Hostile Microenvironment Research Articles

Uncovering the protective role of lipid droplet accumulation against acid-induced oxidative stress and cell death in osteosarcoma

Extracellular acidosis stemming from altered tumor metabolism promotes cancer progression by enabling tumor cell adaptation to the hostile microenvironment. In osteosarcoma, we have previously shown that acidosis increases tumor cell survival alongside substantial lipid droplet accumulation. In this study, we explored the role of lipid droplet formation in mitigating cellular stress induced by extracellular acidosis in osteosarcoma cells, thereby enhancing tumor survival during progression. Specifically, we examined how lipid droplets shield against reactive oxygen species induced by extracellular acidosis. We demonstrated that lipid droplet biogenesis is critical for acid-exposed tumor cell survival, as it starts shortly after acid exposure (24 h) and inversely correlates with ROS levels (DCFH-DA assay), lipid peroxidation (Bodipy assay), and the antioxidant response, as also revealed by NRF2 transcript. Additionally, extracellular metabolites, such as lactate, and interaction with mesenchymal stromal cells within the tumor microenvironment intensify lipid droplet build-up in osteosarcoma cells. Critically, upon targeting two key proteins implicated in LD formation - PLIN2 and DGAT1 - cell viability significantly declined while ROS production escalated. In summary, our findings underscore the vital reliance of acid-exposed tumor cells on lipid droplet formation to scavenge oxidative stress. We conclude that the rewiring of lipid metabolism driven by microenvironmental cues is of paramount importance for the survival of metabolically altered osteosarcoma cells in acidic condition. Overall, we suggest that targeting key members of lipid droplet biogenesis may eradicate more aggressive and resistant tumor cells, uncovering potential new treatment strategies for osteosarcoma.

K2FeO4-Enhanced Photodynamic Therapy of Breast Cancer via In Situ Synthesis of Fe2O3 and O2.

Photodynamic Therapy (PDT) offers a promising minimally invasive treatment for breast cancer, but its efficacy is limited by the hostile tumor microenvironment (TME), including hypoxia and high glutathione (GSH) levels. Although various strategies to improve oxygen concentration or reduce reactive oxygen species (ROS) resistance for enhanced PDT have been explored, they typically require intricate design and complex synthesis of multifunctional nanocarriers. Thus, this study introduces a facile K2FeO4-induced strategy to enhance PDT efficiency in breast cancer through the tumor in situ synthesis of Fe2O3 and O2. Inspired by the successful application of K2FeO4 in ecological remediation and hemostasis, K2FeO4 reacts with GSH, biological system, H2O2, and water, to generate Fe2O3 and O2. Intratumoral injection of K2FeO4 improves the TME, followed by Ce6 administration to enhance PDT through synergistic ferroptosis. This approach boosts PDT efficacy significantly by increasing ROS generation, lipid peroxidation, and inhibiting GSH and GPX4. Proteomic analysis revealed alterations in key pathways, including endocytosis and energy metabolism. This K2FeO4-PDT strategy creates a positive feedback loop by enhancing oxidative stress, providing an interesting and promising approach to PDT.

Radiotherapy enhances the anti-tumor effect of CAR-NK cells for hepatocellular carcinoma

