Inflammation and regeneration最新文献

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.

The gastrointestinal (GI) tract constitutes a sophisticated system integral to digestion, nutrient absorption, and overall health, with its functionality predominantly hinging on the distinctive properties of diverse stem cell types. This review systematically investigates the pivotal roles of stem cells across the esophagus, stomach, small intestine, and colon, emphasizing their crucial contributions to tissue homeostasis, repair mechanisms, and regeneration. Each segment of the GI tract is characterized by specialized stem cell populations that exhibit distinct functional attributes, highlighting the necessity for tailored therapeutic approaches in the management of gastrointestinal disorders.Emerging research has shed light on the functional heterogeneity of GI stem cells, with ISCs in the small intestine displaying remarkable turnover rates and regenerative potential, whereas colonic stem cells (CSCs) are essential for the preservation of the colonic epithelial barrier. The intricate interplay between stem cells and their microenvironment-or niche-is fundamentally important for their functionality, with critical signaling pathways such as Wnt and Notch exerting substantial influence over stem cell behavior. The advent of organoid models derived from GI stem cells offers promising avenues for elucidating disease mechanisms and for the preclinical testing of novel therapeutic interventions.Despite notable advancements in foundational research on GI stem cells, the translation of these scientific discoveries into clinical practice remains limited. As of 2025, Japan's clinical GI disease guidelines do not endorse any stem cell-based therapies, underscoring the existing disconnect between research findings and clinical application. This scenario accentuates the urgent need for sustained efforts to bridge this divide and to cultivate innovative strategies that synergize stem cell technology with conventional treatment modalities.Future investigations should be directed toward unraveling the mechanisms that underpin stem cell dysfunction in various gastrointestinal pathologies, as well as exploring combination therapies that harness the regenerative capacities of stem cells in conjunction with immunomodulatory treatments. By fostering collaborative endeavors between basic researchers and clinical practitioners, we can deepen our understanding of GI stem cells and facilitate the translation of this knowledge into effective therapeutic interventions, ultimately enhancing patient outcomes in gastrointestinal diseases.

Background: We previously reported that a vascular endothelial stem cell population resides in pre-existing blood vessels in mice and may contribute to vascular endothelial cells in liver injury or hind limb ischemia models in the long-term. However, whether such stem cells exist in humans and can differentiate specifically into vascular endothelial cells have not been determined. We hypothesized that CD157⁺ vascular endothelial cells in humans may also possess high angiogenic potential.

Methods: First, human-derived induced pluripotent stem cells were differentiated into vascular endothelial cells and the expression of CD157 was monitored during the differentiation process. We found that CD157 emerged 11 days after the induction of differentiation, peaked at 14 days, and then declined by 24 days. We also evaluated blood vessel formation by 14- and 24-day-old vascular endothelial cells.

Results: It was found that 14-day-old cells, when CD157 expression was at its peak, formed more blood vessels than 24-day-old cells.

Conclusion: These results suggest that vascular endothelial cells expressing CD157 have high angiogenic potential and may exist as vascular endothelial stem cells.

Background: Aging-associated dysbiosis leads to chronic inflammation and the development of a range of aging-related diseases. The gut microbiota crosstalks with the host by providing lipid metabolites and modulating metabolic functions. However, the precise mechanism by which the gut microbiota regulates aging is unknown. The objective of this study was to examine the impact of the gut microbiota on the transcriptome and lipidome associated with aging in mouse liver.

Methods: RNA-sequencing was conducted on the livers of young and aged male and female-specific pathogen-free (SPF) and germ-free (GF) mice to comprehensively analyze transcriptomic alterations with aging. We also reanalyzed our previously reported results on aging-associated changes in the hepatic lipidome to investigate the gut microbiota-dependent hepatic lipidome signatures associated with aging.

Results: In contrast to the findings in male mice, the changes in hepatic transcriptome associated with aging were attenuated in female GF mice compared with those in SPF mice. In particular, the gene sets associated with inflammatory signatures (i.e., inflammation and tissue remodeling) were found to be suppressed in female GF mice. The ChIP-Atlas database predicted that transcription factors associated with sex differences may be involved in the gene signature of aged female GF mice. Significant differences in the lipid profile were observed between aged SPF and GF female mice, including in bile acids, sterol sulfates, lysophospholipids, oxidized triacylglycerols, vitamin D, and phytoceramides. Moreover, notable alterations were identified in the quality of phospholipids and sphingolipids. Integrated transcriptomic and lipidomic analysis identified candidate enzymes responsible for the change of lipid profiles in aged female mice.

Conclusions: The findings of this study offer new insights into the molecular mechanisms through which the gut microbiota regulates aging-related phenotypes such as inflammation in the liver, possibly through modulating lipid metabolism in a sex-dependent manner.

