Inflammation and Regeneration最新文献

{"title":"Increased neutrophils in inflammatory bowel disease accelerate the accumulation of amyloid plaques in the mouse model of Alzheimer's disease.","authors":"Ryusei Kaneko,&nbsp;Ako Matsui,&nbsp;Mahiro Watanabe,&nbsp;Yoshihiro Harada,&nbsp;Mitsuhiro Kanamori,&nbsp;Natsumi Awata,&nbsp;Mio Kawazoe,&nbsp;Tomoaki Takao,&nbsp;Yutaro Kobayashi,&nbsp;Chie Kikutake,&nbsp;Mikita Suyama,&nbsp;Takashi Saito,&nbsp;Takaomi C Saido,&nbsp;Minako Ito","doi":"10.1186/s41232-023-00257-7","DOIUrl":"https://doi.org/10.1186/s41232-023-00257-7","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is one of the neurodegenerative diseases and characterized by the appearance and accumulation of amyloid-β (Aβ) aggregates and phosphorylated tau with aging. The aggregation of Aβ, which is the main component of senile plaques, is closely associated with disease progression. App^NL-G-F mice, a mouse model of AD, have three familial AD mutations in the amyloid-β precursor gene and exhibit age-dependent AD-like symptoms and pathology. Gut-brain interactions have attracted considerable attention and inflammatory bowel disease (IBD) has been associated with a higher risk of dementia, especially AD, in humans. However, the underlying mechanisms and the effects of intestinal inflammation on the brain in AD remain largely unknown. Therefore, we aimed to investigate the effects of intestinal inflammation on AD pathogenesis.</p><p><strong>Methods: </strong>Wild-type and App^NL-G-F mice at three months of age were fed with water containing 2% dextran sulfate sodium (DSS) to induce colitis. Immune cells in the brain were analyzed using single-cell RNA sequencing (scRNA-seq) analysis, and the aggregation of Aβ protein in the brain was analyzed via immunohistochemistry.</p><p><strong>Results: </strong>An increase in aggregated Aβ was observed in the brains of App^NL-G-F mice with acute intestinal inflammation. Detailed scRNA-seq analysis of immune cells in the brain showed that neutrophils in the brain increased after acute enteritis. Eliminating neutrophils by antibodies suppressed the accumulation of Aβ, which increased because of intestinal inflammation.</p><p><strong>Conclusion: </strong>These results suggest that neutrophils infiltrate the AD brain parenchyma when acute colitis occurs, and this infiltration is significantly related to disease progression. Therefore, we propose that neutrophil-targeted therapies could reduce Aβ accumulation observed in early AD and prevent the increased risk of AD due to colitis.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2023-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10015716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9483683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune-mediated myogenesis and acetylcholine receptor clustering promote a slow disease progression in ALS mouse models.","authors":"Cassandra Margotta,&nbsp;Paola Fabbrizio,&nbsp;Marco Ceccanti,&nbsp;Chiara Cambieri,&nbsp;Gabriele Ruffolo,&nbsp;Jessica D'Agostino,&nbsp;Maria Chiara Trolese,&nbsp;Pierangelo Cifelli,&nbsp;Veronica Alfano,&nbsp;Christian Laurini,&nbsp;Silvia Scaricamazza,&nbsp;Alberto Ferri,&nbsp;Gianni Sorarù,&nbsp;Eleonora Palma,&nbsp;Maurizio Inghilleri,&nbsp;Caterina Bendotti,&nbsp;Giovanni Nardo","doi":"10.1186/s41232-023-00270-w","DOIUrl":"https://doi.org/10.1186/s41232-023-00270-w","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease in terms of onset and progression rate. This may account for therapeutic clinical trial failure. Transgenic SOD1G93A mice on C57 or 129Sv background have a slow and fast disease progression rate, mimicking the variability observed in patients. Based on evidence inferring the active influence of skeletal muscle on ALS pathogenesis, we explored whether dysregulation in hindlimb skeletal muscle reflects the phenotypic difference between the two mouse models.</p><p><strong>Methods: </strong>Ex vivo immunohistochemical, biochemical, and biomolecular methodologies, together with in vivo electrophysiology and in vitro approaches on primary cells, were used to afford a comparative and longitudinal analysis of gastrocnemius medialis between fast- and slow-progressing ALS mice.