BackgroundChimeric antigen receptor (CAR)-NK cell therapy has shown remarkable clinical efficacy and safety in the treatment of hematological malignancies. However, this efficacy was limited in solid tumors owing to hostile tumor microenvironment (TME). Radiotherapy is commonly used for solid tumors and proved to improve the TME. Therefore, the combination with radiotherapy would be a potential strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors.MethodsGlypican-3 (GPC3) was used as a target antigen of CAR-NK cell for hepatocellular carcinoma (HCC). To promote migration towards HCC, CXCR2-armed CAR-NK92 cells targeting GPC3 were first developed, and their cytotoxic and migration activities towards HCC cells were evaluated. Next, the effects of irradiation on the anti-tumor activity of CAR-NK92 cells were assessed in vitro and in HCC-bearing NCG mice. Lastly, to demonstrate the potential mechanism mediating the sensitized effect of irradiation on CAR-NK cells, the differential gene expression profiles induced by irradiation were analyzed and the expression of some important ligands for the NK-cell activating receptors were further determined by qRT-PCR and flow cytometry.ResultsIn this study, we developed CXCR2-armed GPC3-targeting CAR-NK92 cells that exhibited specific and potent killing activity against HCC cells and the enhanced migration towards HCC cells. Pretreating HCC cells with irradiation enhanced in vitro anti-HCC effect and migration activity of CXCR2-armed CAR-NK92 cells. We further found that only high-dose (8 Gy) but not low-dose (2 Gy) irradiation in one fraction could significantly enhanced in vivo anti-HCC activity of CXCR2-armed CAR-NK92 cells. Irradiation with 8 Gy significantly up-regulated the expression of NK cell-activating ligands on HCC cells.ConclusionsOur results indicate the evidence that irradiation could efficiently enhance the anti-tumor effect of CAR-NK cells in solid tumor model. The combination with radiotherapy would be an attractive strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors.

Thermosensitive hyaluronic acid-manganese-capsaicin complex nanogel improving NKG2D/CAR-T melanoma treatment through adjusting tumor microenvironment

Intratumorally injection of CAR-T cells to treat melanoma can reduce the incidence of systemic side effects and ensure an adequate concentration of CAR-T cells. However, few targeting ligands and hostile tumor microenvironment (TME) inhibit the CAR-T cells' survival and infiltration. An in situ hyaluronic acid‑manganese-capsaicin complex nanogel (HA-Mn-CAP Gel) was designed by forming complex nanogel based on the main skeleton material of hyaluronic acid (HA). It targeted CD44 and TRPV1 receptors through HA and CAP, concentrated and released Mn at melanoma, subsequently relieving the hypoxia in the tumor and increasing the expression of CAR-T cells' specific ligands. Cell experiments showed that HA-Mn-CAP Gel significantly enhanced the expression of representative NKG2D ligands (MICA/B and ULBP2/5/6) >2.7 times on A375 melanoma cells. Sequential administration of HA-Mn-CAP Gel and NKG2D/CAR-T increased the tumor inhibition rate about 1.5 times that of the NKG2D/CAR-T group in melanoma-bearing NSG mice. The results of immunohistochemistry and immunofluorescence assays showed that the combined HA-Mn-CAP Gel and NKG2D/CAR-T significantly increased the proliferation and infiltration of T cells, especially for CD8+ cells. Therefore, the new promising strategy of increasing the target ligand expression and adjusting TME before administering CAR-T cells is suitable for treating solid tumors.

Therapeutic advantage of combinatorial CAR T cell and chemo-therapies.

Chimeric antigen receptor (CAR) T cell therapies have transformed outcomes for many patients with hematological malignancies. However, some patients do not respond to CAR T cell treatment, and adapting CAR T cells for solid and brain tumors has been met with many challenges including a hostile tumor microenvironment and poor CAR T cell persistence. Thus, it is unlikely that CAR T cell therapy alone will be sufficient for consistent, complete tumor clearance across cancer patients. Combinatorial therapies of CAR T cells and chemotherapeutics are a promising approach for overcoming this as chemotherapeutics could augment CAR T cells for improved anti-tumor activity or work in tandem with CAR T cells to clear tumors. Herein, we review efforts towards achieving successful CAR T cell and chemical drug combination therapies. We focus on combination therapies with approved chemotherapeutics as these will be more easily translated to the clinic, but also review non-approved chemotherapeutics and drug screens designed to reveal promising new CAR T cell and chemical drug combinations. Together, this review highlights the promise of CAR T cell and chemotherapy combinations with specific focus on how combinatorial therapy overcomes challenges faced by either monotherapy and supports the potential of this therapeutic strategy to improve outcomes for cancer patients. Significance Statement Improving currently available CAR T cell products via combinatorial therapy with chemotherapeutics has the potential to drastically expand the types of cancers and number of patients that could benefit from these therapies when neither alone has been sufficient to achieve tumor clearance. Herein, we provide a thorough review of the current efforts towards studying CAR T and chemotherapy combinatorial therapies and provide perspectives on optimal ways to identify new and effective combinations moving forward.

