Extracellular Matrix Research Articles

Design and Applications of Extracellular Matrix Scaffolds in Tissue Engineering and Regeneration

Tissue engineering is a growing field with multidisciplinary players in cell biology, engineering, and medicine, aiming to maintain, restore, or enhance functions of tissues and organs. The extracellular matrix (ECM) plays fundamental roles in tissue development, maintenance, and repair, providing not only structural support, but also critical biochemical and biomechanical cues that regulate cell behavior and signaling. Although its specific composition varies across different tissue types and developmental stages, matrix molecules influence various cell functional properties in every tissue. Given the importance of ECM in morphogenesis, tissue homeostasis, and regeneration, ECM-based bioscaffolds, developed through tissue engineering approaches, have emerged as pivotal tools for recreating the native cellular microenvironment. The aim of this study is to present the main categories of these scaffolds (i.e., natural, synthetic, and hybrid), major fabrication techniques (i.e., tissue decellularization and multidimensional bioprinting), while highlighting the advantages and disadvantages of each category, focusing on biological activity and mechanical performance. Scaffold properties, such as mechanical strength, elasticity, biocompatibility, and biodegradability are essential to their function and integration into host tissues. Applications of ECM-based bioscaffolds span a range of engineering and regenerative strategies, including cartilage, bone, cardiac tissue engineering, and skin wound healing. Despite promising advances, challenges remain in standardization, scalability, and immune response modulation, with future directions directed towards improving ECM-mimetic platforms.

Heparanase-Inhibiting Polymeric Heparan Sulfate Mimetic Attenuates Myeloma Tumor Growth and Bone Metastasis.

Multiple myeloma (MM) is the second most common hematologic malignancy, heavily relying on the bone marrow microenvironment for its growth, leading to severe clinical complications. A critical factor of MM progression is the aberrant expression of heparanase (HPSE), an enzyme responsible for degrading heparan sulfate (HS) chains in the extracellular matrix (ECM) and cell surface. This degradation fosters tumor cell proliferation, migration, and resistance to chemotherapy. Consequently, targeting HPSE has emerged as a promising therapeutic strategy for MM, though clinical application of HPSE inhibitors remains limited. Herein, we report a HS-mimicking glycopolymer as a highly effective HPSE inhibitor that demonstrates a significant reduction in the viability of myeloma cells. Furthermore, this HS mimetic downregulates HPSE expression and prevents ECM degradation. In vivo analyses reveal that this polymeric HS mimetic significantly inhibited the growth of MPC-11 myeloma tumors, achieving a tumor growth inhibition (TGI) index of 85.77%, surpassing the clinically tested SST0001, which had a TGI value of 67.78%. Additionally, the glycopolymer exhibited promising efficacy against metastatic CAG human myeloma, comparable to bortezomib, a widely used proteasome inhibitor for MM treatment. A combined treatment further reduced tumor burden. These results highlight the remarkable potential of HS-mimicking glycopolymer as a promising therapeutic option for MM.

Advances in Hydrogel Drug Delivery Systems for Myocardial Infarction Treatment.

Myocardial infarction (MI) has the highest mortality rate among cardio-vascular diseases. Hydrogel biomaterials mimicking the extracellular matrix (ECM) have recently demonstrated excellent biocompatibility, low immunogenicity, favorable biode-gradability, and multifunctionality, showcasing significant potential for MI treatment. Hydrogels can provide mechanical support to the damaged myocardium, alleviating pathological remodeling. Moreover, their porous structure makes them ideal carriers for localized and sustained drug delivery. Hydrogels derived from various matrices-including polysaccharides, polypeptides, proteins, decellularized extracellular matrix (dECM), and synthetic polymers-exhibit distinct properties in terms of biocompatibility, mechanical performance, and drug delivery capacity. These hydrogels support tissue regeneration and enable targeted release of diverse therapeutics, meeting the varied therapeutic demands of myocardial repair. Specific signals within the MI microenvironment-such as low pH, overexpression of specific enzymes, and elevated reactive oxygen species (ROS) levels-can trigger responsive drug release from hydrogels, significantly enhancing therapeutic efficacy while reducing systemic side effects. This review summarizes recent advances in hydrogel-based drug delivery systems for MI treatment, focusing particularly on the characteristics and advantages of different hydrogel materials for myocardial repair. Furthermore, the responsive drug release behavior of hydrogels is analyzed in the context of the cardiac injury microenvironment, providing a reference for future research.