</p><p><strong>Results: </strong>We reported that slow-progressing mice counteracted muscle denervation atrophy by increasing acetylcholine receptor clustering, enhancing evoked currents, and preserving compound muscle action potential. This matched with prompt and sustained myogenesis, likely triggered by an early inflammatory response switching the infiltrated macrophages towards a M2 pro-regenerative phenotype. Conversely, upon denervation, fast-progressing mice failed to promptly activate a compensatory muscle response, exhibiting a rapidly progressive deterioration of muscle force.</p><p><strong>Conclusions: </strong>Our findings further pinpoint the pivotal role of skeletal muscle in ALS, providing new insights into underestimated disease mechanisms occurring at the periphery and providing useful (diagnostic, prognostic, and mechanistic) information to facilitate the translation of cost-effective therapeutic strategies from the laboratory to the clinic.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2023-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9996869/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9321109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JAK inhibition ameliorates bone destruction by simultaneously targeting mature osteoclasts and their precursors.","authors":"Shinya Yari,&nbsp;Junichi Kikuta,&nbsp;Hotaka Shigyo,&nbsp;Yu Miyamoto,&nbsp;Daisuke Okuzaki,&nbsp;Yuki Furusawa,&nbsp;Masafumi Minoshima,&nbsp;Kazuya Kikuchi,&nbsp;Masaru Ishii","doi":"10.1186/s41232-023-00268-4","DOIUrl":"https://doi.org/10.1186/s41232-023-00268-4","url":null,"abstract":"<p><strong>Background: </strong>Rheumatoid arthritis (RA) is characterized by chronic inflammation and resultant cartilage/bone destruction because of aberrantly activated osteoclasts. Recently, novel treatments with several Janus kinase (JAK) inhibitors have been shown to successfully ameliorate arthritis-related inflammation and bone erosion, although their mechanisms of action for limiting bone destruction remain unclear. Here, we examined the effects of a JAK inhibitor on mature osteoclasts and their precursors by intravital multiphoton imaging.</p><p><strong>Methods: </strong>Inflammatory bone destruction was induced by local injection of lipopolysaccharides into transgenic mice carrying reporters for mature osteoclasts or their precursors. Mice were treated with the JAK inhibitor, ABT-317, which selectively inhibits the activation of JAK1, and then subjected to intravital imaging with multiphoton microscopy. We also used RNA sequencing (RNA-Seq) analysis to investigate the molecular mechanism underlying the effects of the JAK inhibitor on osteoclasts.</p><p><strong>Results: </strong>The JAK inhibitor, ABT-317, suppressed bone resorption by blocking the function of mature osteoclasts and by targeting the migratory behaviors of osteoclast precursors to the bone surface. Further exhaustive RNA-Seq analysis demonstrated that Ccr1 expression on osteoclast precursors was suppressed in the JAK inhibitor-treated mice; the CCR1 antagonist, J-113863, altered the migratory behaviors of osteoclast precursors, which led to the inhibition of bone destruction under inflammatory conditions.</p><p><strong>Conclusions: </strong>This is the first study to determine the pharmacological actions by which a JAK inhibitor blocks bone destruction under inflammatory conditions; this inhibition is beneficial because of its dual effects on both mature osteoclasts and immature osteoclast precursors.