resolution, quantitative measures of enzyme activity in situ within tissue‐like 3D microenvironments. Here, a Förster resonance energy transfer (FRET) sensor of MMP activity is incorporated into fully synthetic hydrogels that mimic many properties of the native ECM. Fluorescence lifetime imaging is then used to provide a real‐time, fluorophore concentration‐independent quantification of MMP activity, establishing a highly accurate, readily adaptable platform for studying MMP dynamics in situ. MCF7 human breast cancer cells encapsulated within hydrogels are then used to detect MMP activity both locally, at the sub‐micron level, and within the bulk hydrogel. This versatile platform may find use in a range of biological studies to explore questions in the dynamics of cancer metastasis, development, and tissue repair by providing high‐resolution, quantitative, and in situ readouts of local MMP activity within native tissue‐like environments. [ABSTRACT FROM AUTHOR]

Abstract Introductions Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the skin. Both genetic and environmental factors contribute to the risk of developing HS, but the pathogenesis of this disease is currently not fully understood. The aim of this study was to further current understanding of the molecular background of HS with the use of global transcriptome analyses. Methods Transcriptome profiling of perilesional and lesional skin of five patients with HS and six healthy control patients was performed by next-generation sequencing. Groups of differentially expressed genes characteristic of the skin of patients with HS were shortlisted by bioinformatic analysis. Results RNA sequencing followed by bioinformatic profiling revealed profound enrichment of inflammatory-related processes in both lesional and perilesional skin of patients with HS. There were, however, distinct differences in the gene expression profiles between the lesional and perilesional skin, with 1488 genes differentially expressed. Genes encoding typical proinflammatory cytokines were profoundly enriched within HS lesions. In contrast, those encoding mediators of extracellular matrix organization were highly expressed mostly in the perilesional area. Conclusions Our study provides novel insights into the mechanisms underlying the pathogenesis of HS, and the results also have potential clinical implications in both diagnosis and therapeutics.

Inflammatory cytokines released by synovium after trauma disturb the gene regulatory network and have been implicated in the pathophysiology of osteoarthritis. A mechanistic understanding of how aging perturbs this process can help identify novel interventions. Here, we introduced network paradigms to simulate cytokine‐mediated pathological communication between the synovium and cartilage. Cartilage‐specific network analysis of injured young and aged murine knees revealed aberrant matrix remodeling as a transcriptomic response unique to aged knees displaying accelerated cartilage degradation. Next, network‐based cytokine inference with pharmacological manipulation uncovered IL6 family member, Oncostatin M (OSM), as a driver of the aberrant matrix remodeling. By implementing a phenotypic drug discovery approach, we identified that the activation of OSM recapitulated an "inflammatory" phenotype of knee osteoarthritis and highlighted high‐value targets for drug development and repurposing. These findings offer translational opportunities targeting the inflammation‐driven osteoarthritis phenotype. [ABSTRACT FROM AUTHOR]

Introductions: Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the skin. Both genetic and environmental factors contribute to the risk of developing HS, but the pathogenesis of this disease is currently not fully understood. The aim of this study was to further current understanding of the molecular background of HS with the use of global transcriptome analyses. Methods: Transcriptome profiling of perilesional and lesional skin of five patients with HS and six healthy control patients was performed by next-generation sequencing. Groups of differentially expressed genes characteristic of the skin of patients with HS were shortlisted by bioinformatic analysis. Results: RNA sequencing followed by bioinformatic profiling revealed profound enrichment of inflammatory-related processes in both lesional and perilesional skin of patients with HS. There were, however, distinct differences in the gene expression profiles between the lesional and perilesional skin, with 1488 genes differentially expressed. Genes encoding typical proinflammatory cytokines were profoundly enriched within HS lesions. In contrast, those encoding mediators of extracellular matrix organization were highly expressed mostly in the perilesional area. Conclusions: Our study provides novel insights into the mechanisms underlying the pathogenesis of HS, and the results also have potential clinical implications in both diagnosis and therapeutics. [ABSTRACT FROM AUTHOR]

In response to injury, humans and many other mammals form a fibrous scar that lacks the structure and function of the original tissue, whereas other vertebrate species can spontaneously regenerate damaged tissues and structures. Peripheral nerves have been identified as essential mediators of wound healing and regeneration in both mammalian and nonmammalian systems, interacting with the milieu of cells and biochemical signals present in the post‐injury microenvironment. This review examines the diverse functions of peripheral nerves in tissue repair and regeneration, specifically during the processes of wound healing, blastema formation, and organ repair. We compare available evidence in mammalian and nonmammalian models, identifying critical nerve‐mediated mechanisms for regeneration and providing future perspectives toward integrating these mechanisms into a therapeutic framework to promote regeneration. Key Findings: Peripheral nerves promote tissue repair and regeneration by modulating the function of key cell types in the injury microenvironment such as keratinocytes and fibroblasts.Mechanisms of neural dependency include secretion of growth factors, neuropeptides, and neurotransmitters, modulation of extracellular matrix degradation, and control of gap junction communication.Future work investigating nerves in regeneration can take advantage of new molecular tools and bioengineering platforms to better define neural‐driven mechanisms. [ABSTRACT FROM AUTHOR]

Simple Summary: This review summarizes the present knowledge of cytotoxic agents and protective systems against these damaging substances in tumors. In tumor cells, enhanced levels of cytotoxic agents are usually counteracted by an overexpression of protective mechanisms. In this manner, tumor cells can even survive therapeutically induced stress situations. Tumor cells also affect immune cells and other cells in their close neighborhood in such a way that cells in this tumor microenvironment change their properties and promote tumor progression. Numerous examples are given for how the disturbed balance between inflammation-associated cytotoxic agents and antagonizing principles is related to tumor growth, tumor cell invasion, and metastasis. A thorough knowledge of these mechanisms is mandatory for the implementation of novel therapeutic approaches against cancers. Chronic inflammatory processes are related to all stages of tumorigenesis. As inflammation is closely associated with the activation and release of different cytotoxic agents, the interplay between cytotoxic agents and antagonizing principles is highlighted in this review to address the question of how tumor cells overcome the enhanced values of cytotoxic agents in tumors. In tumor cells, the enhanced formation of mitochondrial-derived reactive species and elevated values of iron ions and free heme are antagonized by an overexpression of enzymes and proteins, contributing to the antioxidative defense and maintenance of redox homeostasis. Through these mechanisms, tumor cells can even survive additional stress caused by radio- and chemotherapy. Through the secretion of active agents from tumor cells, immune cells are suppressed in the tumor microenvironment and an enhanced formation of extracellular matrix components is induced. Different oxidant- and protease-based cytotoxic agents are involved in tumor-mediated immunosuppression, tumor growth, tumor cell invasion, and metastasis. Considering the special metabolic conditions in tumors, the main focus here was directed on the disturbed balance between the cytotoxic agents and protective mechanisms in late-stage tumors. This knowledge is mandatory for the implementation of novel anti-cancerous therapeutic approaches. [ABSTRACT FROM AUTHOR]

