Cell Types Research Articles

Bioprinting of Cells, Organoids and Organs-on-a-Chip Together with Hydrogels Improves Structural and Mechanical Cues

The 3D bioprinting technique has made enormous progress in tissue engineering, regenerative medicine and research into diseases such as cancer. Apart from individual cells, a collection of cells, such as organoids, can be printed in combination with various hydrogels. It can be hypothesized that 3D bioprinting will even become a promising tool for mechanobiological analyses of cells, organoids and their matrix environments in highly defined and precisely structured 3D environments, in which the mechanical properties of the cell environment can be individually adjusted. Mechanical obstacles or bead markers can be integrated into bioprinted samples to analyze mechanical deformations and forces within these bioprinted constructs, such as 3D organoids, and to perform biophysical analysis in complex 3D systems, which are still not standard techniques. The review highlights the advances of 3D and 4D printing technologies in integrating mechanobiological cues so that the next step will be a detailed analysis of key future biophysical research directions in organoid generation for the development of disease model systems, tissue regeneration and drug testing from a biophysical perspective. Finally, the review highlights the combination of bioprinted hydrogels, such as pure natural or synthetic hydrogels and mixtures, with organoids, organoid–cell co-cultures, organ-on-a-chip systems and organoid-organ-on-a chip combinations and introduces the use of assembloids to determine the mutual interactions of different cell types and cell–matrix interferences in specific biological and mechanical environments.

Histological characterization of rat vocal fold across different postnatal periods.

To evaluate the vocal fold histological characteristics during different postnatal periods in rats, especially older rats. Sprague-Dawley rats aged 4 days, 4 and 12 weeks, and 12 and 24 months were used for the experiment. Five larynges were obtained for each age and cut into 5-μm consecutive sections. The expression of Ki-67 was assessed using immunohistochemistry to examine cell proliferation. Elastic van Gieson staining was used to detect the collagen and elastin concentrations. The cell type was determined using multicolor immunofluorescence. Ki-67 was not expressed in the macula flava (MF) of 12-week-, 12-month-, and 24-month-old adults. Collagen fibers in the lamina propria (LP) increased with age. The elastic fiber concentrations in the LP decreased significantly at 24 months (p < .01) but remained stable in the MF. All posterior MF cells showed strong glial fibrillary acidic protein and vimentin-positive reactions with weaker expressions of CD68 and α-smooth muscle actin (α-SMA). The myofibroblasts (α-SMA-positive) and macrophages (CD68-positive) in the LP of the 24-month-old rats were significantly the highest (p < .01). The extracellular matrix in the LP increases with age, presenting as an increase in collagen with the loss of elastin, which may be due to myofibroblast proliferation. Moreover, the cellular properties or extracellular matrix components of the mature MF in rats are comparable to those in humans.

Integrative Modeling of Signaling Network Dynamics Identifies Cell Type-Selective Therapeutic Strategies for FGFR4-Driven Cancers.

Oncogenic FGFR4 signaling represents a potential therapeutic target in various cancer types, including triple-negative breast cancer and hepatocellular carcinoma. However, resistance to FGFR4 single-agent therapy remains a major challenge, emphasizing the need for effective combinatorial treatments. Our study sought to develop a comprehensive computational model of FGFR4 signaling and to provide network-level insights into resistance mechanisms driven by signaling dynamics. An integrated approach, combining computational network modeling with experimental validation, uncovered potent AKT reactivation following FGFR4 targeting in triple-negative breast cancer cells. Analyzing the effects of cotargeting specific network nodes by systematically simulating the model predicted synergy of cotargeting FGFR4 and AKT or specific ErbB kinases, which was subsequently confirmed through experimental validation; however, cotargeting FGFR4 and PI3K was not synergistic. Protein expression data from hundreds of cancer cell lines was incorporated to adapt the model to diverse cellular contexts. This revealed that although AKT rebound was common, it was not a general phenomenon. For example, ERK reactivation occurred in certain cell types, including an FGFR4-driven hepatocellular carcinoma cell line, in which there is a synergistic effect of cotargeting FGFR4 and MEK but not AKT. In summary, this study offers key insights into drug-induced network remodeling and the role of protein expression heterogeneity in targeted therapy responses. These findings underscore the utility of computational network modeling for designing cell type-selective combination therapies and enhancing precision cancer treatment. Significance: Computational predictive modeling of signaling networks can decipher mechanisms of cancer cell resistance to targeted therapies and enable identification of more effective cancer type-specific combination treatment strategies.