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2023-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9983229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10832015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular vesicles derived from mesenchymal stem cells - a novel therapeutic tool in infectious diseases.","authors":"Tasaduq Manzoor,&nbsp;Afnan Saleem,&nbsp;Nida Farooq,&nbsp;Lateef Ahmad Dar,&nbsp;Junaid Nazir,&nbsp;Sahar Saleem,&nbsp;Sameena Ismail,&nbsp;Mudasir Bashir Gugjoo,&nbsp;Parvaiz A Shiekh,&nbsp;Syed Mudasir Ahmad","doi":"10.1186/s41232-023-00266-6","DOIUrl":"https://doi.org/10.1186/s41232-023-00266-6","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are nano-sized lipid-bilayer encapsulated vesicles produced by the cells. These EVs are released into the surrounding space by almost all cell types. The EVs help in intercellular communication via their payloads which contain various proteins, lipids, and nucleic acids generated from the donor cells and allow for synergistic responses in surrounding cells. In recent years, EVs have been increasingly important in treating infectious diseases, including respiratory tract infections, urinary tract infections, wound infections, sepsis, and intestinal infections. Studies have confirmed the therapeutic value of mesenchymal stem cell-derived EVs (MSC-EVs) for treating infectious diseases to eliminate the pathogen, modulate the resistance, and restore tissue damage in infectious diseases. This can be achieved by producing antimicrobial substances, inhibiting pathogen multiplication, and activating macrophage phagocytic activity. Pathogen compounds can be diffused by inserting them into EVs produced and secreted by host cells or by secreting them as microbial cells producing EVs carrying signalling molecules and DNA shielding infected pathogens from immune attack. EVs play a key role in infectious pathogenesis and hold great promise for developing innovative treatments. In this review, we discuss the role of MSC-EVs in treating various infectious diseases.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2023-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9970864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9073128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell therapy for Parkinson's disease with induced pluripotent stem cells.","authors":"Asuka Morizane","doi":"10.1186/s41232-023-00269-3","DOIUrl":"https://doi.org/10.1186/s41232-023-00269-3","url":null,"abstract":"<p><p>Parkinson's disease (PD) is the second most common neurodegenerative disease and a prime target of cell therapies. In fact, aborted fetal tissue has been used as donor material for such therapies since the 1980s. These cell therapies, however, suffer from several problems, such as a short supply of donor materials, quality instability of the tissues, and ethical restrictions. The advancement of stem cell technologies has enabled the production of donor cells from pluripotent stem cells with unlimited scale, stable quality, and less ethical problems. Several research groups have established protocols to induce dopamine neural progenitors from pluripotent stem cells in a clinically compatible manner and confirmed efficacy and safety in non-clinical studies. Based on the results from these non-clinical studies, several clinical trials of pluripotent stem cell-based therapies for PD have begun. In the context of immune rejection, there are several modes of stem cell-based therapies: autologous transplantation, allogeneic transplantation without human leukocyte antigen-matching, and allogeneic transplantation with matching. In this mini-review, several practical points of stem cell-based therapies for PD are discussed.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2023-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9969678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10805642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular niches for hematopoietic stem cells in bone marrow under normal and malignant conditions.","authors":"Yoshiki Omatsu","doi":"10.1186/s41232-023-00267-5","DOIUrl":"https://doi.org/10.1186/s41232-023-00267-5","url":null,"abstract":"<p><p>Throughout adult life, most lineages of blood cells, including immune cells, are generated from hematopoietic stem cells (HSCs) in the bone marrow. HSCs are thought to require special microenvironments, termed niches, for their maintenance in the bone marrow; however, the identity of the HSC cellular niche has been a subject of long-standing debate. Although diverse candidates have been proposed so far, accumulated studies demonstrate that the bone marrow-specific population of fibroblastic reticular