While most mammalian tissue regeneration is limited, the Murphy Roths Large (MRL/MpJ) mouse has been identified to regenerate several tissues, including tendon. Recent studies have indicated that this regenerative response is innate to the tendon tissue and not reliant on a systemic inflammatory response. Therefore, we hypothesized that MRL/MpJ mice may also exhibit a more robust homeostatic regulation of tendon structure in response to mechanical loading. To assess this, MRL/MpJ and C57BL/6J flexor digitorum longus tendon explants were subjected to stress‐deprived conditions in vitro for up to 14 days. Explant tendon health (metabolism, biosynthesis, and composition), matrix metalloproteinase (MMP) activity, gene expression, and tendon biomechanics were assessed periodically. We found a more robust response to the loss of mechanical stimulus in the MRL/MpJ tendon explants, exhibiting an increase in collagen production and MMP activity consistent with previous in vivo studies. This greater collagen turnover was preceded by an early expression of small leucine‐rich proteoglycans and proteoglycan‐degrading MMP‐3, promoting efficient regulation and organization of newly synthesized collagen and allowing for more efficient overall turnover in MRL/MpJ tendons. Therefore, mechanisms of MRL/MpJ matrix homeostasis may be fundamentally different from that of B6 tendons and may indicate better recovery from mechanical microdamage in MRL/MpJ tendons. We demonstrate here the utility of the MRL/MpJ model in elucidating mechanisms of efficient matrix turnover and its potential to shed light on new targets for more effective treatments for degenerative matrix changes brought about by injury, disease, or aging. [ABSTRACT FROM AUTHOR]

Beyond its actions on the nervous system, amitriptyline (AM) has been shown to lower inflammatory, angiogenic, and fibrogenic markers in a few pathological conditions in human and in experimental animal models. However, its effects on foreign body reaction (FBR), a complex adverse healing process, after biomedical material implantation are not known. We have evaluated the effects of AM on the angiogenic and fibrogenic components on a model of implant‐induced FBR. Sponge disks were implanted subcutaneously in C57BL/6 mice, that were treated daily with oral administration of AM (5 mg/kg) for seven consecutive days in two protocols: treatment was started on the day of surgery and the implants were removed on the seventh day after implantation and treatment started 7 days after implantation and the implants removed 14 after implantation. None of the angiogenic (vessels, Vascular endothelial growth factor (VEGF), and interleukin‐1β (IL‐1β) or fibrogenic parameters (collagen, TGF‐β, and fibrous capsule) and giant cell numbers analyzed were attenuated by AM in 7‐day‐old implants. However, AM was able to downregulate angiogenesis and FBR in 14‐day‐old implants. The effects of AM described here expands its range of actions as a potential agent capable of attenuating fibroproliferative processes that may impair functionality of implantable devices. [ABSTRACT FROM AUTHOR]

Background: Visible light (VL) is known to induce pigmentation in dark‐skinned individuals and immediate erythema in light‐skinned individuals. However, the effects of accumulated low‐dose VL exposure across skin types are not well established. Methods: Thirty‐one healthy subjects with light (Fitzpatrick skin types [FST] I‐II, n = 13) and dark (FST V‐VI, n = 18) skin types were enrolled. Subjects' buttocks were exposed daily to VL, wavelength 400–700 nm, with a dose of 120 J/cm2 at 50 mW/cm2, for four consecutive days. Microarray using Affymetrix GeneChip (49,395 genes) was performed followed by qRT‐PCR on skin samples. Results: Repeated low‐dose VL irradiation induced immediate pigment darkening and delayed tanning in dark‐skinned individuals while no discernable pigmentation and erythema were observed in light‐skinned individuals. Top ten upregulated genes by repeated VL exposure in microarray included melanogenic genes such as tyrosinase (TYR), tyrosinase‐related protein‐1 (TYRP1), dopachrome tautomerase (DCT), premelanosome protein (PMEL), melan‐A (MLANA), and solute carrier family 24, member 5 (SLC24A5) and genes involved in inflammation/matrix remodeling/cell signaling including chemokine (C‐C motif) ligand 18 (CCL18), BCL2‐related protein A1 (BCL2A1), and cartilage oligomeric matrix protein (COMP). In qRT‐PCR CCL18 was upregulated in light skin with a greater extent (mean fold change ± SD; 4.03 ± 3.28, p =.04) than in dark‐skinned individuals (1.91 ± 1.32, p =.07) while TYR was not significantly upregulated in both skin types. Conclusion: This study highlights the genes upregulated by cumulative VL exposure involved in pigmentation, immune response, oxidation/reduction, and matrix remodeling across skin types providing relevant information on daily solar exposure. [ABSTRACT FROM AUTHOR]

Abstract Hypoxia in the neonatal period is associated with early manifestations of adverse cardiovascular health in adulthood including higher risk of hypertension and atherosclerosis. We hypothesize that this occurs due to activation of lysyl oxidases (LOXs) and the remodeling of the large conduit vessels, leading to early arterial stiffening. Newborn C57Bl/6 mice were exposed to hypoxia (FiO2 = 11.5%) from postnatal day 1 (P1) to postnatal day 11 (P11), followed by resumption of normoxia. Controls were maintained in normoxia. Using in vivo (pulse wave velocity; PWV) and ex vivo (tensile testing) arterial stiffness indexes, we determined that mice exposed to neonatal hypoxia had significantly higher arterial stiffness compared with normoxia controls by young adulthood (P60), and it increased further by P120. Echocardiography performed at P60 showed that mice exposed to hypoxia displayed a compensated dilated cardiomyopathy. Western blotting revelated that neonatal hypoxia accelerated age‐related increase in LOXL2 protein expression in the aorta and elevated LOXL2 expression in the PA at P11 with a delayed decay toward normoxic controls. In the heart and lung, gene and protein expression of LOX/LOXL2 were upregulated at P11, with a delayed decay when compared to normoxic controls. Neonatal hypoxia results in a significant increase in arterial stiffness in early adulthood due to aberrant LOX/LOXL2 expression. This suggests an acceleration in the mechanical decline of the cardiovascular system, that contributes to increased risk of hypertension in young adults exposed to neonatal hypoxia that may increase susceptibility to further insults.