The Epigenetic Hallmarks of Cancer.

Cancer is a complex disease in which several molecular and cellular pathways converge to foster the tumoral phenotype. Notably, in the latest iteration of the cancer hallmarks, "nonmutational epigenetic reprogramming" was newly added. However, epigenetics, much like genetics, is a broad scientific area that deserves further attention due to its multiple roles in cancer initiation, progression, and adaptive nature. Herein, we present a detailed examination of the epigenetic hallmarks affected in human cancer, elucidating the pathways and genes involved, and dissecting the disrupted landscapes for DNA methylation, histone modifications, and chromatin architecture that define the disease. Significance: Cancer is a disease characterized by constant evolution, spanning from its initial premalignant stages to the advanced invasive and disseminated stages. It is a pathology that is able to adapt and survive amidst hostile cellular microenvironments and diverse treatments implemented by medical professionals. The more fixed setup of the genetic structure cannot fully provide transformed cells with the tools to survive but the rapid and plastic nature of epigenetic changes is ready for the task. This review summarizes the epigenetic hallmarks that define the ecological success of cancer cells in our bodies.

Scaffold-free 3D culture systems for stem cell-based tissue regeneration.

Recent advances in scaffold-free three-dimensional (3D) culture methods have significantly enhanced the potential of stem cell-based therapies in regenerative medicine. This cutting-edge technology circumvents the use of exogenous biomaterial and prevents its associated complications. The 3D culture system preserves crucial intercellular interactions and extracellular matrix support, closely mimicking natural biological niches. Therefore, stem cells cultured in 3D formats exhibit distinct characteristics, showcasing their capabilities in promoting angiogenesis and immunomodulation. This review aims to elucidate foundational technologies and recent breakthroughs in 3D scaffold-free stem cell engineering, offering comprehensive guidance for researchers to advance this technology across various clinical applications. We first introduce the various sources of stem cells and provide a comparative analysis of two-dimensional (2D) and 3D culture systems. Given the advantages of 3D culture systems, we delve into the specific fabrication and harvesting techniques for cell sheets and spheroids. Furthermore, we explore their applications in pre-clinical studies, particularly in large animal models and clinical trials. We also discuss multidisciplinary strategies to overcome existing limitations such as insufficient efficacy, hostile microenvironments, and the need for scalability and standardization of stem cell-based products.

CAR T cells in solid tumors and metastasis: paving the way forward.

CAR T cell therapy, hailed as a breakthrough in cancer treatment due to its remarkable outcomes in hematological malignancies, encounters significant hurdles when applied to solid tumors. While notable responses to CAR T cells remain sporadic in these patients, challenges persist due to issues such as on-target off-tumor toxicity, difficulties in their trafficking and infiltration into the tumor, and the presence of a hostile and immunosuppressive microenvironment. This review aims to explore recent endeavors aimed at overcoming these obstacles in CAR T cell therapy for solid tumors. Specifically, we will delve into promising strategies for enhancing tumor specificity through antigen targeting, addressing tumor heterogeneity, overcoming physical barriers, and counteracting the immune-suppressive microenvironment.

In Vivo Monitoring and Magnetically‐Enhanced Delivery of CAR T‐Cells to Solid Tumor