cells with long processes, termed CXC chemokine ligand 12-abundant reticular cells (which overlap strongly with leptin receptor-expressing cells), termed CAR/LepR⁺ cells, are the pivotal cellular component of niches for HSCs and lymphoid progenitors. Sinusoidal endothelial cells (ECs) are also important for hematopoietic homeostasis and regeneration. Hematopoiesis is altered dynamically by various stimuli such as inflammation, infection, and leukemia, all of which affect cellular niches and alter their function. Therefore, it is important to consider situations in which stimuli affect HSCs, either via direct interaction or indirectly via the hematopoietic niches. In this review, the dynamics of cellular niches in the steady state and disease are described, with a focus on CAR/LepR⁺ cells and ECs.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2023-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9327215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Injury-induced interleukin-1 alpha promotes Lgr5 hair follicle stem cells de novo regeneration and proliferation via regulating regenerative microenvironment in mice.","authors":"Guang Yang,&nbsp;Haiyan Chen,&nbsp;Qun Chen,&nbsp;Jiayi Qiu,&nbsp;Mulan Qahar,&nbsp;Zhimeng Fan,&nbsp;Weiwei Chu,&nbsp;Edward E Tredget,&nbsp;Yaojiong Wu","doi":"10.1186/s41232-023-00265-7","DOIUrl":"https://doi.org/10.1186/s41232-023-00265-7","url":null,"abstract":"<p><strong>Background: </strong>The hair follicles (HFs) are barely regenerated after loss in injuries in mammals as well as in human beings. Recent studies have shown that the regenerative ability of HFs is age-related; however, the relationship between this phenomenon and the stem cell niche remains unclear. This study aimed to find a key secretory protein that promotes the HFs regeneration in the regenerative microenvironment.</p><p><strong>Methods: </strong>To explore why age affects HFs de novo regeneration, we established an age-dependent HFs regeneration model in leucine-rich repeat G protein-coupled receptor 5 (Lgr5) + /mTmG mice. Proteins in tissue fluids were analyzed by high-throughput sequencing. The role and mechanism of candidate proteins in HFs de novo regeneration and hair follicle stem cells (HFSCs) activation were investigated through in vivo experiments. The effects of candidate proteins on skin cell populations were investigated by cellular experiments.</p><p><strong>Results: </strong>Mice under 3-week-old (3W) could regenerate HFs and Lgr5 HFSCs, which were highly correlated with the immune cells, cytokines, IL-17 signaling pathway, and IL-1α level in the regeneration microenvironment. Additionally, IL-1α injection induced de novo regeneration of HFs and Lgr5 HFSCs in 3W mouse model with a 5 mm wound, as well as promoted activation and proliferation of Lgr5 HFSCs in 7-week-old (7W) mice without wound. Dexamethasone and TEMPOL inhibited the effects of IL-1α. Moreover, IL-1α increased skin thickness and promoted the proliferation of human epidermal keratinocyte line (HaCaT) and skin-derived precursors (SKPs) in vivo and in vitro, respectively.</p><p><strong>Conclusions: </strong>In conclusion, injury-induced IL-1α promotes HFs regeneration by modulating inflammatory cells and oxidative stress-induced Lgr5 HFSCs regeneration as well as promoting skin cell populations proliferation. This study uncovers the underlying molecular mechanisms enabling HFs de novo regeneration in an age-dependent model.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2023-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9940372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9326726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A lesion-selective albumin-CTLA4Ig as a safe and effective treatment for collagen-induced arthritis.","authors":"Fu-Yao Jiang,&nbsp;Yan-Zhu Zhang,&nbsp;Yuan-Hong Tai,&nbsp;Chien-Yu Chou,&nbsp;Yu-Ching Hsieh,&nbsp;Ya-Chi Chang,&nbsp;Hsiao-Chen Huang,&nbsp;Zhi-Qin Li,&nbsp;Yuan-Chin Hsieh,&nbsp;I-Ju Chen,&nbsp;Bo-Cheng Huang,&nbsp;Yu-Cheng Su,&nbsp;Wen-Wei Lin,&nbsp;Hsin-Chieh Lin,&nbsp;Jui-I Chao,&nbsp;Shyng-Shiou F Yuan,&nbsp;Yun-Ming Wang,&nbsp;Tian-Lu Cheng,&nbsp;Shey-Cherng Tzou","doi":"10.1186/s41232-023-00264-8","DOIUrl":"https://doi.org/10.1186/s41232-023-00264-8","url":null,"abstract":"<p><strong>Background: </strong>CTLA4Ig is a dimeric fusion protein of the extracellular domain of cytotoxic T-lymphocyte protein 4 (CTLA4) and an Fc (Ig) fragment of human IgG₁ that is approved for treating rheumatoid arthritis. However, CTLA4Ig may induce adverse effects. Developing a lesion-selective variant of CTLA4Ig may improve safety while maintaining the efficacy of the treatment.