Cardiorenal syndrome (CRS) is represented as an intricate dysfunctional interplay between the heart and kidneys, marked by cardiorenal inflammation and fibrosis. Unlike other organs, the repair process in cardiorenal injury involves a regenerative phase characterized by proliferation and polyploidization, followed by a subsequent pathogenic phase of fibrosis. In CRS, acute or chronic cardiorenal injury leads to hyperactive inflammation and fibrotic remodeling, associated with injury-mediated immune cell (Macrophages, Monocytes, and T-cells) infiltration and myofibroblast activation. An inflammatory to fibrotic transition corresponds with macrophage transition (M1-M2) associated with increased TGF-β response. Chronic inflammation disrupts hemodynamic pathways, leading to imbalanced oxidative stress and the production of cytokines and growth factors that promote fibrotic stimulation, contributing to pathological cardiorenal remodeling. The inflammatory response paves the pre-fibrotic cardiorenal niche and drives subsequent fibrotic remodeling by activated myofibroblasts. A fibrotic cardiorenal response in CRS is characterized by increased and degradation-resistant deposition of extracellular proteins especially fibrillar Collagen -I, -III, -V, and non-fibrillar Collagen-IV by active myofibroblasts. Recent advances in basic research animal models of CRS have advanced the knowledge of cardiorenal fibrosis. However, a significant need for clinical applications, trials, and evaluation is still needed. Circulating biomarkers like procollagen peptides and TGF-β have clinically been associated with cardiorenal fibrosis diagnosis in CRS. Treatments targeting the fibrotic pathways have also shown efficacy in amelioration of cardiorenal fibrosis in preclinical models. Recent combination therapies targeting multiple fibrotic pathways have been shown to offer promising results. Understanding the heterogenic pathological progression and fibrogenesis could identify novel therapeutic approaches for clinical CRS diagnosis and treatment., (© The Author(s) 2025. Published by Oxford University Press on behalf of the ERA.)

The coordinated movement of cell collectives is essential for normal epithelial tissue development, maintenance, and cancer progression. Here, we report on a minimal 3D extracellular matrix (ECM) system wherein both invasive collective migration (ICM) and rotational collective migration (RCM) arise spontaneously from individually seeded epithelial cells of mammary and hepatic origin, regardless of whether they express adherens junctions, and lead to ductal-like and acinar-like structures, respectively. Quantitative microscopy and cellular Potts modeling reveal that initial differences in cell protrusion dynamics and matrix-remodeling localization generate RCM and ICM behavior in confining 3D ECM. Matrix-remodeling activity by matrix metalloproteinases (MMPs) is localized to the base of protrusions in cells that initiate ICM, whereas RCM does not require MMPs and is associated with ITGβ1-mediated remodeling localized globally around the cell body. Further analysis in vitro and in vivo supports the concept that distinct matrix-remodeling strategies encode collective migration behaviors and tissue structure., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Extracellular matrix (ECM)-mimicking biomaterials are considered effective tissue-engineered scaffolds for regenerative medicine because of their biocompatibility, biodegradability, and bioactivity. ECM-mimicking biomaterials preserve natural microstructures and matrix-related bioactive components and undergo continuous matrix remodeling upon transplantation. The interaction between host immune cells and transplanted ECM-mimicking biomaterials has attracted considerable attention in recent years. Transplantation of biomaterials may initiate injuries and early pro-inflammation reactions characterized by infiltration of neutrophils and M1 macrophages. Pro-inflammation reactions may lead to degradation of the transplanted biomaterial and drive the matrix into a fetal-like state. ECM degradation leads to the release of matrix-related bioactive components that act as signals for cell migration, proliferation, and differentiation. In late stages, pro-inflammatory cells fade away, and anti-inflammatory cells emerge, which involves macrophage polarization to the M2 phenotype and leukocyte activation to T helper 2 (Th2) cells. These anti-inflammatory cells interact with each other to facilitate matrix deposition and tissue reconstruction. Deposited ECM molecules serve as vital components of the mature tissue and influence tissue homeostasis. However, dysregulation of matrix remodeling results in several pathological conditions, such as aggressive inflammation, difficult healing, and non-functional fibrosis. In this review, we summarize the characteristics of inflammatory responses in matrix remodeling after transplantation of ECM-mimicking biomaterials. Additionally, we discuss the intrinsic linkages between matrix remodeling and tissue regeneration. Extracellular matrix (ECM)-mimicking biomaterials are effectively used as scaffolds in tissue engineering and regenerative medicine. However, dysregulation of matrix remodeling can cause various pathological conditions. Here, the review describes the characteristics of inflammatory responses in matrix remodeling after transplantation of ECM-mimicking biomaterials. Additionally, we discuss the intrinsic linkages between matrix remodeling and tissue regeneration. We believe that understanding host immune responses to matrix remodeling of transplanted biomaterials is important for directing effective tissue regeneration of ECM-mimicking biomaterials. Considering the close relationship between immune response and matrix remodeling results, we highlight the need for studies of the effects of clinical characteristics on matrix remodeling of transplanted biomaterials. Schematic of ideal pro-regenerative matrix remodeling induced by host immune cells in the context of ECM-mimicking biomaterials. After the transplantation of ECM-mimicking biomaterials, ECM is remodeled into a fetal-like state for pro-regenerative reactions and then switch to a mature state for tissue homeostasis and function recovery. Neutrophils, Macrophage and Th cells are main cell types responsible for matrix remodeling during tissue regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