Contribution of the arterial cells to atherosclerosis and plaque formation.

Atherosclerosis is commonly known as an inflammatory disease that is characterized by lipid deposition in the arterial wall, causing gradual restriction or complete blockade of blood flow, which can cause complications such as myocardial infarction, stroke, or peripheral artery disease. Several factors contribute to initiation and progression of atherosclerotic plaque formation. The role of macrophages and leukocytes in atherosclerosis has been well explored. Here, we provide an overview of what has been reported on the role and impact of the arterial cells on plaque formation, and vice versa. The atherogenic environment can trigger transformation and dedifferentiation of the endothelial cells (ECs), smooth muscle cells, and fibroblasts (FBs) whereby they can either directly contribute to plaque formation or influence its composition. Recent studies have demonstrated the plasticity in the identity of the arterial cells, the formation of intermediate cell types that share the characteristics of multiple cell types, and have revealed novel roles and functions for these cells in atherosclerosis. The potential for all vascular cells to cross-transdifferentiate, and detection of cells with mosaic characteristics in the atherosclerotic plaques reveal that the plaque environment is a complex and dynamic environment that could regulate the disease progression independent from the circulating lipid levels. We will also provide an overview on the interplay between sex and atherosclerosis, which has remained an underexplored area.

Spatial Transcriptomics of the Respiratory System.

Over the last decade, single-cell genomics has revealed remarkable heterogeneity and plasticity of cell types in the lungs and airways. The challenge now is to understand how these cell types interact in three-dimensional space to perform lung functions, facilitating airflow and gas exchange while simultaneously providing barrier function to avoid infection. An explosion in novel spatially resolved gene expression technologies, coupled with computational tools that harness machine learning and deep learning, now promise to address this challenge. Here, we review the most commonly used spatial analysis workflows, highlighting their advantages and limitations, and outline recent developments in machine learning and artificial intelligence that will augment how we interpret spatial data. Together these technologies have the potential to transform our understanding of the respiratory system in health and disease, and we showcase studies in lung development, COVID-19, lung cancer, and fibrosis where spatially resolved transcriptomics is already providing novel insights.

Bioprocess strategies for enhanced performance in single‐use bioreactors for biomolecule synthesis: A biokinetic approach

AbstractSingle‐use bioreactors (SUB) have made a significant impact on the field of bioprocessing, becoming increasingly popular for biomolecule synthesis due to their many advantages, such as minimizing contamination risks and streamlining processes. Extensive research has been conducted on the hydrodynamic conditions within single‐use bioreactors, with a focus on parameters like mixing time, oxygen transfer rate, and stress levels to improve cell cultivation procedures. Several studies have demonstrated that SUB can effectively nurture various cell types, including those that generate monoclonal antibodies, yielding outcomes similar to conventional bioreactor systems, thus highlighting their adaptability and effectiveness in biomolecule processing. SUB equipped with wave mechanisms have shown to display comparable metabolic behaviors and fermentation consistency to conventional bioreactors, confirming their dependability in supporting fungal growth and metabolite generation. Mechanical stirring for agitation leads to high shear forces alongside enhanced monitoring and control, influencing microbial physiology and macro‐morphologies. This underscores the importance of operational factors such as rocking speed, rocking angle, and gas flow rate. Overall, the integration of single‐use bioreactors in biomolecule synthesis is expected to expand, driven by the need for increased yields and cost‐effective manufacturing solutions.

Salinity-Induced Photorespiration in Populus Vascular Tissues Facilitate Nitrogen Reallocation.

