Inflammation and regeneration最新文献

Background: CD157 marks a population of tissue-resident vascular endothelial stem cells (VESCs) in mice known for their critical role in homeostatic endothelial cell (EC) turnover and the rapid response to vascular damage in the liver by regeneration. Nevertheless, the mechanism underlying the maintenance and differentiation of postnatal VESCs under both physiological and pathological conditions remains unclear.

Methods: APJ knockout (KO) mice were utilized to explore the role of apelin/APJ signaling in VESC functionality. Flow cytometry, colony-forming unit assays, and in vitro differentiation experiments were conducted to characterize VESC populations. Partial hepatectomy (PHx) was performed to assess vascular regeneration.

Results: APJ deficiency led to an accumulation of VESCs in the liver of adult mice, which displayed enhanced colony-forming capacity but delayed differentiation into mature ECs. APJ KO mice exhibited impaired vascular regeneration following PHx, linked to compromised VESC differentiation. Transcriptomic analysis revealed upregulation of transcription factors EGR1 and EGR2 and downregulation of Ccnd1 in APJ KO VESCs, implicating disrupted cell cycle regulation. Additionally, APJ deletion reduced collagen IV levels, weakening the basement membrane and contributing to the maintenance of VESCs in an undifferentiated state.

Conclusion: APJ signaling is critical for balancing VESC self-renewal and differentiation. APJ deficiency disrupts this balance, leading to impaired vascular regeneration in the liver due to delayed VESC differentiation. This defect is associated with altered transcriptional regulation, favoring a proliferative, undifferentiated state and extracellular matrix changes that weaken structural integrity. These findings highlight the apelin/APJ pathway as a potential therapeutic target to enhance vascular regeneration in regenerative medicine.

By balancing immunity and tolerance, dendritic cells (DCs) are key regulators of immune responses. Recent studies have highlighted the crucial role of these cells in connective tissue diseases. Conventional DCs (cDCs) and plasmacytoid DCs (pDCs) exhibit distinct contributions to disease progression. In systemic lupus erythematosus and systemic sclerosis, pDCs primarily drive pathogenesis via excessive type I interferon production, whereas in rheumatoid arthritis (RA), cDCs play a major role in promoting autoreactive T cell activation. Emerging DC subsets, such as inflammatory DC3s and LAMP3⁺ DCs, have been implicated in RA synovitis. In vasculitis, tissue-resident vascular DCs appear to regulate localized inflammation. Despite advances in single-cell analysis, the functional roles of specific DC subsets remain underexplored in several autoimmune conditions. Understanding DC heterogeneity and function in disease-specific contexts may lead to novel therapeutic strategies targeting DC-mediated immune dysregulation.

Background: Ocular affections are serious damage to the ocular tissue that results in impaired vision or blindness. Cell-based therapies are a potentially effective therapeutic technique that entails using stem-like precursor cells to induce differentiation of specific cell types and implanting the cells to improve vision in the affected tissue area.

Methods: Numerous clinical trials were started to investigate the potential benefits of stem cells for treating ocular affections, based on several encouraging findings from the preclinical research. Following our review, data were collected from various databases, "Google Scholar, Springer, Elsevier, Egyptian Knowledge Bank, ProQuest, and PubMed" using different keywords such as corneal ulcer, retinopathy, glaucoma, ocular regeneration, and stem cells to investigate the various methods for regeneration of ocular affections. The data were obtained and analyzed.

Results: This review includes tables that show all types of stem cells that were used to treat ocular diseases, such as mesenchymal stem cells (MSCs), hematopoietic stem cells, neural stem cells, embryonic stem cells, and induced pluripotent stem cells. The several characteristics of MSCs that aid in the restoration and regeneration of injured ocular tissue are outlined in this paper, along with their potential applications in the management of ocular degenerative diseases, as determined by physical, histological, immunohistochemical, and biochemical evaluations. Finally, our review highlights the most effective regenerative strategies that assist in rapid ocular regeneration in a variety of animal models, including mice, rats, rabbits, and goats.

Conclusion: With the promising results of multiple preclinical studies, stem cell therapy is still a great choice for treating ocular degenerative illnesses. To improve the clinical outcomes, co-transplantation of two or more cell types may be a possibility for future treatment alternatives.

Background: Genomic analyses of psychiatric disorders, including autism spectrum disorder (ASD), have revealed many susceptibility genes, suggesting that such disorders may be caused by multiple factors. In this sense, it has long been a question whether there is an abnormal genetic status that comprehensively explains the pathogenesis of neuropsychiatric disorders or a"promising upstream treatment target"that normalizes symptoms.

Methods: To address this question, we provide important clues with respect to GASC1 (JMJD2 C/KDM4 C), which is a histone demethylase that prominently targets trimethylated histone H3 at lysine 9 (H3 K9 me3). Gasc1 hypomorphic mutant mice were analyzed using molecular biological, biochemical, behavioral battery tests, histological, and electrophysiological techniques.