The manuscript details the major components of the tumor stroma and reviews recent research on each tumor stroma component in targeted drug delivery, which is divided into two main sections: using the tumor stroma to target the tumor and targeting and remodeling the tumor stroma. [Display omitted] The tumor stroma plays a crucial role in tumor progression, and the interactions between the extracellular matrix, tumor cells, and stromal cells collectively influence tumor progression and the efficacy of therapeutic agents. Currently, utilizing components of the tumor stroma for drug delivery is a noteworthy strategy. A number of targeted drug delivery systems designed based on tumor stromal components are entering clinical trials. Therefore, this paper provides a thorough examination of the function of tumor stroma in the advancement of targeted drug delivery systems. One approach is to use tumor stromal components for targeted drug delivery, which includes certain stromal components possessing inherent targeting capabilities like HA, laminin, along with targeting stromal cells homologously. Another method entails directly focusing on tumor stromal components to reshape the tumor stroma and facilitate drug delivery. These drug delivery systems exhibit great potential in more effective cancer therapy strategies, such as precise targeting, enhanced penetration, improved safety profile, and biocompatibility. Ultimately, the deployment of these drug delivery systems can deepen our comprehension of tumor stroma and the advanced development of corresponding drug delivery systems. [ABSTRACT FROM AUTHOR]

Collective cell migration on extracellular matrix (ECM) networks is a key biological process involved in development, tissue homeostasis and diseases such as metastatic cancer. During invasion of epithelial cancers, cell clusters migrate through the surrounding stroma, which is comprised primarily of networks of collagen-I fibers. There is growing evidence that the rheological and topological properties of collagen networks can impact cell behavior and cell migration dynamics. During migration, cells exert mechanical forces on their substrate, resulting in an active remodeling of ECM networks that depends not only on the forces produced, but also on the molecular mechanisms that dictate network rheology. One aspect of collagen network rheology whose role is emerging as a crucial parameter in dictating cell behavior is network viscoelasticity. Dynamic reorganization of ECM networks can induce local changes in network organization and mechanics, which can further feed back on cell migration dynamics and cell-cell rearrangement. A number of studies, including many recent publications, have investigated the mechanisms underlying structural changes to collagen networks in response to mechanical force as well as the role of collagen rheology and topology in regulating cell behavior. In this mini-review, we explore the cause-consequence relationship between collagen network viscoelasticity and cell rearrangements at various spatiotemporal scales. We focus on structural alterations of collagen-I networks during collective cell migration and discuss the main rheological parameters, and in particular the role of viscoelasticity, which can contribute to local matrix stiffening during cell movement and can elicit changes in cell dynamics.

Cell migration is essential for a variety of biological processes, such as embryogenesis, wound healing, and the immune response. After more than a century of research—mainly on flat surfaces—, there are still many unknowns about cell motility. In particular, regarding how cells migrate within 3D matrices, which more accurately replicate in vivo conditions. We present a novel in silico model of 3D mesenchymal cell migration regulated by the chemical and mechanical profile of the surrounding environment. This in silico model considers cell’s adhesive and nuclear phenotypes, the effects of the steric hindrance of the matrix, and cells ability to degradate the ECM. These factors are crucial when investigating the increasing difficulty that migrating cells find to squeeze their nuclei through dense matrices, which may act as physical barriers. Our results agree with previous in vitro observations where fibroblasts cultured in collagen-based hydrogels did not durotax toward regions with higher collagen concentrations. Instead, they exhibited an adurotactic behavior, following a more random trajectory. Overall, cell’s migratory response in 3D domains depends on its phenotype, and the properties of the surrounding environment, that is, 3D cell motion is strongly dependent on the context.

Calcified aortic valve disease (CAVD) was previously regarded as a passive process associated with valve degeneration and calcium deposition. However, recent studies have shown that the occurrence of CAVD is an active process involving complex changes such as endothelial injury, chronic inflammation, matrix remodeling, and neovascularization. CAVD is the ectopic accumulation of calcium nodules on the surface of the aortic valve, which leads to aortic valve thickening, functional stenosis, and ultimately hemodynamic disorders. CAVD has become an important cause of death from cardiovascular disease. The discovery of therapeutic targets to delay or block the progression of CAVD and the clinical application of transcatheter aortic valve implantation (TAVI) provide new ideas for the prevention and treatment of CAVD. This article summarizes the pathogenesis of CAVD and provides insight into the future directions of CAVD diagnosis and treatment.

It has been suggested that curvature progression in adolescent idiopathic scoliosis occurs through irreversible changes in the intervertebral discs. Strains of mice have been identified who differ in their disc wedging response upon extended asymmetrical compression. Annulus fibrosus (AF) tissue remodeling could contribute to the faster disc wedging progression previously observed in these mice. Differences in collagen remodeling capacity of AF cells between these in‐bred mice strains were compared using an in vitro microtissue system. AF cells of 8–10‐week‐old LG/J ("fast‐healing") and C57BL/6J ("normal healing") mice were embedded in a microtissue platform and cultured for 48 h. Hereafter, tissues were partially released and cultured for another 96 h. Microtissue surface area and waistcoat contraction, collagen orientation, and collagen content were measured. After 96 h postrelease, microtissues with AF cells of LG/J mice showed more surface area contraction (p <.001) and waistcoat contraction (p =.002) than C57BL/6J microtissues. Collagen orientation did not differ at 24 h after partial release. However, at 96 h, collagen in the microtissues from LG/J AF cells was aligned more than in those from C57BL/6J mice (p <.001). Collagen content did not differ between microtissues at 96 h. AF cells of inbred LG/J mice were better able to remodel and realign their collagen fibers than those from C57BL/6J mice. The remodeling of AF tissue could be contributing to the faster disc wedging progression observed in LG/J mice. [ABSTRACT FROM AUTHOR]