Adaptation to abiotic stress is critical for the survival of perennial tree species. Salinity affects plant growth and productivity by interfering with major biosynthetic processes. Detrimental effects of salinity may vary between different plant tissues and cell types. However, spatial molecular mechanisms controlling plant responses to salinity stress are not yet thoroughly understood in perennial trees. We used laser capture microdissection in clones of Populus tremula x alba to isolate palisade and vascular cells of intermediary leaf from plants exposed to 150 mM NaCl for 10 days, followed by a recovery period. Cell-specific changes in proteins and metabolites were determined. Salinity induced a vascular-specific accumulation of proteins associated with photorespiration, and the accumulation of serine, 3-phosphoglycerate and NH4 + suggesting changes in N metabolism. Accumulation of the GLUTAMINE SYNTHETASE 2 protein, and increased GS1.1 gene expression, indicated that NH4 + produced in photorespiration was assimilated to glutamine, the main amino acid translocated in Populus trees. Further analysis of total soluble proteins in stems and roots showed the accumulation of bark storage proteins induced by the salinity treatments. Collectively, our results suggest that the salt-induced photorespiration in vascular cells mediates N-reallocation in Populus, an essential process for the adaptation of trees to adverse conditions.

Adipose-derived Stem Cells for Treatment of Diabetic Foot Ulcers: A Review

Abstract: This study investigates the therapeutic potential of adipose-derived stem cells (ASCs) in diabetic foot ulcers (DFUs). The goal is to further research regenerative medicine by improving knowledge of ASC-based therapies in diabetic wound management. A comprehensive literature review included studies from reputable databases, including PubMed and the Cochrane Library. We paid particular attention to the clinical, in vivo, and in vitro investigations of the utility and effectiveness of ASCs in treating DFU. We also highlighted novel isolation techniques and application methods for ASCs in chronic wound management. ASCs have shown great potential in regenerative interventions for diabetes, especially in DFU management. These cells facilitate wound repair by differentiating into different cell types, promoting angiogenesis, secreting growth factors, reducing inflammation, and increasing wound perfusion. However, the current body of research on ASC applications for DFU still requires further investigation. This shows the importance of thoroughly studying their biological mechanisms and therapeutic uses. This review establishes that ASC-based treatments effectively enhance outcomes for patients suffering from DFU. We recommend further investigation of the functionality of ASCs and therapeutic approaches to maximize their therapeutic potential in managing diabetic wounds, thereby advancing the development of regenerative medicine.

Evaluation of enzymatic protocols to optimize efficiency of bovine adipose tissue-derived mesenchymal stromal cell isolation

Evaluation of enzymatic protocols to optimize efficiency of bovine adipose tissue-derived mesenchymal stromal cell isolation

XQTLatlas: a comprehensive resource for human cellular-resolution multi-omics genetic regulatory landscape.

Understanding how genetic variants influence molecular phenotypes in different cellular contexts is crucial for elucidating the molecular and cellular mechanisms behind complex traits, which in turn has spurred significant advances in research into molecular quantitative trait locus (xQTL) at the cellular level. With the rapid proliferation of data, there is a critical need for a comprehensive and accessible platform to integrate this information. To meet this need, we developed xQTLatlas (http://www.hitxqtl.org.cn/), a database that provides a multi-omics genetic regulatory landscape at cellular resolution. xQTLatlas compiles xQTL summary statistics from 151 cell types and 339 cell states across 55 human tissues. It organizes these data into 20 xQTL types, based on four distinct discovery strategies, and spans 13 molecular phenotypes. Each entry in xQTLatlas is meticulously annotated with comprehensive metadata, including the origin of the tissue, cell type, cell state and the QTL discovery strategies utilized. Additionally, xQTLatlas features multiscale data exploration tools and a suite of interactive visualizations, facilitating in-depth analysis of cell-level xQTL. xQTLatlas provides a valuable resource for deepening our understanding of the impact of functional variants on molecular phenotypes in different cellular environments, thereby facilitating extensive research efforts.

Single-cell transcriptome and chromatin accessibility mapping of upper lip and primary palate fusion.

Cleft lip and/or primary palate (CL/P) represent a prevalent congenital malformation, the aetiology of which is highly intricate. Although it is generally accepted that the condition arises from failed fusion between the upper lip and primary palate, the precise mechanism underlying this fusion process remains enigmatic. In this study, we utilized transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) to interrogate lambdoidal junction tissue derived from C57BL/6J mouse embryos at critical stages of embryogenesis (10.5, 11.5 and 12.5 embryonic days). We successfully identified distinct subgroups of mesenchymal and ectodermal cells involved in the fusion process and characterized their unique transcriptional profiles. Furthermore, we conducted cell differentiation trajectory analysis, revealing a dynamic repertoire of genes that are sequentially activated or repressed during pseudotime, facilitating the transition of relevant cell types. Additionally, we employed scATAC data to identify key genes associated with the fusion process and demonstrated differential chromatin accessibility across major cell types. Finally, we constructed a dynamic intercellular communication network and predicted upstream transcriptional regulators of critical genes involved in important signalling pathways. Our findings provide a valuable resource for future studies on upper lip and primary palate development, as well as congenital defects.

