{"title":"810-nm Photobiomodulation Evokes Glutamate Release in Normal and Rotenone-Dysfunctional Cortical Nerve Terminals by Modulating Mitochondrial Energy Metabolism.","authors":"Silvia Ravera, Elisa Farsetti, Guido Maura, Manuela Marcoli, Matteo Bozzo, Chiara Cervetto, Andrea Amaroli","doi":"10.3390/cells14020067","DOIUrl":"10.3390/cells14020067","url":null,"abstract":"<p><p>The dysfunction of mitochondria, the primary source of cellular energy and producer of reactive oxygen species (ROS), is associated with brain aging and neurodegenerative diseases. Scientific evidence indicates that light in the visible and near-infrared spectrum can modulate mitochondrial activity, a phenomenon known in medicine as photobiomodulation therapy (PBM-t). The beneficial effects of PBM-t on dementia and neurodegeneration have been reviewed in the literature. However, the molecular mechanisms underlying these findings have yet to be fully elucidated. This study investigates the mechanism behind dose-dependent glutamate release in nerve terminals after irradiation with 810 nm, 1 W for 60 s continuous, 1 cm<sup>2</sup>, 1 W/cm<sup>2</sup>, 60 J, 60 J/cm<sup>2</sup> (810 nm-1 W) or 810 nm, 0.1 W for 60 s continuous, 1 cm<sup>2</sup>, 0.1 W/cm<sup>2</sup>, 6 J, 6 J/cm<sup>2</sup> (810 nm-0.1 W), focusing on mitochondrial activities. The results show that PBM modulated the mitochondrial metabolism of cortical nerve terminals and supported a power-dependent increase in oxidative phosphorylation (OxPhos) activity when stimulated with pyruvate plus malate (P/M) or succinate (succ) as respiratory substrates. The PBM-induced increase in OxPhos was sensitive to adding rotenone (Complex I inhibitor) and antimycin A (Complex III inhibitor) when synaptosomes were stimulated with P/M, but only to antimycin A when stimulated with succ. This allowed us to observe that the glutamate efflux, disrupted in the presence of rotenone, was partially restored by PBM due to the increase in the OxPhos pathway led by Complex II. This evidence suggests that PBM, acting on mitochondria, could facilitate physiological communication within the neuron-astrocyte network through vesicular glutamate release, potentially regulating healthy brain function and brain dysfunction.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 2","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11764165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2025-01-07DOI: 10.3390/cells14020063
Makiko Nakagawa, Tadashi Nakagawa
{"title":"CUL4-Based Ubiquitin Ligases in Chromatin Regulation: An Evolutionary Perspective.","authors":"Makiko Nakagawa, Tadashi Nakagawa","doi":"10.3390/cells14020063","DOIUrl":"10.3390/cells14020063","url":null,"abstract":"<p><p>Ubiquitylation is a post-translational modification that modulates protein function and stability. It is orchestrated by the concerted action of three types of enzymes, with substrate specificity governed by ubiquitin ligases (E3s), which may exist as single proteins or as part of multi-protein complexes. Although Cullin (CUL) proteins lack intrinsic enzymatic activity, they participate in the formation of active ubiquitin ligase complexes, known as Cullin-Ring ubiquitin Ligases (CRLs), through their association with ROC1 or ROC2, along with substrate adaptor and receptor proteins. Mammalian genomes encode several CUL proteins (CUL1-9), each contributing to distinct CRLs. Among these CUL proteins, CUL1, CUL3, and CUL4 are believed to be the most ancient and evolutionarily conserved from yeast to mammals, with CUL4 uniquely duplicated in vertebrates. Genetic evidence strongly implicates CUL4-based ubiquitin ligases (CRL4s) in chromatin regulation across various species and suggests that, in vertebrates, CRL4s have also acquired a cytosolic role, which is facilitated by a cytosol-localizing paralog of CUL4. Substrates identified through biochemical studies have elucidated the molecular mechanisms by which CRL4s regulate chromatin and cytosolic processes. The substantial body of knowledge on CUL4 biology amassed over the past two decades provides a unique opportunity to explore the functional evolution of CRL4. In this review, we synthesize the available structural, genetic, and biochemical data on CRL4 from various model organisms and discuss the conserved and novel functions of CRL4s.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 2","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11763709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2025-01-07DOI: 10.3390/cells14020064