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a stroma-rich carcinoma, and pancreatic stellate cells (PSCs) are a major component of this dense stroma. PSCs play significant roles in metastatic progression and chemoresistance through cross-talk with cancer cells. Preclinical in vitro tumor model of invasive phenotype should incorporate three-dimensional (3D) culture of cancer cells and PSCs in extracellular matrix (ECM) for clinical relevance and predictability. Methods PANC-1 cells were cultured as tumor spheroids (TSs) using our previously developed minipillar chips, and co-cultured with PSCs, both embedded in collagen gels. Effects of PSC co-culture on ECM fiber network, invasive migration of cancer cells, and expression of epithelial-mesenchymal transition (EMT)-related proteins were examined. Conditioned media was also analyzed for secreted factors involved in cancer cell-PSC interactions. Inhibitory effect on cancer cell invasion was compared between gemcitabine and paclitaxel at an equitoxic concentration in PANC-1 TSs co-cultured with PSCs. Results Co-culture condition was optimized for the growth of TSs, activation of PSCs, and their interaction. Increase in cancer cell invasion via ECM remodeling, invadopodia formation and EMT, as well as drug resistance was recapitulated in the TS-PSC co-culture, and appeared to be mediated by cancer cell-PSC interaction via multiple secreted factors, including IL-6, IL-8, IGF-1, EGF, TIMP-1, uPA, PAI-1, and TSP-1. Compared to gemcitabine, paclitaxel showed a greater anti-invasive activity, which was attributed to suppresion of invadopodia formation in cancer cells as well as to PSC-specific cytotoxicity abrogating its paracrine signaling. Conclusions Here, we established 3D co-culture of TSs of PANC-1 cells and PSCs using minipillar histochips as a novel tumoroid model of PDAC. Our results indicate usefulness of the present co-culture model and multiplex quantitative analysis method not only in studying the role of PSCs and their interactions with tumor cell towards metastatic progression, but also in the drug evaluation of stroma-targeting drugs.

Platelet-derived growth factors (PDGFs) are powerful inducers of cellular mitosis, migration, angiogenesis, and matrix modulation that play pivotal roles in the development, homeostasis, and healing of cardiac tissues. PDGFs are key signaling molecules and important drug targets in the treatment of cardiovascular disease as multiple researchers have shown that delivery of recombinant PDGF ligands during or after myocardial infarction can reduce mortality and improve cardiac function in both rodents and porcine models. The mechanism involved cannot be easily elucidated due to the complexity of PDGF regulatory activities, crosstalk with other protein tyrosine kinase activators, and diversity of the pathological milieu. This review outlines the possible roles of PDGF ligands A and B in the healing of cardiac tissues including reduced cell death, improved vascularization, and improved extracellular matrix remodeling to improve cardiac architecture and function after acute myocardial injury. This review may highlight the use of recombinant PDGF-A and PDGF-B as a potential therapeutic modality in the treatment of cardiac injury.

Background: Recognizing only sharp elevation in a short period of time, the COVID-19 SARS-CoV-2 propagation is more and more marked in the whole world. Induced inflammation afterwards infection engenders a high infiltration of immune cells and cytokines that triggers matrix metalloproteinases (MMPs) activation. These endopeptidases are mediators of the lung extracellular matrix (ECM), a basic element for alveoli structure and gas exchange. Methods: When immune cells, MMPs, secreted cytokines and several other mediators are gathered a pathological matrix remodeling occurs. This phenomenon tends to tissue destruction in the first place and a pulmonary hypertrophy and fibrosis in the second place. Findings: After pathological matrix remodeling establishment, pathological diseases take place even after infection state. Since post COVID-19 pulmonary fibrosis is an emerging complication of the disease, there is an urge to better understand and characterize the implication of ECM remodeling during SARS-CoV-2 infection. Conclusion: Targeting MMPs and their inhibitors could be a probable solution for occurred events since there are many cured patients that remain with severe sequels even after the end of infection. [ABSTRACT FROM AUTHOR]

The mechano-response of highly loaded tissues such as bones or tendons is well investigated, but knowledge regarding the mechano-responsiveness of adjacent tissues such as the subacromial bursa is missing. For a better understanding of the physiological role of the bursa as a friction-reducing structure in the joint, the study aimed to analyze whether and how bursa-derived cells respond to physiological and pathological mechanical loading. This might help to overcome some of the controversies in the field regarding the role of the bursa in the development and healing of shoulder pathologies. Cells of six donors seeded on collagen-coated silicon dishes were stimulated over 3 days for 1 or 4 h with 1, 5, or 10% strain. Orientation of the actin cytoskeleton, YAP nuclear translocation, and activation of non-muscle myosin II (NMM-II) were evaluated for 4 h stimulations to get a deeper insight into mechano-transduction processes. To investigate the potential of bursa-derived cells to adapt their matrix formation and remodeling according to mechanical loading, outcome measures included cell viability, gene expression of extracellular matrix and remodeling markers, and protein secretions. The orientation angle of the actin cytoskeleton increased toward a more perpendicular direction with increased loading and lowest variations for the 5% loading group. With 10% tension load, cells were visibly stressed, indicated by loss in actin density and slightly reduced cell viability. A significantly increased YAP nuclear translocation occurred for the 1% loading group with a similar trend for the 5% group. NMM-II activation was weak for all stimulation conditions. On the gene expression level, only the expression of TIMP2 was down-regulated in the 1 h group compared to control. On the protein level, collagen type I and MMP2 increased with higher/longer straining, respectively, whereas TIMP1 secretion was reduced, resulting in an MMP/TIMP imbalance. In conclusion, this study documents for the first time a clear mechano-responsiveness in bursa-derived cells with activation of mechano-transduction pathways and thus hint to a physiological function of mechanical loading in bursa-derived cells. This study represents the basis for further investigations, which might lead to improved treatment options of subacromial bursa-related pathologies in the future.