Elongation factor 1A1 inhibition elicits changes in lipid droplet size, the bulk transcriptome, and cell type-associated gene expression in MASLD mouse liver.

Eukaryotic elongation factor 1A1 (EEF1A1), originally identified for its role in protein synthesis, has additional functions in diverse cellular processes. Of note, we previously discovered a role for EEF1A1 in hepatocyte lipotoxicity. We also demonstrated that a 2-wk intervention with the EEF1A1 inhibitor didemnin B (DB) (50 µg/kg) decreased liver steatosis in a mouse model of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) [129S6/SvEvTac mice fed Western diet (42% fat) for 26 wk]. Here, we further characterized the hepatic changes occurring in these mice by assessing lipid droplet (LD) size, bulk differential expression, and cell type-associated alterations in gene expression. Consistent with the previously demonstrated decrease in hepatic steatosis, we observed decreased median LD size in response to DB. Bulk RNA sequencing (RNA-Seq) followed by gene set enrichment analysis revealed alterations in pathways related to energy metabolism and proteostasis in DB-treated mouse livers. Deconvolution of bulk data identified decreased cell type association scores for cholangiocytes, mononuclear phagocytes, and mesenchymal cells in response to DB. Overrepresentation analyses of bulk data using cell type marker gene sets further identified hepatocytes and cholangiocytes as the primary contributors to bulk differential expression in response to DB. Thus, we show that chemical inhibition of EEF1A1 decreases hepatic LD size and decreases gene expression signatures associated with several liver cell types implicated in MASLD progression. Furthermore, changes in hepatic gene expression were primarily attributable to hepatocytes and cholangiocytes. This work demonstrates that EEF1A1 inhibition may be a viable strategy to target aspects of liver biology implicated in MASLD progression.NEW & NOTEWORTHY Chemical inhibition of EEF1A1 decreases hepatic lipid droplet size and decreases gene expression signatures associated with liver cell types that contribute to MASLD progression. Furthermore, changes in hepatic gene expression are primarily attributable to hepatocytes and cholangiocytes. This work highlights the therapeutic potential of targeting EEF1A1 in the setting of MASLD, and the utility of RNA-Seq deconvolution to reveal valuable information about tissue cell type composition and cell type-associated gene expression from bulk RNA-Seq data.

Hypoxic Memory Mediates Prolonged Tumor-Intrinsic Type I Interferon Suppression to Promote Breast Cancer Progression.

Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIF). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell lines and common breast cancer cell lines, hypoxia downregulated tumor-intrinsic type I IFN signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a "hypoxic memory" phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for circulating tumor cells during the metastatic cascade. Significance: Long-term cellular memory of hypoxia leads to sustained suppression of tumor-intrinsic type I IFN signaling and the antigen presentation pathway that facilitates tumorigenesis and metastasis. See related commentary by Purdy and Ford, p. 3125.

Immunofluorescence Staining of Murine Spinal Cord Sections to Evaluate Microglial Activation and Astrogliosis.

Microglia and astrocytes are the main components of the central nervous system (CNS). Upon activation, microglia is able to phagocyte cell debris, pathogens, and toxins; astrocytes support neuronal functions, blood-brain barrier (BBB) homeostasis, and neurotransmitter uptake and metabolism. Furthermore, both cell types can produce cytokines and chemokines. Aging impacts microglia and astrocytes by promoting the production of pro-inflammatory cytokines, impairing microglial phagocytosis and motility and astrocyte glutamate uptake. During neurodegenerative and neuroinflammatory diseases, the aging process may be accelerated contributing to the alteration of CNS glial cells functions. Multiple sclerosis (MS) is an autoimmune, demyelinating disease in which immunosenescence can promote the conversion from relapsing-remitting form to progressive disease. The murine model of experimental autoimmune encephalomyelitis (EAE) allows to investigate MS pathogenesis. Furthermore, EAE can be developed as acute or progressive, mimicking different forms of human MS. Microglia and astrocytes report morphological and functional changes during neuroinflammation that can be investigated in different ways. We here present a protocol for the study of glial cell activation in the spinal cord tissue of EAE mice.