Anoikis resistance in gastric cancer: a comprehensive review

Abstract Gastric cancer (GC) is a predominant malignant neoplasia responsible for cancer death worldwide. Because of the difficulty in early diagnosis as well as its high metastasis rate, GC shows an increasing incidence and poor prognosis. Conventional treatments for GC, such as chemotherapy, radiotherapy, and surgical resection, still fail to achieve curative effects because of drug resistance, a mechanism that leads to a reduction of 5-year survival for GC patients. Anoikis, a particular type of programmed cell death, is activated upon cancer cell detachment from the extracellular matrix, playing a crucial role in antagonizing the progression of several malignant tumors. Because GC cells metastasize mainly in the nearby sites in the peritoneum, a better comprehension of the molecular mechanisms involved in the anchorage-independent growth as well as metastatic spreading is crucial to counteract GC progression. In this context, this review critically examines the molecular mechanisms of anoikis, key pathways and regulatory networks, and the role of anoikis resistance in GC. Furthermore, it summarizes potential therapeutic strategies for targeting anoikis-resistant cells. By collecting and analyzing existing literature, this work aims to bridge gaps in the comprehension of the relation between anoikis resistance and GC pathophysiology, providing novel insights and directions for future research in this field.

Metastasis-promoting functions of myeloid cells.

The tumor metastatic dissemination and colonization is a highly complex, multi-step process that requires cooperation between cancer and host cells. Among these, cells of myeloid lineage mobilized from the bone marrow are crucial in facilitating tumor metastatic outgrowth. Recent studies indicate that myeloid cells of bone marrow origin, including myeloid-derived suppressor cells (MDSCs), macrophages, and progenitor cells, promote distant metastasis through immunological and non-immunological mechanisms. These cells are key contributors to creating an immunosuppressive microenvironment in the invaded tissue and draining lymph nodes, protecting metastatic cells from immunosurveillance, and promoting resistance to immunotherapy. Furthermore, the myeloid cells mediate the remodeling of the extracellular matrix (ECM) in a metastatic niche via enzymes MMP9 and Hyal2, stimulating angiogenesis and establishing a metastasis-permissive microenvironment. This review describes recent findings demonstrating the metastasis-promoting functions of recruited marrow-derived myeloid cells throughout metastatic colonization and suggests new therapeutic avenues.

3D-Printing of Electroconductive MXene-Based Micro-Meshes in a Biomimetic Hyaluronic Acid-Based Scaffold Directs and Enhances Electrical Stimulation for Neural Repair Applications.

No effective treatments are currently available for central nervous system neurotrauma although recent advances in electrical stimulation suggest some promise in neural tissue repair. It is hypothesized that structured integration of an electroconductive biomaterial into a tissue engineering scaffold can enhance electroactive signaling for neural regeneration. Electroconductive 2D Ti3C2Tx MXene nanosheets are synthesized from MAX-phase powder, demonstrating excellent biocompatibility with neurons, astrocytes and microglia. To achieve spatially-controlled distribution of these MXenes, melt-electrowriting is used to 3D-print highly-organized PCL micro-meshes with varying fiber spacings (low-, medium-, and high-density), which are functionalized with MXenes to provide highly-tunable electroconductive properties (0.081±0.053-18.87±2.94 S/m). Embedding these electroconductive micro-meshes within a neurotrophic, immunomodulatory hyaluronic acid-based extracellular matrix (ECM) produced a soft, growth-supportive MXene-ECM composite scaffold. Electrical stimulation of neurons seeded on these scaffolds promoted neurite outgrowth, influenced by fiber spacing in the micro-mesh. In a multicellular model of cell behavior, neurospheres stimulated for 7 days on high-density MXene-ECM scaffolds exhibited significantly increased axonal extension and neuronal differentiation, compared to low-density scaffolds and MXene-free controls. The results demonstrate that spatial-organization of electroconductive materials in a neurotrophic scaffold can enhance repair-critical responses to electrical stimulation and that these biomimetic MXene-ECM scaffolds offer a promising new approach to neurotrauma repair.

Blocking calcium-MYC regulatory axis inhibits early dedifferentiation of chondrocytes and contributes to cartilage regeneration.