Sasi Kumar Jagadeesan, Ahmad Galuta, Ryan Vimukthi Sandarage, Eve Chung Tsai
{"title":"Transcriptomic and Functional Landscape of Adult Human Spinal Cord NSPCs Compared to iPSC-Derived Neural Progenitor Cells.","authors":"Sasi Kumar Jagadeesan, Ahmad Galuta, Ryan Vimukthi Sandarage, Eve Chung Tsai","doi":"10.3390/cells14020064","DOIUrl":"10.3390/cells14020064","url":null,"abstract":"<p><p>The adult human spinal cord harbors diverse populations of neural stem/progenitor cells (NSPCs) essential for neuroregeneration and central nervous system repair. While induced pluripotent stem cell (iPSC)-derived NSPCs offer significant therapeutic potential, understanding their molecular and functional alignment with bona fide spinal cord NSPCs is crucial for developing autologous cell therapies that enhance spinal cord regeneration and minimize immune rejection. In this study, we present the first direct transcriptomic and functional comparison of syngeneic adult human NSPC populations, including bona fide spinal cord NSPCs and iPSC-derived NSPCs regionalized to the spinal cord (iPSC-SC) and forebrain (iPSC-Br). RNA sequencing analysis revealed distinct transcriptomic profiles and functional disparities among NSPC types. iPSC-Br NSPCs exhibited a close resemblance to bona fide spinal cord NSPCs, characterized by enriched expression of neurogenesis, axon guidance, synaptic signaling, and voltage-gated calcium channel activity pathways. Conversely, iPSC-SC NSPCs displayed significant heterogeneity, suboptimal regional specification, and elevated expression of neural crest and immune response-associated genes. Functional assays corroborated the transcriptomic findings, demonstrating superior neurogenic potential in iPSC-Br NSPCs. Additionally, we assessed donor-specific influences on NSPC behavior by analyzing gene expression and differentiation outcomes across syngeneic populations from multiple individuals. Donor-specific factors significantly modulated transcriptomic profiles, with notable variability in the alignment of iPSC-derived NSPCs to bona fide spinal cord NSPCs. Enrichment of pathways related to neurogenesis, axon guidance, and synaptic signaling varied across donors, highlighting the impact of genetic and epigenetic individuality on NSPC behavior.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 2","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11763936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2025-01-07DOI: 10.3390/cells14020069
Aiman B Awan, Maryiam Jama Ali Osman, Omar M Khan
{"title":"Ubiquitination Enzymes in Cancer, Cancer Immune Evasion, and Potential Therapeutic Opportunities.","authors":"Aiman B Awan, Maryiam Jama Ali Osman, Omar M Khan","doi":"10.3390/cells14020069","DOIUrl":"10.3390/cells14020069","url":null,"abstract":"<p><p>Ubiquitination is cells' second most abundant posttranslational protein modification after phosphorylation. The ubiquitin-proteasome system (UPS) is critical in maintaining essential life processes such as cell cycle control, DNA damage repair, and apoptosis. Mutations in ubiquitination pathway genes are strongly linked to the development and spread of multiple cancers since several of the UPS family members possess oncogenic or tumor suppressor activities. This comprehensive review delves into understanding the ubiquitin code, shedding light on its role in cancer cell biology and immune evasion. Furthermore, we highlighted recent advances in the field for targeting the UPS pathway members for effective therapeutic intervention against human cancers. We also discussed the recent update on small-molecule inhibitors and PROTACs and their progress in preclinical and clinical trials.