Effect of concentration and electrical charge of maltodextrin, and packing factor on electrospinning processing

The power law ηrel ∼ Ca of maltodextrins with higher entanglement concentrations (Ce) of dextrose equivalent (DE) 4, 10, and 18 exhibits an unusually high exponent a, ranging from 10.34 to 14.38 in congested solutions where particles occupy significant space. This contrasts with the dilute exponents (a ∼ 2) typically observed in polymer–solvent systems. To address this issue, several viscosity factors were evaluated using the Einstein–Roscoe and Mooney equations, which demonstrated viscosity dependence due to volume fraction (ϕ) > 0.35, shape, crowding factor (k) packing factor (1/k∼0.5) and centered cubic cell (CC), particularly for larger chain sizes (> 20 glucoses) in DE-4. Chain electrical charges significantly stiffen the chain and increase its length beyond the theoretically predicted Kuhn persistent length (Lp), which seems to be responsible for the exponential increase in viscosity. Normalizing the viscosity/charge data revealed a log–log plot consistent with the exponent a of the general power law theory. In addition to concentration, electrospinning processing is influenced by strong particle–particle charge interactions, (ϕ), packing factor (1/k), CC, and chain sizes. The Maxwell model demonstrated poor interaction for DE-4 (modulus ∼286 Pa at maximum ϕ due to loose packing of CC, in contrast to DE-18, which exhibited a modulus of 994 Pa for a solution with maximum ϕ>0.5 and a congested solution of 52% w/v, packing factor of 0.68, and high particle–particle interaction of the body-centered cubic (BCC) cell, favoring electrospun fiber formation. The packing factor, ϕ, and cell type, are highly sensitive and have potential applications in food systems, 3D bioprinting, among many other scientific domains.

Morphological characteristics and distribution identification of telocytes in Tibetan sheep testis and epididymis

Telocytes (TCs) are a type of stromal cell discovered in the various organs of different animals and have many potential functions, including angiogenesis, signalling, and substance transport. However, the TCs have not been detected in the testis or epididymis of Tibetan sheep. This study investigated the position, characteristics, and distribution of TCs in the testis and epididymis of Tibetan sheep using transmission electron microscopy (TEM), toluidine blue staining, immunohistochemistry, and double immunofluorescence to elucidate their possible functions. TEM revealed that TCs were often found near basement membranes and capillaries and were characterised by large nuclei, elongated cytoplasmic protrusions, and many secretory vesicles. We also observed via toluidine staining that TCs were present near basement membrane and interstitial capillaries. Immunohistochemistry and double immunofluorescence revealed the positive expression of CD117, vimentin, platelet derived growth factor receptor α(PDGFRα), PDGFRα + CD117, and PDGFRα + vimentin in TCs. Additionally, we inferred that TCs participates in the formation of the blood–testis and blood–epididymis barriers, as well as in material transport and a stable microenvironment. This study presents the first evidence of the presence of TCs near the basement membrane and blood vessels in the testis and epididymis of Tibetan sheep. These findings provide new insights into the function of TCs in the reproductive systems of plateau animals.

Modelling and investigating memory immune responses in infectious disease. Application to influenza a virus and sars-cov-2 reinfections

Understanding effector and memory immune responses against influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and re-infections is extremely important, given that they are now endemic in the community. The goal of this study is to investigate the role of memory cells and antibodies in the immune responses against IAV and SARS-CoV-2 re-infections. To this end, we adapt a previously-published within-host mathematical model (Sadria & Layton, 2021) for the primary immune response against SARS-CoV-2 infections, by including two types of memory immune cells, i.e., memory CD8+ T-cells and memory B-cells, and by parametrising the new model with values specific to the two viruses. We first investigate the long-term dynamics of the model by identifying the virus-free steady states and studying the conditions that ensure the stability of these states. Then, we investigate the transient dynamics of this in-host model by simulating different viral reinfection times: 20 days, 60 days and 400 days after the first encounter with the pathogen. This allows us to highlight which memory immune components have the greatest impact on the viral elimination depending on the time of reinfection. Our results suggest that memory immune responses have a greater impact in the case of IAV infections compared to SARS-CoV-2 infections. Moreover, we observe that the immune response after a secondary infection is more efficient when the reinfection occurs at a shorter time.