Tissue engineering technology for cartilage regeneration has increasingly emerged as a preferred method for repairing cartilage defects. However, the loss of chondrocyte-specific phenotypes during in vitro expansion, commonly referred to as dedifferentiation, impedes cartilage regeneration. Current research has yet to fully elucidate this phenomenon, hindering the development of improved cartilage regeneration. Our study employed single-cell sequencing and transposase-accessible chromatin sequencing to identify biomarkers, cell lineages and cellular characteristics within auricular chondrocytes during in vitro expansion. Our results showed that lower passage (P3) chondrocytes exhibited more dedifferentiated phenotypes with increased chromatin accessibility, while higher passage (P6) chondrocytes demonstrated hypertrophic characteristics. Furthermore, we identified that increased calcium influx was closely associated with the early dedifferentiation of chondrocytes, while inhibiting calcium signaling in early dedifferentiated cell could reverse cell phenotypes and promoted cartilage regeneration. In-depth mechanism research revealed that the expression of MYC mRNA was downregulated by increased calcium influx, which subsequently reduced SOX5/SOX6 levels, important transcription factors for chondrocytes, leading to diminished extracellular matrix production and early dedifferentiation. In conclusion, we provide a comprehensive understanding of chondrocyte dedifferentiation and propose new strategies for optimizing cartilage regeneration systems.

Engineerable mesenchymal stem cell-derived extracellular vesicles as promising therapeutic strategies for pulmonary fibrosis.

Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease characterized by fibroblast activation, excessive extracellular matrix deposition, and irreversible lung damage. Current therapeutic interventions, including anti-fibrotic medications and lung transplantation, are constrained by limited efficacy, adverse side effects, and logistical challenges. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free therapeutic approach due to their safety, scalability, and capacity to deliver bioactive cargo. These nano-sized vesicles replicate the regenerative and immunomodulatory properties of their parent cells, targeting dysregulated signaling pathways and pathological cellular phenotypes associated with PF. MSC-EVs modulate fibrosis by restoring alveolar epithelial cell function, suppressing myofibroblast activation, and regulating immune responses, such as macrophage polarization and neutrophil infiltration. However, challenges such as limited clinical efficacy and insufficient targeting hinder the broad application of MSC-EVs. Engineering strategies like preconditioning, drug loading, and surface modification can solve the above issues. Our review synthesizes PubMed/Google Scholar literature up to Feb. 2025 on MSC-EVs' targeted PF therapy and engineering strategies, aiming to translate preclinical insights into clinical use.

Editorial on sartans and skeletal muscle regeneration: rethinking fibrosis as a modifiable target in traumatic injury

Abstract Traumatic muscle injuries are common yet often lead to incomplete recovery, despite the high regenerative potential of skeletal muscle. A major obstacle is fibrosis, which replaces functional tissue with disorganised extracellular matrix, impairing contractility and healing. Central to this maladaptive response is the TGF-β1 pathway, a conserved fibrogenic signal also implicated in cardiac, hepatic, and renal fibrosis. This has prompted interest in repurposing antifibrotic agents, particularly angiotensin II receptor blockers (ARBs), or sartans. These drugs, widely used for hypertension, inhibit TGF-β1 activation via AT1R antagonism. Preclinical studies in murine models have shown that sartans reduce collagen deposition, promote muscle regeneration, and improve functional outcomes after injury. Some also activate additional regenerative pathways, such as PPAR-γ. Although no clinical trials have evaluated ARBs for muscle injuries, preliminary data from orthopaedic settings suggest potential benefits. Given their safety, availability, and biological plausibility, sartans represent a promising avenue for therapeutic modulation of fibrosis in muscle trauma. Future research should clarify optimal timing, dosing, and patient selection to translate these findings into clinical practice.

Macrophages migrate persistently and directionally upon entering 2D confinement in the presence of extracellular matrix.

Cells sense and respond to their environment in a myriad of ways. In many instances, they must integrate simultaneous cues ranging from the physical properties and composition of the extracellular matrix to guidance cues that stimulate chemotaxis or haptotaxis. How cells make sense of multiple simultaneous cues is an ongoing physiologically relevant area of research. The present study seeks to contribute to the understanding of multi-cue sensing by understanding how the transition to a confined setting with or without an added haptotactic gradient alters macrophage migration. We found that the transition to confinement is itself a directional cue capable of driving persistent migration hours after macrophages enter the confined environment. Next, we found that a haptotactic fibronectin gradient made cells even more directionally persistent under confinement. Finally, Arp2/3 complex deletion rendered macrophages unresponsive to the haptotactic gradient, but they retained directionally persistent migration due to their transition to confinement. These findings may be particularly relevant for cells that move from an adherent 2D environment into a confining 3D environment, like leukocytes and circulating tumor cells that extravasate into peripheral tissue.