AbstractChimeric antigen receptor (CAR) T‐cell therapy demonstrates efficacy for the treatment of hematologic cancers, but remains challenging in solid tumors because of the hostile tumor microenvironment and heterogeneity that restrict the infiltration and activity of CAR T‐cells. The lack of clinical imaging methods to monitor CAR T‐cell therapy in patients limits the potential to enhance the therapeutic approach and predict patient response. Here, a straightforward, non‐invasive method for Magnetic Resonance Imaging (MRI) tracking and magnetic targeting of CAR T‐cells to enhance T‐cell trafficking to solid tumors, in a setting that can be deployed in clinics, is reported. Iron oxide nanoparticles are loaded into T‐cells, allowing MRI detection and magnetic cell guidance, while preserving T‐cell viability, functions, and CAR specificity to target epidermal growth factor receptor (EGFR)‐expressing tumors. Longitudinal MRI monitoring of T‐cells over 14 days reveals differences in tumor infiltration rates and antitumor efficacy between EGFR‐targeted CAR T‐cells and non‐transduced T‐cell. Moreover, an external magnet placed over the tumor enhances the infiltration of CAR T‐cells and increases their antitumor effect. MRI monitoring and magnetic guidance represent a dual‐pronged clinically feasible therapeutic strategy to control and promote CAR T‐cells delivery into solid tumors, thereby improving the precision, efficacy, and safety of the treatment.

The Art of Nano-CAR T Cells in Ovarian Cancer Management

The combination of nanotechnology and CAR T-cell therapeutics heralds a paradigm shift in the management of ovarian cancer, a disease characterized by substantial obstacles such as antigenic heterogeneity, an immunosuppressive tumor microenvironment, and physical barriers to treatment efficacy. This paper examines these obstacles critically and proposes innovative nano-engineered solutions, such as the development of nano-CAR T cells and nanoparticle-mediated delivery of CAR genes and immunomodulatory agents, as strategic approaches to improve CAR T-cell delivery, survival, and function within the hostile tumor microenvironment. The convergence of these two disciplines represents a promising strategy for overcoming these obstacles and optimizing the therapeutic potential of CAR T cells in solid malignancies. To translate this promising approach into a viable clinical reality in the fight against ovarian cancer, however, additional scientific research and rigorous clinical trials are required to ensure safety, optimize the design, and establish standardized production and application protocols.

Harnessing the Power of NK Cell Receptor Engineering as a New Prospect in Cancer Immunotherapy.

Natural killer (NK) cells have recently gained popularity as an alternative for cancer immunotherapy. Adoptive cell transfer employing NK cells offers a safer therapeutic option compared to T-cell-based therapies, due to their significantly lower toxicity and the availability of diverse autologous and allogeneic NK cell sources. However, several challenges are associated with NK cell therapies, including limited in vivo persistence, the immunosuppressive and hostile tumor microenvironment (TME), and the lack of effective treatments for solid tumors. To address these limitations, the modification of NK cells to stably produce cytokines has been proposed as a strategy to enhance their persistence and proliferation. Additionally, the overexpression of activating receptors and the blockade of inhibitory receptors can restore the NK cell functions hindered by the TME. To further improve tumor infiltration and the elimination of solid tumors, innovative approaches focusing on the enhancement of NK cell chemotaxis through the overexpression of chemotactic receptors have been introduced. This review highlights the latest advancements in preclinical and clinical studies investigating the engineering of activating, inhibitory, and chemotactic NK cell receptors; discusses recent progress in cytokine manipulation; and explores the potential of combining the chimeric antigen receptor (CAR) technology with NK cell receptors engineering.

TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells

Metabolic rewiring promotes cancer cell adaptation to a hostile microenvironment, representing a hallmark of cancer. This process involves mitochondrial function and is mechanistically linked to the balance between mitochondrial biogenesis (MB) and mitophagy. The molecular chaperone TRAP1 is overexpressed in 60–70% of human colorectal cancers (CRC) and its over-expression correlates with poor clinical outcome, being associated with many cancer cell functions (i.e. adaptation to stress, protection from apoptosis and drug resistance, protein synthesis quality control, metabolic rewiring from glycolysis to mitochondrial respiration and vice versa). Here, the potential new role of TRAP1 in regulating mitochondrial dynamics was investigated in CRC cell lines and human CRCs. Our results revealed an inverse correlation between TRAP1 and mitochondrial-encoded respiratory chain proteins both at transcriptional and translational levels. Furthermore, TRAP1 silencing is associated with increased mitochondrial mass and mitochondrial DNA copy number (mtDNA-CN) as well as enhanced MB through PGC-1α/TFAM signalling pathway, promoting the formation of new functioning mitochondria and, likely, underlying the metabolic shift towards oxidative phosphorylation. These results suggest an involvement of TRAP1 in regulating MB process in human CRC cells.Key messagesTRAP1 inversely correlates with protein-coding mitochondrial gene expression in CRC cells and tumours.TRAP1 silencing correlates with increased mitochondrial mass and mtDNA copy number in CRC cells.TRAP1 silencing favours mitochondrial biogenesis in CRC cells.