In vitro study of the UV-filter homosalate effects on rat and human thyroid cells

Homosalate is a UV-B filter, commonly used in sunscreens and personal-care products. Homosalate was shown to exert estrogenic and anti-androgenic effects in animal models, while few data are available on the effects of Homosalate on thyroid cells. The aim of this study was to evaluate if Homosalate exposure could exert adverse effect on thyroid cells in vitro.FRTL-5 and NHT were treated with increasing concentration of Homosalate for 24-48-72 h. Cell viability was assessed by WST-1. Cell proliferation was evaluated by cristal violet. Micronucleus staining was performed to assess genotoxicity. mRNA levels of thyroid-related genes (TSHR, TPO, TG, NIS, and PAX8) were evaluated by RT-PCR. Changes in ROS production by FRTL-5 and NHT were assessed with H2DCFDA.Homosalate significantly reduced cell viability after 72 h in FRTL-5 starting from the concentration 250 μM, while in NHT, Homosalate exposure significantly reduced cell viability after 48 and 72 h only at highest concentration (2000 μM). Cell proliferation was not modified by Homosalate at any concentration and time-point. Homosalate significantly up-regulated mRNA expression levels of TPO and Tg genes in FRTL-5, while a significant increase only in Tg mRNA expression was observed in NHT. No changes in ROS production was found in both cell types.The present study suggest that the effects of Homosalate exposure may differ according to the type of cell tested. The in vitro exposure of thyroid cells to Homosalate produces: i) cytotoxicity at high concentrations or after long time of incubation, ii) genotoxicity only in rat thyroid cells at the highest concentration, iii) upregulation of Tg mRNA in both thyroid cell types and of TPO mRNA in rat thyroid cells, iv) no changes in cell proliferation or oxidative stress. Further studies on the effects of Homosalate on thyroid cells should be encouraged.

RNAs in tumour-derived extracellular vesicles and their significance in the tumour microenvironment.

Small extracellular vesicles (sEVs) secreted by various types of cells serve as crucial mediators of intercellular communication within the complex tumour microenvironment (TME). Tumour-derived small extracellular vesicles (TDEs) are massively produced and released by tumour cells, recapitulating the specificity of their cell of origin. TDEs encapsulate a variety of RNA species, especially messenger RNAs, microRNAs, long non-coding RNAs, and circular RNAs, which release to the TME plays multifaced roles in cancer progression through mediating cell proliferation, invasion, angiogenesis, and immune evasion. sEVs act as natural delivery vehicles of RNAs and can serve as useful targets for cancer therapy. This review article provides an overview of recent studies on TDEs and their RNA cargo, with emphasis on the role of these RNAs in carcinogenesis.

Macrophages dying from ferroptosis promote microglia-mediated inflammatory responses during spinal cord injury

The neurological deficits following traumatic spinal cord injury are associated with severe patient disability and economic consequences. Currently, an increasing number of studies are focusing on the importance of ferroptosis during acute organ injuries. However, the spatial and temporal distribution patterns of ferroptosis during SCI and the details of its role are largely unknown. In this study, in vivo experiments revealed that microglia are in close proximity to macrophages, the major cell type that undergoes ferroptosis following SCI. Furthermore, we found that ferroptotic macrophages aggravate SCI by inducing the proinflammatory properties of microglia. In vitro studies further revealed ferroptotic macrophages increased the expression of IL-1β, IL-6, and IL-23 in microglia. Mechanistically, due to the activation of the NF-κB signaling pathway, the expression of IL-1β and IL-6 was increased. In addition, we established that increased levels of oxidative phosphorylation cause mitochondrial reactive oxygen species generation and unfolded protein response activation and trigger an inflammatory response marked by an increase in IL-23 production. Our findings identified that targeting ferroptosis and IL-23 could be an effective strategy for promoting neurological recovery after SCI.