Effects of Dextrazide on Metabolism of Extracellular Matrix in Mouse Organs during Chronic BCG-Induced Granulomatosis

The objective: to study effects of dextrazide on fibrotic complications in the organs of mice with chronic BCG-induced inflammation.Subjects and Methods. We used intact mice and animals that were given the BCG vaccine. Six months after the infection, infected mice were administered NaCl and dextrazide intraperitoneally for three months, after which inter-organ remodeling of the extracellular matrix was assessed.Results. Dextrazide exhibited antifibrotic activity, the mechanisms of which varied between organs. In the liver, fibrosis reduction was achieved mainly through collagen degradation, in the lungs through collagen degradation and suppression of collagen synthesis, and in the spleen through suppression of synthesis. Additionally, the levels of hyaluronan and perlecan decreased in all organs, especially in the lungs, while the levels of galactose in proteoglycans increased. Changes in collagen and proteoglycan metabolism were associated with the local regulation system of the extracellular matrix. Administration of dextrazide caused an elevated activity of degrading enzymes (hyaluronidases and matrix metalloproteinases) in the liver and, especially, in the spleen, while their activity in the lungs remained at the level in the infected mice. At the same time, the level and activity of protease inhibitors (tissue inhibitors of metalloproteinases-1 and -2, α2-macroglobulin) were reduced in the liver and lungs, while in the spleen, on the contrary, their levels were elevated and corresponded to the level in the infected mice.

Identifying congestion phenotypes using unsupervised machine learning in acute heart failure

Abstract Aims Data-driven clustering techniques may improve heart failure (HF) categorisation and provide prognostic insights. The present study aimed to elucidate the underlying pathophysiology of acute HF phenotypes based on pulmonary and systemic congestion at both the tissue (PTC, pulmonary tissue congestion; STC, systemic tissue congestion) and intravascular (PIVC, pulmonary intravascular congestion; SIVC, systemic intravascular congestion) level and to assess the association of identified phenotypes with a composite outcome of HF hospitalisation and death. Methods and results Nineteen clinical, laboratory, and echocardiographic congestion markers were analyzed using clustering techniques to identify phenotypes in patients with worsening HF in the Nancy-HF cohort (n = 741), followed by validation of the clustering model in the BIOSTAT-CHF cohort (n = 4254). Network analysis was conducted using 363 proteins to identify underlying biological pathways. Five congestion phenotypes were identified: (1) PTC-dilated left ventricle (LV), (2) PTC-HFpEF, (3) PTC, STC-atrial fibrillation (AF), (4) PIVC-dilated left atrium (LA) and LV and (5) Global congestion. Compared with the ‘PTC-dilated LV’ phenotype, the risk of composite outcome was higher in ‘PTC, STC-AF’ and ‘Global’ congestion phenotypes [adjusted HR: 1.74 (1.13–2.67) and 2.41 (1.60–3.63), respectively]. In BIOSTAT-CHF, ‘Global’ congestion phenotype was associated with significantly higher risk [HR: 1.64 (1.04–2.58)]. In network analysis, the immune response pathway was linked to all phenotypes. ‘PTC-HFpEF’ was related to lipid, protein and angiotensin metabolism, ‘PTC, STC-AF’ was related to kinase-mediated signalling, extracellular matrix organisation and TNF-regulated cell death, while ‘PIVC-dilated LA & LV’ was related to kinase-mediated signalling and hemostasis. Conclusion In worsening HF, clustering techniques identified clinical congestion profiles associated with both long-term clinical risk and differences in biomarkers, suggesting potential different underlying pathophysiologies. These clusters can be applied using the available online model to identify phenotypes as well as associated risks (https://cic-p-nancy.fr/ai-cong-hf/).