Butyrate is a short-chain fatty acid (SCFA) derived from microbiota and is involved in a range of cell processes in a concentration-dependent manner. Low concentrations of sodium butyrate (NaBu) were shown to be proangiogenic. However, the mechanisms associated with these effects are not yet fully known. Here, we investigated the contribution of the SCFA receptor GPR43 in the proangiogenic effects of local treatment with NaBu and its effects on matrix remodeling using the sponge-induced fibrovascular tissue model in mice lacking the Gpr43 gene (Gpr43-KO) and the wild-type (WT) mice. We demonstrated that NaBu (0.2 mM intraimplant) treatment enhanced the neovascularization process, blood flow, and VEGF levels in a GPR43-dependent manner in the implants. Moreover, NaBu was able to modulate matrix remodeling aspects of the granulation tissue such as proteoglycan production, collagen deposition, and α-smooth muscle actin (α-SMA) expression in vivo, besides increasing transforming growth factor (TGF)-β1 levels in the fibrovascular tissue, in a GPR43-dependent manner. Interestingly, NaBu directly stimulated L929 murine fibroblast migration and TGF-α1 and collagen production in vitro. GPR43 was found to be expressed in human dermal fibroblasts, myofibroblasts, and endothelial cells. Overall, our findings evidence that the metabolite-sensing receptor GPR43 contributes to the effects of low dose of NaBu in inducing angiogenesis and matrix remodeling during granulation tissue formation. These data provide important insights for the proposition of new therapeutic approaches based on NaBu, beyond the highly explored intestinal, anti-inflammatory, and anticancer purposes, as a local treatment to improve tissue repair, particularly, by modulating granulation tissue components. [ABSTRACT FROM AUTHOR]

Abstract Recent advances in our understanding of the dynamics of cellular cross-talk have highlighted the significance of host-versus-tumor effect that can be harnessed with immune therapies. Tumors exploit immune checkpoints to evade adaptive immune responses. Cancer immunotherapy has witnessed a revolution in the past decade with the development of immune checkpoint inhibitors (ICIs), monoclonal antibodies against cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or their ligands, such as PD1 ligand 1 (PD-L1). ICIs have been reported to have activity against a broad range of tumor types, in both solid organ and hematologic malignancy contexts. However, less than one-third of the patients achieve a durable and meaningful treatment response. Expression of immune checkpoint ligands (e.g., PD-L1), mutational burden and tumor-infiltrating lymphocytes are currently used as biomarkers for predicting response to ICIs. However, they do not reliably predict which patients will benefit from these therapies. There is dire need to discover novel biomarkers to predict treatment efficacy and to identify areas for development of combination strategies to improve response rates. Emerging evidence suggests key roles of tumor extracellular matrix (ECM) components and their proteolytic remodeling products in regulating each step of the cancer-immunity cycle. Here we review tumor matrix dynamics and matrix remodeling in context of anti-tumor immune responses and immunotherapy and propose the exploration of matrix-based biomarkers to identify candidates for immune therapy.

• Material-dependent biomineralization achieved in vitro. • Performance of gold standard acid-etched titanium confirmed in in vitro test system. • Biomineralization leads to functional integration of dental implant material. • Use of carbon coating increases biomineralization and osseointegration. • Established in vitro test system mimics in vivo situation after implantation. Before application in dental practice, novel dental materials are tested in vitro and in vivo to ensure safety and functionality. However, transferability between preclinical and clinical results is often limited. To increase the predictive power of preclinical testing, a biomimetic in vitro test system that mimics the wound niche after implantation was developed. First, predetermined implant materials were treated with human blood plasma, M2 macrophages and bone marrow stromal stem cells. Thereby, the three-dimensional wound niche was simulated. Samples were cultured for 28 days, and subsequently analyzed for metabolic activity and biomineralization. Second test level involved a cell-infiltrated bone substitute material for an osseointegration assay to measure mechanical bonding between dental material and bone. Standard and novel dental materials validated the developed test approach. The developed test system for dental implant materials allowed quantification of biomineralization on implant surface and assessment of the functional stability of mineralized biomaterial-tissue interface. Human blood plasma, M2 macrophages and bone marrow stromal stem cells proved to be crucial components for predictive assessment of implant materials in vitro. Biocompatibility was demonstrated for all tested materials, whereas the degree of deposited mineralized extracellular matrix and mechanical stability differed between the tested materials. Highest amount of functional biomineralization was determined to be on carbon-coated implant surface. As an ethical alternative to animal testing, the established in vitro dental test system provides an economic and mid-throughput evaluation of novel dental implant materials or modifications thereof, by applying two successive readout levels: biomineralization and osseointegration. [ABSTRACT FROM AUTHOR]

The tonicity-responsive enhancer binding protein (TonEBP) plays an important role in intervertebral disc and axial skeleton embryogenesis. However, the contribution of this osmoregulatory transcription factor in postnatal intervertebral disc homeostasis is not known in vivo. Here, we show for the first time that TonEBP-deficient mice have pronounced age-related degeneration of the intervertebral disc with annular and endplate herniations. Using FTIR-imaging spectroscopy, quantitative immunohistochemistry, and tissue-specific transcriptomic analysis, we provide morphological and molecular evidence that the overall phenotype is driven by a replacement of water-binding proteoglycans with fibrocartilaginous matrix. Whereas TonEBP deficiency in the AF compartment caused tissue fibrosis associated with alterations in actin cytoskeleton and adhesion molecules, predominant changes in pro-inflammatory pathways were seen in the NP compartment of mutants, underscoring disc compartment-specific effects. Additionally, TonEBP-deficient mice presented with compromised trabecular bone properties of vertebrae. These results provide the first in vivo support to the long-held hypothesis that TonEBP is crucial for postnatal homeostasis of the spine and controls a multitude of functions in addition to cellular osmoadaptation. • TonEBP-deficiency causes pronounced age-dependent intervertebral disc degeneration. • Fibrocartilaginous matrix changes are associated with actin rearrangements and altered expression of adhesion molecules. • TonEBP-deficient mice show suppressed expression of immune-related and pro-inflammatory genes. • Vertebral bodies of TonEBP-deficient mice show compromised trabecular bone. [ABSTRACT FROM AUTHOR]