Results: Mice homozygous for a hypomorphic mutation in Gasc1 exhibited abnormal behaviors, including hyperactivity, stereotyped behaviors, and impaired learning and memory, which are reminiscent of those of human psychiatric disorders. Electrophysiological studies of hippocampal slices revealed decreased paired-pulse facilitation and enhanced long-term potentiation, suggesting synaptic dysfunction in the mutants. Increased dendritic spine density in CA1 neurons was also detected in the mutants. Intriguingly, genetic linkage studies of human ASD have mapped a susceptibility locus on chromosome 9p24.1, which contains 78 genes, including the GASC1 gene.

Conclusion: Taken together, our data suggest that histone demethylation plays a pivotal role in normal brain development and higher-order brain functions in both mice and humans.

The liver presents a unique immune system. Liver diseases are closely associated with the immune system. Disruption of the tightly regulated balance between immune activation and tolerance induction leads to the development and worsening of immune-related liver diseases. T cells play diverse crucial roles in the immune system, and they have long been known to induce inflammation through direct tissue damage by effector molecules and the recruitment of effector cells via chemokines. Additionally, T cells interact with B cells to induce autoantibodies, promoting tissue inflammation and dysfunction through the deposition of IgG and immune complexes in the tissues. Recent advances in omics technologies, including single-cell RNA sequencing and spatial transcriptomics, have elucidated the role of T cells in the progression and recovery of liver fibrosis. Moreover, comprehensive and unbiased information can now be obtained from small samples of human and mouse tissues, which advances our understanding of tissue-specific functions of T cells, including resident memory T cells, peripheral helper T cells, and tissue Tregs. However, significant unmet needs remain in the fields of immune-related liver diseases. In this review, we discuss the T cell biology and its role in autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), and metabolic-associated steatohepatitis (MASH), which are non-viral liver diseases exhibiting a strong involvement of immunity and inflammation. Furthermore, the latest therapeutic concepts for the diseases and associated drugs targeting T cells have been overviewed.

The choroid plexus (ChP) is a highly vascularized tissue located within the brain ventricles. Traditionally recognized for its primary role in cerebrospinal fluid (CSF) production, recent research has unveiled a far more complex and dynamic picture of the ChP's contributions to brain health and homeostasis. The ChP is composed of tight-junction-bound epithelial cells and the underlying stroma-rich fenestrated capillaries of blood vessels. This unique architecture creates a barrier between the peripheral blood and CSF, regulating the brain's internal environment. The discovery that CSF enters the brain parenchyma via the perivascular space, coupled with the identification of a functional brain lymphatic system linked to CSF turnover, further highlights the ChP as a gatekeeper of waste clearance and fluid homeostasis. This review will cover the development and histology of ChP, focusing on the dynamic response of the blood-CSF barrier in the context of systemic inflammation, a process whose molecular mechanisms have recently been elucidated.

Ca²⁺ signals play a crucial role in maintaining cardiovascular homeostasis, including regulation of the heartbeat, blood pressure, and adaptation to changes in the external environment. Conversely, abnormal Ca²⁺ signaling is often involved in the onset and progression of cardiovascular diseases, such as cardiac hypertrophy, heart failure, arteriosclerosis, and hypertension. In excitable cells, such as cardiac myocytes and vascular smooth muscle cells (VSMCs), membrane depolarization, and the subsequent elevation of cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt) via voltage-dependent Ca²⁺ channels (VDCCs) cause muscle contraction, which is known as excitation-contraction coupling (E-C coupling). Elevated [Ca²⁺]_cyt can also activate Ca²⁺-dependent enzymes, in some cases leading to changes in gene expression patterns and contributing to long-term cellular responses. This mechanism is referred to as excitation-transcription coupling (E-T coupling), and it is involved in both the adaptive and pathological responses of the cardiovascular system to chronic stimulation. Specific intracellular regions, known as Ca²⁺ microdomains, exhibit localized increases in [Ca²⁺]_cyt. Such localized Ca²⁺ signaling is now known to be one of the molecular mechanisms controlling the diversity of Ca²⁺ responses. These Ca²⁺ microdomains are often formed by complexes consisting of Ca²⁺ channels and downstream Ca²⁺-dependent enzymes localized by scaffolding proteins. This review outlines some of the molecular mechanisms and roles of Ca²⁺ microdomain-based E-T coupling in cardiac myocytes and VSMCs. First, we discuss the major molecular components that are essential for functional Ca²⁺ microdomains. For example, VDCC (Ca_V1.2 channel), ryanodine receptor (RyR), Ca²⁺-dependent enzymes (Ca²⁺/CaM-dependent kinase [CaMK], calcineurin [CaN], and calpain), and scaffolding proteins (A-kinase anchoring proteins [AKAPs], caveolin, and junctophilin). Next, we discuss the roles of Ca²⁺ microdomain-based E-T coupling in physiological and pathophysiological remodeling in cardiac myocytes and vascular smooth muscle cells.