Hyaluronic Acid in Immune Response

This review summarizes the available evidence on hyaluronic acid’s (HA’s) role in immune response. HA is one of many components in the extracellular matrix that transmits signals from the extracellular microenvironment to cellular effector systems in immune cells. The final effect of these interactions depends on the type of cells and receptors used and the size of HA particles. HA’s activation of intracellular signaling pathways leads to an immune response involving the release of pro- or anti-inflammatory cytokines and chemokines. These play a crucial role in defense mechanisms, such as protecting against pathogens and tissue healing after injuries. HA, as a signaling particle, is also involved in the intensification of the cytokine storm during COVID-19. Multifold increases in HA content in the lungs and the strength of its impact on the immune system define an “HA storm”. The molecular mechanisms involved in inflammation and initiation, including the promotion of cancer, also begin in the microenvironment, and hyaluronic acid is a key element. In this paper, we focus on intra- and intercellular signaling pathways using HA participation rather than injection preparation based on HA use for esthetic treatment.

Porous Decellularized Nerve Grafts Facilitate Recellularization and Nerve Regeneration in a Rat Model of Critical Long-Gap Peripheral Nerve Injury.

Severe peripheral nerve injury (PNI) requiring nerve graft remains a clinical challenge due to limitations associated with currently available grafts. While decellularized nerve grafts (DNGs) are commonly used, their efficacy is largely restricted to short-gap repairs due to their acellular and dense structure, which poses a persistent challenge in the treatment of critical long-gap nerve defects. It is hypothesized that making porous DNGs (PDNGs) can create a suitable microenvironment that would facilitate the cell infiltration, recellularization, and further axonal growth to enhance nerve regeneration. In this study, PDNGs are generated and their ability are evaluated to support cell proliferation and penetration in vitro. Their potential to promote nerve regeneration in vivo using a rat model of sciatic nerve transection followed by implantation of a 30mm-long graft is further evaluated. It is found that PDNGs facilitated greater cellular infiltration within the grafts and enhanced angiogenesis compared to the traditional compact DNGs. In vivo analysis further reveals thicker myelin sheaths in the PDNG group, along with improved axonal alignment. Taken together, PDNGs enhanced nerve regeneration by reorganizing the porous structure into an extracellular matrix that supported cell infiltration, revascularization, and remyelination, all of which contribute to nerve repair.

Role of Perturbations of Epigenetic Processes in Cardiac Hypertrophy and Fibrotic Scarring.

Cardiac hypertrophy and fibrotic scarring are fundamental contributors to the progression of heart failure and are associated with poor clinical outcomes. Recent advancements in cardiovascular research have emphasized the central role of epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs, in regulating the gene expression changes underlying these pathological processes. A comprehensive literature review was conducted using databases, including PubMed, Scopus, and Web of Science. Predefined keywords and inclusion/exclusion criteria were applied to select relevant studies focusing on epigenetic regulation in cardiac hypertrophy and fibrosis. Particular attention was given to studies involving DNA methyltransferases, TET enzymes, histone deacetylases, demethylases, chromatin remodeling complexes, and non-coding RNAs. Methodological transparency was ensured through a structured screening and data extraction process. The review highlights the dynamic regulation of cardiac gene expression by epigenetic factors. DNA methylation and demethylation influence fibroblast activation and extracellular matrix deposition. Histone-modifying enzymes reshape chromatin architecture, altering transcriptional accessibility. Chromatin remodeling complexes regulate nucleosome positioning during stress responses. Emerging insights into epigenetic memory and transgenerational epigenetic inheritance further reveal the heritable nature of disease susceptibility. These epigenetic perturbations collectively orchestrate the maladaptive gene expression patterns seen in cardiac hypertrophy and fibrosis. Understanding their roles provides a mechanistic basis for identifying biomarkers and therapeutic targets. The review also discusses recent omics-based technologies that aid in the characterization of epigenetic alterations, thereby expanding diagnostic and therapeutic horizons. Epigenetic mechanisms are pivotal in the development and progression of cardiac hypertrophy and fibrosis. Advances in epigenomic profiling are facilitating the development of precise and targeted interventions. This review underscores the potential of epigenetic therapies and calls for intensified research efforts to translate these findings into clinical applications.