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 2","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11763706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The <i>MCPH7</i> Gene Product STIL Is Essential for Dendritic Spine Formation.","authors":"Tohru Matsuki, Hidenori Tabata, Masashi Ueda, Hideaki Ito, Koh-Ichi Nagata, Yumi Tsuneura, Shima Eda, Kenji Kasai, Atsuo Nakayama","doi":"10.3390/cells14020062","DOIUrl":"10.3390/cells14020062","url":null,"abstract":"<p><p>Dendritic spine formation/maintenance is highly dependent on actin cytoskeletal dynamics, which is regulated by small GTPases Rac1 and Cdc42 through their downstream p21-activated kinase/LIM-kinase-I/cofilin pathway. ARHGEF7, also known as ß-PIX, is a guanine nucleotide exchange factor for Rac1 and Cdc42, thereby activating Rac1/Cdc42 and the downstream pathway, leading to the upregulation of spine formation/maintenance. We found that STIL, one of the primary microcephaly gene products, is associated with ARHGEF7 in dendritic spines and that knockdown of <i>Stil</i> resulted in a significant reduction in dendritic spines in neurons both in vitro and in vivo. Rescue experiments indicated that the STIL requirement for spine formation/maintenance depended on its coiled coil domain that mediates the association with ARHGEF7. The overexpression of Rac1/Cdc42 compensated for the spine reduction caused by STIL knockdown. FRET experiments showed that Rac activation is impaired in STIL knockdown neurons. Chemical long-term potentiation, which triggers Rac activation, promoted STIL accumulation in the spine and its association with ARHGEF7. The dynamics of these proteins further supported their coordinated involvement in spine formation/maintenance. Based on these findings, we concluded that the centrosomal protein STIL is a novel regulatory factor essential for spine formation/maintenance by activating Rac and its downstream pathway, possibly through the association with ARHGEF7.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 2","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11764357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2025-01-07DOI: 10.3390/cells14020066
Jianan Chen, Qiong Wu, Anders E Berglund, Robert J Macaulay, Arnold B Etame
{"title":"Comprehensive Analysis Identifies <i>THEMIS2</i> as a Potential Prognostic and Immunological Biomarker in Glioblastoma.","authors":"Jianan Chen, Qiong Wu, Anders E Berglund, Robert J Macaulay, Arnold B Etame","doi":"10.3390/cells14020066","DOIUrl":"10.3390/cells14020066","url":null,"abstract":"<p><p>Glioblastoma (GBM) is a highly aggressive brain tumor characterized by its ability to evade the immune system, hindering the efficacy of current immunotherapies. Recent research has highlighted the important role of immunosuppressive macrophages in the tumor microenvironment (TME) in driving this immune evasion. In this study, we are the first to identify <i>THEMIS2</i> as a key regulator of tumor-associated macrophage (TAM)-mediated immunosuppression in GBM. We found that a high <i>THEMIS2</i> expression is associated with poor patient outcomes and increased infiltration of immune cells, particularly macrophages. Functional analyses revealed <i>THEMIS2</i>'s critical involvement in immune-related pathways, including immune response activation, mononuclear cell differentiation, and the positive regulation of cytokine production. Additionally, single-cell RNA sequencing data demonstrated that macrophages with a high <i>THEMIS2</i> expression were associated with increased phagocytosis, immune suppression, and enhanced tumor growth. These findings suggest that <i>THEMIS2</i> could serve as both a prognostic marker and a therapeutic target for enhancing anti-tumor immunity in GBM.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 2","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11764009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2025-01-07DOI: 10.3390/cells14020068
Ryan Conesa-Bakkali, Macarena Morillo-Huesca, Jonathan Martínez-Fábregas
{"title":"Non-Canonical, Extralysosomal Activities of Lysosomal Peptidases in Physiological and Pathological Conditions: New Clinical Opportunities for Cancer Therapy.","authors":"Ryan Conesa-Bakkali, Macarena Morillo-Huesca, Jonathan Martínez-Fábregas","doi":"10.3390/cells14020068","DOIUrl":"10.3390/cells14020068","url":null,"abstract":"<p><p>Lysosomes are subcellular compartments characterised by an acidic pH, containing an ample variety of acid hydrolases involved in the recycling of biopolymers. Among these hydrolases, lysosomal proteases have merely been considered as end-destination proteases responsible for the digestion of waste proteins, trafficked to the lysosomal