CircRNAs expression profile and potential roles of circRERE-PMN in pre-metastatic lungs.

The successful pulmonary metastasis of malignant cancer cells depends on the survival of circulating tumor cells in a distant and hostile microenvironment. The formation of a pre-metastatic niche (PMN) creates a supportive environment for subsequent metastasis. Circular RNAs (circRNAs) are increasingly acknowledged as crucial elements in the mechanisms of metastasis due to their stable structures and functions, making them promising early metastasis detection markers. However, the specific expression patterns and roles of circRNAs in the lungs before metastasis remain largely unexplored. Our research aims to chart the circRNA expression profile and assess their impact on the lung PMN. We developed a lung PMN model and employed comprehensive RNA sequencing to analyze the differences in circRNA expression between normal and pre-metastatic lungs. We identified 38 significantly different circRNAs, primarily involved in metabolism, apoptosis, and inflammation pathways. We then focused on one specific circRNA, circ:chr4:150406196 - 150406664 (circRERE-PMN), which exhibited a significant change in expression and was prevalent in myeloid-derived suppressor cells (MDSCs), alveolar epithelial cells, and macrophages within the pre-metastatic lung environment. CircRERE-PMN was found to potentially regulate apoptosis and the expression of cytokines and chemokines through its interaction with the downstream target HUR in alveolar epithelial cells. Overall, our study highlights the crucial role of circRNAs in the formation of lung PMNs, supporting their potential as diagnostic or therapeutic targets for lung metastasis.

Mitochondria Transplantation to Bone Marrow Stromal Cells Promotes Angiogenesis During Bone Repair.

Angiogenesis is crucial for successful bone defect repair. Co-transplanting Bone Marrow Stromal Cells (BMSCs) and Endothelial Cells (ECs) has shown promise for vascular augmentation, but it face challenges in hostile tissue microenvironments, including poor cell survival and limited efficacy. In this study, the mitochondria of human BMSCs are isolated and transplanted to BMSCs from the same batch and passage number (BMSCsmito). The transplanted mitochondria significantly boosted the ability of BMSCsmito-ECs to promote angiogenesis, as assessed by in vitro tube formation and spheroid sprouting assays, as well as in vivo transplantation experiments in balb/c mouse and SD rat models. The Dll4-Notch1 signaling pathway is found to play a key role in BMSCsmito-induced endothelial tube formation. Co-transplanting BMSCsmito with ECs in a rat cranial bone defect significantly improves functional vascular network formation, and improve bone repair outcomes. These findings thus highlight that mitochondrial transplantation, by acting through the DLL4-Notch1 signaling pathway, represents a promising therapeutic strategy for enhancing angiogenesis and improving bone repair. Hence, mitochondrial transplantation to BMSCS as a therapeutic approach for promoting angiogenesis offers valuable insights and holds much promise for innovative regenerative medicine therapies.