Background: The clinical application of mesenchymal stem cells (MSCs) has garnered attention due to their remarkable capacity to differentiate into adipocytes, chondrocytes, and osteoblasts. However, the quality of MSC culture varies from batch to batch, which poses challenges in ensuring consistent cellular quality across batches. Consequently, it becomes imperative to identify specific markers that can distinguish superior and slightly inferior MSCs.

Methods: Human bone marrow-derived MSC clones were isolated and subjected to flow cytometry analysis to assess the expression of NRP2, VEGFR, and plexinA1. The osteogenic and adipogenic differentiation potentials were evaluated using Alizarin Red S and Oil Red O staining, respectively. Furthermore, the migration capacity was assessed through the scratch healing assay.

Results: Nine out of twenty MSC clones significantly expressed NRP2. NRP2-expressing MSC clones (NRP2⁺ MSCs) retained superior proliferation and differentiation capacities, along with increased migratory capacity compared to non-expressing MSC clones (NRP2^- MSCs). In addition, the activation of VEGF-C/NRP2 signaling augmented the potential of MSCs in cell proliferation and differentiation.

Conclusion: In contrast to NRP2^- MSCs, NRP2⁺ MSCs exhibited superior proliferation, differentiation abilities, and migration capacity. Moreover, the stimulation of VEGF-C/NRP2 signaling further enhanced the proliferation and differentiation rates, indicating a role of NRP2 in the maintenance of MSC stemness. Hence, NRP2 holds potential as a cell surface marker for identifying beneficial MSCs for regenerative medicine.

Peripheral nerve injuries (PNI) occur in approximately 13-23 per 100,000 individuals, predominantly affecting young and middle-aged adults. These injuries often require a lengthy recovery period, placing substantial burdens on healthcare systems and national economies. Current treatment strategies have not significantly shortened this lengthy regenerative process, highlighting the urgent need for innovative therapeutic interventions. Chemokines were originally noted for their powerful ability to recruit immune cells; however, as research has advanced, it has become increasingly evident that their role in peripheral nerve repair has been underestimated. In this review, we provide the first comprehensive overview of chemokine expression and activity during peripheral nerve injury and regeneration. We summarize the existing literature on chemokine family members, detailing their expression patterns and localization in injured nerves to facilitate further mechanistic investigations. For chemokines that remain controversial, such as CXCL1 and CCL2, we critically examine experimental methodologies and discuss factors underlying conflicting results, ultimately affirming their contributions to promoting nerve repair. Importantly, we highlight the dual nature of chemokines: in the early stages of injury, they initiate reparative responses, activate Schwann cells, regulate Wallerian degeneration, and support nerve recovery; but when the axons are connected and the repair enters the later stages, their persistent proinflammatory effects during later stages may impede the healing process. Additionally, we emphasize that certain chemokines, including CXCL5, CXCL12, and CCL2, can act directly on neurons/axons, thereby accelerating axonal regeneration. Future research should focus on precisely mapping the localization and temporal expression profiles of these chemokines and exploring therapeutic approaches.

Background: Ectopic fat is also formed in muscles as well as the liver, where adipose-derived mesenchymal stem cells (ADSCs) promote adipogenesis. On the other hand, after muscle injury, muscle satellite cells (SCs) contribute to muscle repair through myodifferentiation. Human ADSCs are multipotent stem cells, but it remains unclear whether they are involved in myoblast differentiation. The aim is to find a novel myogenic cytokine and its signaling pathway that promotes the differentiation of human ADSCs-a potential source of new muscle precursor cells-into myoblasts.

Methods: An array kit was used to detect cytokines produced by ADSCs. After treating ADSCs with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-C) and different JAK inhibitors, MyHC1, a myodifferentiation marker, was detected by immunofluorescence staining and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression status of signaling molecules was determined by Western blotting and the recruitment of transcription factors to the MYOG promoter by chromatin immunoprecipitation (ChIP).

Results: IL-6 was detected at high concentrations in the culture supernatant of ADSCs. ADSCs stimulated with 5-aza-C became strongly positive for MyHC1 on day 21 post-stimulation. When co-stimulated with 5-aza-C and IL-6/sIL-6R, ADSCs became positive for MyHC1 protein and upregulated MYOG mRNA as early as day 14 post-stimulation. Co-stimulation with 5-aza-C and IL-6/sIL-6R resulted in phosphorylation of STAT1 and STAT3. The addition of a JAK2 inhibitor, but not JAK1/3 inhibitors, abolished the MyHC1 positivity and phosphorylation of STAT1 and STAT3. Co-stimulation with 5-aza-C and IL-6/sIL-6R during the myogenesis process resulted in the recruitment of STAT1, but not STAT3, to the MYOG promoter. Myoblast differentiation induced by stimulation with 5-aza-C was enhanced by activation of the IL-6/JAK2/STAT1/MYOG pathway.

Conclusions: Therefore, sustained IL-6/JAK2/STAT1 activation may serve as an important driver of human ADSC differentiation into myoblast, suggesting an important candidate signaling pathway for ameliorating muscle atrophy.