Advanced Injectable Human‐Derived Microgels for Improved Cell Delivery and Tissue Regeneration

Abstract The development of effective cell delivery therapies faces challenges regarding cell viability and retention after injection. Hydrogel‐based materials, designed to mimic extracellular matrix components for cell protection during injection and to enhance local availability, often rely on animal‐derived components that raise immunogenicity concerns. Alternatively, those employing polysaccharides and synthetic polymers may exhibit suboptimal cell adhesive properties. This study showcases the development of injectable human protein‐derived cell carrier microgels made from methacryloyl platelet lysates. These microgels sustain cell viability by providing an enriched and cost‐effective environment of growth factors and proteins while promoting the outward migration of mesenchymal stem cells through controlled enzyme‐mediated degradation. Employing a solvent‐free and reproducible method using superhydrophobic surfaces, human‐derived microgels are successfully fabricated via light irradiation, with sizes adjustable by varying droplet volume. Additionally, the incorporation of collagenase facilitates enzyme‐mediated cell migration without compromising viability. Injectability tests confirm that microgel administration preserves both size and morphology, and their effectiveness in filling irregular defects in a porcine tissue highlights their suitability for therapeutic applications. Ultimately, these microgels can be modified to include magnetic nanoparticles, enabling spatial control and fixation using an external magnetic field, and potential imaging capabilities, positioning them as promising candidates for personalized cell therapies.

Contribution of a LysM domain-containing protein regulated by VicRK to streptococcus sanguinis virulence

ABSTRACT Streptococcus sanguinis is a commensal member of the oral microbiome involved in opportunistic cardiovascular infections. In the present study, we investigated the contribution of ssa_0094, a gene strongly regulated by the two-component system VicRK, to functions associated with biofilm formation, immune evasion and cardiovascular virulence. In silico analysis showed that ssa_0094 encodes a protein with a LysM domain, which is highly conserved among S. sanguinis. Although not an ubiquitous gene, several commensal streptococcal species of the oronasopharynx and zoonotic strains of Streptococcus suis harbour ssa_0094 homologues. A ssa_0094 isogenic mutant (SK0094) showed defects in initiating biofilms on saliva-coated surfaces, reduced hydrophobicity and lower production of amyloid-like components when compared to the parent strain (SK36) or to the complemented mutant (SK0094+), although it showed mild changes in DNA release and production of H2O2. Deletion of ssa_0094 also impaired S. sanguinis binding to multiple human glycoproteins of plasma and/or extracellular matrix (ECM) (plasminogen, fibronectin, fibrinogen, fibrin, type I collagen and elastin), and promoted clear increases in C3b deposition, and in induction of NEtosis by neutrophils of peripheral blood. Moreover, SK0094 showed impaired invasiveness into HCAEC cells and reduced ex vivo persistence in human blood, but no clear change in virulence in a Galleria mellonella infection model. These findings indicate that ssa_0094 is highly conserved within S. sanguinis strains required for biofilm initiation as well as for multiple functions of immune evasion and cardiovascular virulence in S. sanguinis in a host-specific fashion.

Dendrobium officinale-derived nanovesicles: a natural therapy for comprehensive regulation of angiogenesis, inflammation, and tissue repair to enhance skin wound healing

Skin wound healing is a multifaceted biological process involving dynamic interactions among various cells and signaling molecules. Angiogenesis is a key component of this repair process. Dendrobium officinale, a traditional medicinal plant, has shown therapeutic promise, particularly through its bioactive nanovesicles. This study investigates the therapeutic potential of Dendrobium officinale-derived nanovesicles (DDNVs) in regulating angiogenesis, inflammation, and tissue repair, to promote enhanced skin wound healing. A full-thickness mouse skin wound model was used to evaluate the in vivo effects of DDNVs on wound closure, angiogenesis, and collagen remodeling. Histological staining (H&E and Masson’s trichrome) and CD31 immunofluorescence were performed. In vitro, DDNVs were tested on Human umbilical vein endothelial cells(HUVECs) and Human keratinocyte cells (HaCaT) cells to assess cell proliferation, migration, and angiogenesis. Confocal microscopy was used to track cellular uptake. Activation of the Akt/eNOS pathway and expression of key genes related to inflammation and matrix remodeling were evaluated by Western blotting and qPCR. DDNVs significantly accelerated wound healing and promoted angiogenesis in vivo, as evidenced by enhanced CD31 expression and collagen remodeling. In vitro, DDNVs entered cells efficiently and stimulated HUVEC and HaCaT proliferation and migration. This was accompanied by activation of the Akt/eNOS signaling pathway, increased expression of eNOS and VEGFR-2, upregulation of extracellular matrix(ECM) components (Vimentin, Fibronectin, COL1A1), and suppression of inflammatory markers such as ICAM-1 and IL-1β. DDNVs exhibit strong potential to enhance skin wound healing by promoting angiogenesis, improving tissue repair, and modulating inflammation. These findings support the clinical development of DDNVs as a novel, plant-derived nanotherapeutic for chronic wound treatment and skin regeneration.