</p><p><strong>Methods: </strong>We linked albumin to the N-terminus of CTLA4Ig (termed Alb-CTLA4Ig) via a substrate sequence of matrix metalloproteinase (MMP). The binding activities and the biological activities of Alb-CTLA4Ig before and after MMP digestion were analyzed by a cell-based ELISA and an in vitro Jurkat T cell activation assay. The efficacy and safety of Alb-CTLA4Ig in treating joint inflammation were tested in mouse collagen-induced arthritis.</p><p><strong>Results: </strong>Alb-CTLA4Ig is stable and inactive under physiological conditions but can be fully activated by MMPs. The binding activity of nondigested Alb-CTLA4Ig was at least 10,000-fold weaker than that of MMP-digested Alb-CTLA4Ig. Nondigested Alb-CTLA4Ig was unable to inhibit Jurkat T cell activation, whereas MMP-digested Alb-CTLA4Ig was as potent as conventional CTLA4Ig in inhibiting the T cells. Alb-CTLA4Ig was converted to CTLA4Ig in the inflamed joints to treat mouse collagen-induced arthritis, showing similar efficacy to that of conventional CTLA4Ig. In contrast to conventional CTLA4Ig, Alb-CTLA4Ig did not inhibit the antimicrobial responses in the spleens of the treated mice.</p><p><strong>Conclusions: </strong>Our study indicates that Alb-CTLA4Ig can be activated by MMPs to suppress tissue inflammation in situ. Thus, Alb-CTLA4Ig is a safe and effective treatment for collagen-induced arthritis in mice.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2023-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9933273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10742788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IFN-γ-STAT1-mediated CD8⁺ T-cell-neural stem cell cross talk controls astrogliogenesis after spinal cord injury.","authors":"Jingyu Wang,&nbsp;Lintao Xu,&nbsp;Deqing Peng,&nbsp;Yongjian Zhu,&nbsp;Zhaowen Gu,&nbsp;Ying Yao,&nbsp;Heyangzi Li,&nbsp;Xi Cao,&nbsp;Chun-Yan Fu,&nbsp;Mingzhi Zheng,&nbsp;Xinghui Song,&nbsp;Yueming Ding,&nbsp;Yueliang Shen,&nbsp;Jinjie Zhong,&nbsp;Ying-Ying Chen,&nbsp;Jue Hu,&nbsp;Lin-Lin Wang","doi":"10.1186/s41232-023-00263-9","DOIUrl":"https://doi.org/10.1186/s41232-023-00263-9","url":null,"abstract":"<p><strong>Background: </strong>Spinal cord injury (SCI) causes nearly all patients to suffer from protracted disabilities. An emerging therapeutic strategy involving the recruitment of endogenous neural stem cells (NSCs) has been developed. However, endogenous NSCs in the adult spinal cord differentiate into mostly astrocytes after traumatic injury, forming glial scars, which is a major cause of regeneration failure in SCI. Thus, understanding which factors drive the activation and differentiation of endogenous NSCs after SCI is critical for developing therapeutic drugs.</p><p><strong>Methods: </strong>The infiltration, state, and location of CD8⁺ T cells in spinal cord after traumatic injury were analyzed by flow cytometry and immunofluorescence (IF) staining. The Basso Mouse Scale (BMS) scores and rotarod testing were used for motor behavioral analysis. NSCs were co-cultured with CD8⁺ T cells. EdU assay was used to detect proliferative cells. Western blotting was used to analyze the expression levels of STAT1, p-STAT1, and p27. ChIP-seq and ChIP-qRT-PCR analyses were used to detect the downstream of STAT1. Nestin-CreERT2::Ai9 transgenic mice were used to genetic lineage tracing of Nestin⁺ NSCs after SCI in vivo.