Background: Psoriasis is a chronic inflammatory disease associated with abnormalities in the immune system. Microsomal prostaglandin E synthase-1 (mPGES-1), a terminal enzyme for prostaglandin (PG) E₂ biosynthesis, is highly expressed in the skin of psoriasis patients. However, the detailed role of mPGES-1 in psoriasis remains unclear. In the present study, we aimed to investigate the role of mPGES-1 in psoriasis-like skin inflammation induced by imiquimod (IMQ), a well-established model of psoriasis.

Methods: Psoriasis was induced in mPGES-1-deficient (mPGES-1^-/-) and wild-type (WT) mice by administering IMQ for 6 days. Psoriasis was evaluated based on the scores of the macroscopic symptoms, including skin scaling, thickness, and redness, and on the histological features. The skin expression of mPGES-1 was determined by real-time polymerase chain reaction and Western blotting. The impact of mPGES-1 deficiency on T-cell immunity was determined by flow cytometry and γδ T-cell depletion in vivo with anti-T-cell receptor (TCR) γδ antibody.

Results: The inflamed skin of mPGES-1^-/- mice showed severe symptoms after the administration of IMQ. Histological analysis further showed significant exacerbation of psoriasis in mPGES-1^-/- mice. In WT mice, the mPGES-1 expression was highly induced at both mRNA and protein levels in the skin, and PGE₂ increased significantly after IMQ administration, while the PGE₂ production was largely abolished in mPGES-1^-/- mice. These data indicate that mPGES-1 is the main enzyme responsible for PGE₂ production in the skin. Furthermore, the lack of mPGES-1 increased the numbers of IL-17A-producing γδ T cells in the skin with IMQ-induced psoriasis, and γδ T-cell depletion resulted in a reduction of the facilitated psoriasis symptoms under the condition of mPGES-1 deficiency.

Conclusions: Our study results demonstrate that mPGES-1 is the main enzyme responsible for skin PGE₂ production, and that mPGES-1 deficiency facilitates the development of psoriasis by affecting the development of T-cell-mediated immunity. Therefore, mPGES-1 might impact both skin inflammation and T-cell-mediated immunity associated with psoriasis.

Innate immune memory (trained immunity) refers to the ability of innate immune cells, such as monocytes and macrophages, to retain a long-term imprint of a prior stimulus through epigenetic and metabolic adaptations, enabling amplified responses upon restimulation. Recent studies have classified innate immune memory into central and peripheral types. Central innate immune memory originates in hematopoietic stem cells (HSCs) within the bone marrow, where epigenetic reprogramming generates a sustained inflammatory bias, contributing to chronic diseases such as atherosclerosis, heart failure, and stroke. Peripheral innate immune memory occurs in monocytes or macrophages that acquire heightened responsiveness after repeated exposure to stimuli in peripheral tissues. This review explores the mechanisms underlying both central and peripheral innate immune memory, their roles in chronic inflammatory diseases, focusing on cardiovascular diseases, and potential strategies to target innate immune memory for therapeutic purposes. Advancing the understanding of these processes could facilitate the development of novel approaches to control inflammatory diseases and immune-related disorders.

Background: Alzheimer's disease (AD) is characterized by amyloid β (Aβ) accumulation in the brain. Recent genome-wide association studies have identified numerous AD risk genes highly expressed in microglia, highlighting their potential role in AD pathogenesis. Although microglia possess phagocytic capacity and have been implicated in Aβ clearance, accumulating evidence suggests their contribution to AD pathogenesis is more complex than initially anticipated.

Main body: This review synthesizes current knowledge on microglial Aβ metabolism in AD, reconciling conflicting data from various studies. We examine evidence supporting the role of microglia in Aβ clearance, including studies on AD risk genes like TREM2 and their impact on microglial phagocytosis. Conversely, we explore findings that challenge this view, such as microglial depletion experiments resulting in unchanged or decreased Aβ accumulation. We propose that the contribution of microglia to Aβ metabolism is context-dependent, varying with disease progression, genetic background, and experimental conditions. Notably, microglia may promote parenchymal amyloid accumulation in early disease stages, while this accumulation-promoting effect may diminish in later stages. We discuss potential mechanisms for this paradoxical effect, including intracellular Aβ aggregation and release of pro-aggregation factors. Additionally, we explore the interplay between microglia-mediated Aβ metabolism and other clearance pathways, such as the glymphatic system, highlighting a potential compensatory relationship between parenchymal amyloid deposition and cerebral amyloid angiopathy.

Conclusion: Our review underscores the complex and dynamic role of microglia in AD pathogenesis. Understanding the stage-specific functions of microglia in Aβ metabolism is crucial for developing targeted interventions. Future research should focus on elucidating the mechanisms of microglial functional changes throughout disease progression and determining the pathological significance of these changes. Exploring potential therapeutic strategies that selectively enhance beneficial microglial functions while mitigating their detrimental effects remains an important goal.