Biventricular electromechanical dysfunction and molecular remodeling in a rat model of advanced pulmonary arterial hypertension

BackgroundPulmonary arterial hypertension (PAH) is a severe condition characterized by elevated pulmonary arterial pressure, leading to significant morbidity and mortality. Despite ongoing research, its pathophysiology remains incompletely understood. Traditionally, PAH has been regarded as predominantly affecting the right ventricle (RV), often overlooking its potential impact on the left ventricle (LV), particularly in patients with preserved LV ejection fraction (EF).MethodsIn this study, we investigate the late-stage effects of PAH on both electrical and mechanical functions, as well as their coupling, in each ventricle using the monocrotaline-treated rat model. Specifically, an integrative approach combining in-vivo epicardial potential mapping, in-situ video kinematic evaluation, and transcriptomic analysis was performed on rats injected with monocrotaline (MCT, n = 22) or saline solution (Physio, n = 16).ResultsOur findings reveal that PAH induces global increases in refractoriness from 88.8 ± 1.9 ms to 152.7 ± 3.9 ms and reductions in conduction velocity in the RV from 0.59 ± 0.01 m/s to 0.55 ± 0.01 m/s and from 0.28 ± 0.01 m/s to 0.25 ± 0.01 m/s along and across the fiber orientation, respectively. Notably, a significant increase in electromechanical delay from 24.9 ± 1.2 ms to 35.8 ± 5.2 ms was also observed in the RV. In the LV, PAH also results in increased refractoriness from 95.4 ± 3.0 ms to 140.0 ± 11.5 ms and reduced transverse conduction velocity by 14%, despite preserved EF. Transcriptomic analysis indicates that while both ventricles exhibit upregulation of extracellular matrix remodeling-related genes, the RV primarily shows downregulation of electromechanical-related genes. On the contrary, an upregulation of the inflammatory pathways was detected mainly in the LV, alongside a downregulation of mitochondrial metabolism-related genes.ConclusionsOur findings revealed that both ventricles showed structural remodeling but only the RV underwent electromechanical alteration, while the LV displayed metabolic and inflammatory alteration. This was further validated by the preserved EF in the advanced stage of PAH. Our work highlights that a more comprehensive understanding of PAH pathophysiology can lead to targeted therapeutic strategies, challenging the conventional RV-centric perspective.

Lysosome-Targeting Nanochimeras Attenuating Liver Fibrosis by Interconnected Transforming Growth Factor-β Reduction and Activin Receptor-Like Kinase 5 Degradation.

Liver fibrosis, characterized by excessive extracellular matrix (ECM) deposition, is predominantly driven by activated hepatic stellate cells (HSCs) through the TGF-β-Smad2/3 signaling pathway. A critical barrier to effective treatment has been the compensatory upregulation of the receptors, which often limits the efficacy of targeted TGF-β inhibition strategies. Our current study introduces a lysosomal targeting degradation chimera (MAP) composed of an antioxidative polydopamine (PDA) nanoparticle conjugated to the ligands specifically targeting ALK5, a TGF-β receptor I, and cation-independent mannose 6-phosphate receptor (CI-M6PR). Notably, CI-M6PR is highly upregulated on the surface of the activated HSCs. These MAPs preferentially accumulated in the fibrotic liver tissues, reduced TGF-β production by scavenging reactive oxygen species, and simultaneously recognized the activated HSCs to facilitate targeted lysosomal degradation of ALK5. The interconnected dual-enhanced mechanisms effectively inhibited the TGF-β-Smad2/3 signaling pathway in HSCs, thus diminishing ECM secretion and attenuating liver fibrosis. Together, the current findings, substantiated by in vitro and in vivo studies, demonstrate potent antifibrotic capacities of MAPs, marking an essential advancement in lysosome-targeting degradation technology for liver fibrosis treatment and expanding potential therapeutic options for this intractable condition.