Travel of unacclimatized subjects to a high altitude has been growing in popularity. Changes in endothelial shedding [circulating endothelial cells (ECs)] and hematopoietic stem and progenitor cells (CPCs) during physical exercise in hypobaric hypoxia, however, are not well understood. We investigated the change in ECs and CPCs when exposed to high altitude, after acute exercise therein, and after an overnight stay in hypobaric hypoxia in 11 healthy unacclimatized subjects. Blood withdrawal was done at baseline (520 m a.s.l.; baseline), after passive ascent to 3,883 m a.s.l. (arrival), after acute physical exercise (±400 m, postexercise) and after an overnight stay at 3,883 m a.s.l. (24 h). Mature blood cells, ECs, and CPCs were assessed by a hematology analyzer and flow cytometry, respectively. The presence of matrix metalloproteinases (MMPs), their activity, and hematopoietic cytokines were assessed in serum and plasma. EC and CPC concentrations significantly decreased after exercise (p = 0.019, p = 0.007, respectively). CPCs remained low until the next morning (24 h, p = 0.002), while EC concentrations returned back to baseline. MMP-9 decreased at arrival (p = 0.021), stayed low postexercise (p = 0.033), and returned to baseline at 24 h (p = 0.035 to postexercise). MMP-activity did not change throughout the study. Circulating MMP-9 concentrations, but not MMP-activity, were associated with EC concentrations (rrm = 0.48, p = 0.010). CPC concentrations were not linked to hematopoietic cytokines. Acute exercise at high altitude attenuated endothelial shedding, but did not enhance regenerative CPCs. Results were not linked to endothelial matrix remodeling or CPC mobilization. These results provide information to better understand the endothelium and immature immune system during an active, short-term sojourn at high altitude.

Tissue remodeling is associated with both normal and abnormal processes including wound healing, fibrosis and cancer. In skin, abnormal remodeling causes permanent structural changes that can lead to hypertropic scarring and keloid formation. Normal remodeling, although fast and efficient in skin, is still imperfect, and a connective tissue scar remains at the wound site1. As a result, methods are needed to optimize tissue remodeling in vivo in all cases of wound repair. Since fibroblast-mediated contraction of engineered 3-D collagen based tissues (RAFTs) represents an in vitro model of the tissue contraction and collagen remodeling that occurs in vivo2, RAFT tissue contraction studies combined with two-photon microscopy (TPM) studies are used to provide information on ways to improve tissue remodeling in vivo. In the RAFT models discussed here, tissue contraction is modulated either by application of exogenous growth factors or photodynamic therapy. During tissue contraction, TPM is used to image changes in Collagen Type I fibers in the RAFT skin models. Tissues are imaged at depth at day 15 after modulation. TPM signal analysis shows that RAFT tissues having the highest collagen density have the fastest rate of decay of fluorescent signal with depth.

Tissue remodeling is associated with both normal and abnormal processes including wound healing, fibrosis and cancer. In skin, abnormal remodeling causes permanent structural changes that can lead to hypertropic scarring and keloid formation. Normal remodeling, although fast and efficient in skin, is still imperfect, and a connective tissue scar remains at the wound site1. As a result, methods are needed to optimize tissue remodeling in vivo in all cases of wound repair. Since fibroblast-mediated contraction of engineered 3-D collagen based tissues (RAFTs) represents an in vitro model of the tissue contraction and collagen remodeling that occurs in vivo2, RAFT tissue contraction studies combined with two-photon microscopy (TPM) studies are used to provide information on ways to improve tissue remodeling in vivo. In the RAFT models discussed here, tissue contraction is modulated either by application of exogenous growth factors or photodynamic therapy. During tissue contraction, TPM is used to image changes in Collagen Type I fibers in the RAFT skin models. Tissues are imaged at depth at day 15 after modulation. TPM signal analysis shows that RAFT tissues having the highest collagen density have the fastest rate of decay of fluorescent signal with depth.

The extracellular matrix (ECM) is a biological substrate composed of collagens, proteoglycans and glycoproteins that ensures proper cell migration and adhesion and keeps the cell architecture intact. The regulation of the ECM composition is a vital process strictly controlled by, among others, proteases, growth factors and adhesion receptors. As it appears, ECM remodeling is also essential for proper neuronal and glial development and the establishment of adequate synaptic signaling. Hence, disturbances in ECM functioning are often present in neurodegenerative diseases like Alzheimer’s disease. Moreover, mutations in ECM molecules are found in some forms of epilepsy and malfunctioning of ECM-related genes and pathways can be seen in, for example, cancer or ischemic injury. Low density lipoprotein receptor-related protein 1 (Lrp1) is a member of the low density lipoprotein receptor family. Lrp1 is involved not only in ligand uptake, receptor mediated endocytosis and lipoprotein transport—functions shared by low density lipoprotein receptor family members—but also regulates cell surface protease activity, controls cellular entry and binding of toxins and viruses, protects against atherosclerosis and acts on many cell signaling pathways. Given the plethora of functions, it is not surprising that Lrp1 also impacts the ECM and is involved in its remodeling. This review focuses on the role of Lrp1 and some of its major ligands on ECM function. Specifically, interactions with two Lrp1 ligands, integrins and tissue plasminogen activator are described in more detail.

Two-photon microscopy (TPM) is a non-invasive biological imaging technique that can be used to selectively image cellular activity and photosensitizer (PS) localization within highly scattering epithelial tissues at depths of approx. 200 μm with submicron resolution. The principal objective of this study was to develop a model system for understanding the impact of photodynamic therapy on cellular and extracellular matrix remodeling in biological tissues. An artificial tissue model (RAFT) composed of collagen, embedded fibroblasts, and macrophage cells has been developed for this purpose. TPM is utilized to monitor extracellular matrix remodeling following PDT by imaging collagen/elastin autofluorescence. Selective uptake of photosensitizers by specific cellular components in the matrix can also be visualized by TPM.

Two-photon microscopy (TPM) is a non-invasive biological imaging technique that can be used to selectively image cellular activity and photosensitizer (PS) localization within highly scattering epithelial tissues at depths of approx. 200 μm with submicron resolution. The principal objective of this study was to develop a model system for understanding the impact of photodynamic therapy on cellular and extracellular matrix remodeling in biological tissues. An artificial tissue model (RAFT) composed of collagen, embedded fibroblasts, and macrophage cells has been developed for this purpose. TPM is utilized to monitor extracellular matrix remodeling following PDT by imaging collagen/elastin autofluorescence. Selective uptake of photosensitizers by specific cellular components in the matrix can also be visualized by TPM.