</p><p><strong>Results: </strong>A prolonged increase of activated CD8⁺ T cells occurs in the injured spinal cords. The behavioral analysis demonstrated that the administration of an anti-CD8 antibody promotes the recovery of locomotor function. Then, we discovered that CD8⁺ T cells suppressed the proliferation of NSCs and promoted the differentiation of NSCs into astrocytes by the IFN-γ-STAT1 pathway in vitro. ChIP-seq and ChIP-qRT-PCR analysis revealed that STAT1 could directly bind to the promoters of astrocyte marker genes GFAP and Aldh1l1. Genetic lineage tracing of Nestin⁺ NSCs demonstrated that most NSCs differentiated into astrocytes following SCI. Depleting CD8⁺ T cells reduced the differentiation of NSCs into astrocytes and instead promoted the differentiation of NSCs into oligodendrocytes.</p><p><strong>Conclusion: </strong>In conclusion, CD8⁺ T cells suppressed the proliferation of NSCs and promoted the differentiation of NSCs into astrocytes by the IFN-γ-STAT1-GFAP/Aldhl1l axis. Our study identifies INF-γ as a critical mediator of CD8⁺ T-cell-NSC cross talk and a potential node for therapeutic intervention in SCI.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2023-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9926765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9287326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Canonical Wnt signaling activation by chimeric antigen receptors for efficient cardiac differentiation from mouse embryonic stem cells.","authors":"Takahiro Sogo,&nbsp;Shu Nakao,&nbsp;Tasuku Tsukamoto,&nbsp;Tomoe Ueyama,&nbsp;Yukihiro Harada,&nbsp;Dai Ihara,&nbsp;Tomoaki Ishida,&nbsp;Masato Nakahara,&nbsp;Koji Hasegawa,&nbsp;Yuka Akagi,&nbsp;Yasuyuki S Kida,&nbsp;Osamu Nakagawa,&nbsp;Teruyuki Nagamune,&nbsp;Masahiro Kawahara,&nbsp;Teruhisa Kawamura","doi":"10.1186/s41232-023-00258-6","DOIUrl":"https://doi.org/10.1186/s41232-023-00258-6","url":null,"abstract":"<p><strong>Background: </strong>Canonical Wnt signaling is involved in a variety of biological processes including stem cell renewal and differentiation, embryonic development, and tissue regeneration. Previous studies reported the stage-specific roles of the Wnt signaling in heart development. Canonical Wnt signal activation by recombinant Wnt3a in the early phase of differentiation enhances the efficiency of myocardial cell production from pluripotent stem cells. However, the hydrophobicity of Wnt proteins results in high cost to produce the recombinant proteins and presents an obstacle to their preparation and application for therapeutics, cell therapy, or molecular analysis of Wnt signaling.</p><p><strong>Methods: </strong>To solve this problem, we generated an inexpensive molecule-responsive differentiation-inducing chimeric antigen receptor (designated as diCAR) that can activate Wnt3a signaling. The extracellular domains of low-density-lipoprotein receptor-related protein 6 (LRP6) and frizzeled-8 (FZD8) were replaced with single-chain Fv of anti-fluorescein (FL) antibody, which can respond to FL-conjugated bovine serum albumin (BSA-FL) as a cognate ligand. We then analyzed the effect of this diCAR on Wnt signal activation and cardiomyocyte differentiation of mouse embryonic stem cells in response to BSA-FL treatment.</p><p><strong>Results: </strong>Embryonic stem cell lines stably expressing this paired diCAR, named Wnt3a-diCAR, showed TCF/β-catenin-dependent transactivation by BSA-FL in a dose-dependent manner. Treatment with either Wnt3a recombinant protein or BSA-FL in the early phase of differentiation revealed similar changes of global gene expressions and resulted in efficient myocardial cell differentiation. Furthermore, BSA-FL-mediated signal activation was not affected by a Wnt3a antagonist, Dkk1, suggesting that the signal transduction via Wnt3a-diCAR is independent of endogenous LRP6 or FZD8.</p><p><strong>Conclusion: </strong>We anticipate that Wnt3a-diCAR enables target-specific signal activation, and could be an economical and powerful tool for stem cell-based regeneration therapy.</p>","PeriodicalId":13588,"journal":{"name":"Inflammation and Regeneration","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2023-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9912504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10693588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}