(Invited) Supramolecular Hydrogels for Fabrications of Wearable Sensors and Medical Scaffolds

While hydrogels have enabled a variety of applications in wearable sensors and electronic skins, they are susceptible to fatigue fracture during their cyclic deformations owing to the inefficient fatigue resistance. Design of hydrogels with excellent mechanical properties and highly stable performance during the practical long-term applications of produced wearable sensors and medical scaffolds remains a tremendous challenge. The supramolecular hydrogels with the topological networks consisting of mechanical interlocked units lead to high toughness and robust fracture resistance. In our studies, a type of polymerizable crosslinker is assembled by the precise host-guest recognition, which is then photocured to construct the conductive hydrogel system. This polymerizable crosslinker having the mobile junctions simultaneously endows the resulting conductive hydrogels with three important features in the applications of strain sensors and scaffolds: (1) high stretchability along with superior fatigue resistance, (2) hydrogels applicable for sensors with high conductivity and sensitivity, and (3) suitability for 3D printing fabrication of sensors with altitude complexity. In addition, we have developed a biological metabolism-inspired hydrogel from the dynamic cross-linked natural polymer for reshaping the hostile rheumatoid arthritis microenvironment. The engineered hydrogel exhibits injectable performance and self-healing ability. When the hydrogel is engineered as a 3D stem cell-laden scaffold, the satisfactory reconstruction of large-scale bone defects in rheumatoid arthritis is achieved with effective antioxidant and anti-inflammatory performance simultaneously.

Proton radiation boosts the efficacy of mesothelin-targeting chimeric antigen receptor T cell therapy in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) represents a challenge in oncology, with limited treatment options for advanced-stage patients. Chimeric antigen receptor T cell (CAR T) therapy targeting mesothelin (MSLN) shows promise, but challenges such as the hostile immunosuppressive tumor microenvironment (TME) hinder its efficacy. This study explores the synergistic potential of combining proton radiation therapy (RT) with MSLN-targeting CAR T therapy in a syngeneic PDAC model. Proton RT significantly increased MSLN expression in tumor cells and caused a significant increase in CAR T cell infiltration into tumors. The combination therapy reshaped the immunosuppressive TME, promoting antitumorigenic M1 polarized macrophages and reducing myeloid-derived suppressor cells (MDSC). In a flank PDAC model, the combination therapy demonstrated superior attenuation of tumor growth and improved survival compared to individual treatments alone. In an orthotopic PDAC model treated with image-guided proton RT, tumor growth was significantly reduced in the combination group compared to the RT treatment alone. Further, the combination therapy induced an abscopal effect in a dual-flank tumor model, with increased serum interferon-γ levels and enhanced proliferation of extratumoral CAR T cells. In conclusion, combining proton RT with MSLN-targeting CAR T therapy proves effective in modulating the TME, enhancing CAR T cell trafficking, and exerting systemic antitumor effects. Thus, this combinatorial approach could present a promising strategy for improving outcomes in unresectable PDAC.

The Spectrum of CAR Cellular Effectors: Modes of Action in Anti-Tumor Immunity.

Chimeric antigen receptor-T cells have spearheaded the field of adoptive cell therapy and have shown remarkable results in treating hematological neoplasia. Because of the different biology of solid tumors compared to hematological tumors, response rates of CAR-T cells could not be transferred to solid entities yet. CAR engineering has added co-stimulatory domains, transgenic cytokines and switch receptors to improve performance and persistence in a hostile tumor microenvironment, but because of the inherent cell type limitations of CAR-T cells, including HLA incompatibility, toxicities (cytokine release syndrome, neurotoxicity) and high costs due to the logistically challenging preparation process for autologous cells, the use of alternative immune cells is gaining traction. NK cells and γδ T cells that do not need HLA compatibility or macrophages and dendritic cells with additional properties such as phagocytosis or antigen presentation are increasingly seen as cellular vehicles with potential for application. As these cells possess distinct properties, clinicians and researchers need a thorough understanding of their peculiarities and commonalities. This review will compare these different cell types and their specific modes of action seen upon CAR activation.

Engineered CAR-NK Cells with Tolerance to H2O2 and Hypoxia Can Suppress Postoperative Relapse of Triple-Negative Breast Cancers.