Travel of unacclimatized subjects to a high altitude has been growing in popularity. Changes in endothelial shedding [circulating endothelial cells (ECs)] and hematopoietic stem and progenitor cells (CPCs) during physical exercise in hypobaric hypoxia, however, are not well understood. We investigated the change in ECs and CPCs when exposed to high altitude, after acute exercise therein, and after an overnight stay in hypobaric hypoxia in 11 healthy unacclimatized subjects. Blood withdrawal was done at baseline (520 m a.s.l.; baseline), after passive ascent to 3,883 m a.s.l. (arrival), after acute physical exercise (±400 m, postexercise) and after an overnight stay at 3,883 m a.s.l. (24 h). Mature blood cells, ECs, and CPCs were assessed by a hematology analyzer and flow cytometry, respectively. The presence of matrix metalloproteinases (MMPs), their activity, and hematopoietic cytokines were assessed in serum and plasma. EC and CPC concentrations significantly decreased after exercise (p = 0.019, p = 0.007, respectively). CPCs remained low until the next morning (24 h, p = 0.002), while EC concentrations returned back to baseline. MMP-9 decreased at arrival (p = 0.021), stayed low postexercise (p = 0.033), and returned to baseline at 24 h (p = 0.035 to postexercise). MMP-activity did not change throughout the study. Circulating MMP-9 concentrations, but not MMP-activity, were associated with EC concentrations (r rm = 0.48, p = 0.010). CPC concentrations were not linked to hematopoietic cytokines. Acute exercise at high altitude attenuated endothelial shedding, but did not enhance regenerative CPCs. Results were not linked to endothelial matrix remodeling or CPC mobilization. These results provide information to better understand the endothelium and immature immune system during an active, short-term sojourn at high altitude. [ABSTRACT FROM AUTHOR]

Microporous annealed particle (MAP) hydrogels are promising materials for delivering therapeutic cells. It has previously been shown that spreading and mechanosensing activation of human mesenchymal stem cells (hMSCs) incorporated in these materials can be modulated by tuning the modulus of the microgel particle building blocks. However, the effects of degradability and functionalization with different integrin-binding peptides on cellular responses has not been explored. In this work, RGDS functionalized and enzymatically degradable poly(ethylene glycol) (PEG) microgels were annealed into MAP hydrogels via thiol-ene click chemistry and photopolymerization. During cell-mediated degradation, the microgel surfaces were remodeled to wrinkles or ridges, but the scaffold integrity was maintained. Moreover, cell spreading, proliferation, and secretion of extracellular matrix proteins were significantly enhanced in faster matrix metalloproteinase degrading (KCGPQGIWGQCK) MAP hydrogels compared to non-degradable controls after 8 days of culture. We subsequently evaluated paracrine activity by hMSCs seeded in the MAP hydrogels functionalized with either RGDS or c(RRETAWA), which is specific for α5β1 integrins, and evaluated the interplay between degradability and integrin-mediated signaling. Importantly, c(RRETAWA) functionalization upregulated secretion of bone morphogenetic protein-2 overall and on a per cell basis, but this effect was critically dependent on microgel degradability. In contrast, RGDS functionalization led to higher overall vascular endothelial growth factor secretion in degradable scaffolds due to the high cell number. These results demonstrate that integrin-binding peptides can modulate hMSC behavior in PEG-based MAP hydrogels, but the results strongly depend on the susceptibility of the microgel building blocks to cell-mediated matrix remodeling. This relationship should be considered in future studies aiming to further develop these materials for stem cell delivery and tissue engineering applications. Microporous annealed particle (MAP) hydrogels are attracting increasing interest for tissue repair and regeneration and have shown superior results compared to conventional hydrogels in multiple applications. Here, we studied the impact of MAP hydrogel degradability and functionalization with different integrin-binding peptides on human mesenchymal stem cells (hMSCs) that were incorporated during particle annealing. Degradability was found to improve cell growth, spreading, and extracellular matrix production regardless of the integrin-binding peptide. Moreover, in degradable MAP hydrogels the integrin-binding peptide c(RRETAWA) was found to increase osteogenic protein expression by hMSCs compared to RGDS-functionalized MAP hydrogels. These results have important implications for the development of a MAP hydrogel-based hMSC delivery system for bone tissue engineering. Image, graphical abstract [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) plays diverse roles in several physiological and pathological conditions. In the brain, the ECM is unique both in its composition and in functions. Furthermore, almost all the cells in the central nervous system contribute to different aspects of this intricate structure. Brain ECM, enriched with proteoglycans and other small proteins, aggregate into distinct structures around neurons and oligodendrocytes. These special structures have cardinal functions in the normal functioning of the brain, such as learning, memory, and synapse regulation. In this review, we have compiled the current knowledge about the structure and function of important ECM molecules in the brain and their proteolytic remodeling by matrix metalloproteinases and other enzymes, highlighting the special structures they form. In particular, the proteoglycans in brain ECM, which are essential for several vital functions, are emphasized in detail. [ABSTRACT FROM AUTHOR]

Fibroblast activation protein (FAP), a cell surface serine protease, is upregulated on a subset of activated fibroblasts (often distinct from α-smooth muscle actin-expressing myofibroblasts) associated with matrix remodeling, including fibroblasts in idiopathic pulmonary fibrosis (Acharya PS, Zukas A, Chandan V, Katzenstein AL, Puré E. Hum Pathol 37: 352–360, 2006.). As FAP+ fibroblasts could be pivotal in either breakdown and/or production of collagen and other matrix components, the goal of this study was to define the role of FAP+ cells in pulmonary fibrosis in two established, but different, mouse models of chronic lung fibrosis: repetitive doses of intratracheal bleomycin and a single dose of an adenoviral vector encoding constitutively active TGF-β1 (Ad-TGFβ). To determine their role in fibrotic remodeling, FAP-expressing cells were depleted by injection of T cells expressing a chimeric antigen receptor specific for murine FAP in mice with established fibrosis. The contribution of FAP to the function of FAP-expressing cells was assessed in FAP knockout mice. Using histological analyses, quantification of soluble collagen content, and flow cytometry, we found that loss of FAP+ cells exacerbated fibrosis in the bleomycin model, a phenotype largely recapitulated by the genetic deletion of FAP, indicating that FAP plays a role in this model. In contrast, depletion of FAP+ cells or genetic deletion of FAP had little effect in the Ad-TGFβ model highlighting the potential for distinct mechanisms driving fibrosis depending on the initiating insult. The role of FAP in human lung fibrosis will need to be well understood to guide the use of FAP-targeted therapeutics that are being developed. [ABSTRACT FROM AUTHOR]