Surgical resection is a primary treatment option for patients with triple-negative breast cancer (TNBC), but it is associated with a high rate of postoperative local and metastatic relapse. Although chimeric antigen receptor-engineered NK (CAR-NK) cell therapy can specifically recognize and eradicate tumor cells, its therapeutic potency toward TNBCs is markedly suppressed by the hostile tumor microenvironment, which restricts the infiltration, survival, and effector functions of CAR-NK cells inside tumor masses. In this study, HER1-overexpressing TNBC-targeted CAR-NK (HER1-CAR-NK) cells were genetically engineered with catalase to endow them with tolerance toward the high levels of oxidative stress and hypoxia inside TNBC tumors through the catalytic decomposition of hydrogen peroxide, which is a principle reactive oxygen species inside tumors, into O2. We refer to these cells as HER1-CAR-CAT-NK cells. Upon intratumoral fixation with an injectable alginate hydrogel, HER1-CAR-CAT-NK cells enabled sustained tumor hypoxia attenuation and exhibited markedly enhanced persistence and effector functions inside TNBC tumors. As a result, locoregional HER1-CAR-CAT-NK cell therapy not only inhibited the growth of local primary residual tumors but also elicited systemic antitumor activity to suppress the growth of distant tumors. This study highlights that genetic engineering of HER1-CAR-NK cells with catalase is a promising strategy to suppress the postoperative local and distant relapse of TNBC tumors.

Multifunctional Molybdenum-Based Nanoclusters Engineered Gelatin Methacryloyl as In Situ Photo-Cross-Linkable Hybrid Hydrogel Dressings for Enhanced Wound Healing.

Skin injuries and wounds present significant clinical challenges, necessitating the development of advanced wound dressings for efficient wound healing and tissue regeneration. In this context, the advancement of hydrogels capable of counteracting the adverse effects arising from undesirable reactive oxygen species (ROS) is of significant importance. This study introduces a hybrid hydrogel with rapid photocuring and excellent conformability, tailored to ameliorate the hostile microenvironment of damaged skin tissues. The hybrid hydrogel, composed of photoresponsive Gelatin Methacryloyl (GelMA) and Molybdenum-based nanoclusters (MNC), exhibits physicochemical characteristics conductive to skin regeneration. In vitro studies demonstrated the cytocompatibility and ROS-responsive behavior of the MNC/GelMA hybrid hydrogels, confirming their ability to promote human dermal fibroblasts (HDF) functions. The incorporation of MNC into GelMA not only enhances HDF adhesion, proliferation, and migration but also shields against oxidative damage induced by hydrogen peroxide (H2O2). Notably, in vivo evaluation in murine full-thickness skin defects revealed that the application of hybrid hydrogel dressings led to reduced inflammation, accelerated wound closure, and enhanced collagen deposition in comparison to control groups. Significantly, this study introduced a convenient approach to develop in situ ROS-scavenging hydrogel dressings to accelerate the wound healing process without the need for exogenous cytokines or medications. We consider that the nanoengineering approach proposed herein offers potential possibilities for the development of therapeutic hydrogel dressings addressing various skin-related conditions.

Molars to Medicine: A Focused Review on the Pre-Clinical Investigation and Treatment of Secondary Degeneration following Spinal Cord Injury Using Dental Stem Cells.

Spinal cord injury (SCI) can result in the permanent loss of mobility, sensation, and autonomic function. Secondary degeneration after SCI both initiates and propagates a hostile microenvironment that is resistant to natural repair mechanisms. Consequently, exogenous stem cells have been investigated as a potential therapy for repairing and recovering damaged cells after SCI and other CNS disorders. This focused review highlights the contributions of mesenchymal (MSCs) and dental stem cells (DSCs) in attenuating various secondary injury sequelae through paracrine and cell-to-cell communication mechanisms following SCI and other types of neurotrauma. These mechanistic events include vascular dysfunction, oxidative stress, excitotoxicity, apoptosis and cell loss, neuroinflammation, and structural deficits. The review of studies that directly compare MSC and DSC capabilities also reveals the superior capabilities of DSC in reducing the effects of secondary injury and promoting a favorable microenvironment conducive to repair and regeneration. This review concludes with a discussion of the current limitations and proposes improvements in the future assessment of stem cell therapy through the reporting of the effects of DSC viability and DSC efficacy in attenuating secondary damage after SCI.