compartment through autophagy and endocytosis. However, recent reports have started to unravel specific roles for these proteases in the regulation of initially unexpected biological processes, both under physiological and pathological conditions. Furthermore, some lysosomal proteases are no longer restricted to the lysosomal compartment, as more novel non-canonical, extralysosomal targets are being identified. Currently, lysosomal proteases are accepted to play key functions in the extracellular milieu, attached to the plasma membrane and even in the cytosolic and nuclear compartments of the cell. Under physiological conditions, lysosomal proteases, through non-canonical, extralysosomal activities, have been linked to cell differentiation, regulation of gene expression, and cell division. Under pathological conditions, these proteases have been linked to cancer, mostly through their extralysosomal activities in the cytosol and nuclei of cells. In this review, we aim to provide a comprehensive summary of our current knowledge about the extralysosomal, non-canonical functions of lysosomal proteases, both under physiological and pathological conditions, with a particular interest in cancer, that could potentially offer new opportunities for clinical intervention.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 2","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11763575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2025-01-07DOI: 10.3390/cells14020070
Enrique Estudillo, Jorge Iván Castillo-Arellano, Emilio Martínez, Edgar Rangel-López, Adolfo López-Ornelas, Roxana Magaña-Maldonado, Laura Adalid-Peralta, Iván Velasco, Itzel Escobedo-Ávila
{"title":"Modeling the Effect of Cannabinoid Exposure During Human Neurodevelopment Using Bidimensional and Tridimensional Cultures.","authors":"Enrique Estudillo, Jorge Iván Castillo-Arellano, Emilio Martínez, Edgar Rangel-López, Adolfo López-Ornelas, Roxana Magaña-Maldonado, Laura Adalid-Peralta, Iván Velasco, Itzel Escobedo-Ávila","doi":"10.3390/cells14020070","DOIUrl":"10.3390/cells14020070","url":null,"abstract":"<p><p>Our knowledge about the consumption of cannabinoids during pregnancy lacks consistent evidence to determine whether it compromises neurodevelopment. Addressing this task is challenging and complex since pregnant women display multiple confounding factors that make it difficult to identify the real effect of cannabinoids' consumption. Recent studies shed light on this issue by using pluripotent stem cells of human origin, which can recapitulate human neurodevelopment. These revolutionary platforms allow studying how exogenous cannabinoids could alter human neurodevelopment without ethical concerns and confounding factors. Here, we review the information to date on the clinical studies about the impact of exogenous cannabinoid consumption on human brain development and how exogenous cannabinoids alter nervous system development in humans using cultured pluripotent stem cells as 2D and 3D platforms to recapitulate brain development.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 2","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11763397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2025-01-06DOI: 10.3390/cells14010060
Abdul Basith Fithroni, Haruki Inoue, Shengli Zhou, Taufik Fatwa Nur Hakim, Takashi Tada, Minoru Suzuki, Yoshinori Sakurai, Manabu Ishimoto, Naoyuki Yamada, Rani Sauriasari, Wolfgang A G Sauerwein, Kazunori Watanabe, Takashi Ohtsuki, Eiji Matsuura
{"title":"Novel Drug Delivery Particles Can Provide Dual Effects on Cancer \"Theranostics\" in Boron Neutron Capture Therapy.","authors":"Abdul Basith Fithroni, Haruki Inoue, Shengli Zhou, Taufik Fatwa Nur Hakim, Takashi Tada, Minoru Suzuki, Yoshinori Sakurai, Manabu Ishimoto, Naoyuki Yamada, Rani Sauriasari, Wolfgang A G Sauerwein, Kazunori Watanabe, Takashi Ohtsuki, Eiji Matsuura","doi":"10.3390/cells14010060","DOIUrl":"10.3390/cells14010060","url":null,"abstract":"<p><p>Boron (B) neutron capture therapy (BNCT) is a novel non-invasive targeted cancer therapy based on the nuclear capture reaction <sup>10</sup>B (n, alpha) <sup>7</sup>Li that enables the death of cancer cells without damaging neighboring normal cells. However, the development of clinically approved boron drugs remains challenging. We have previously reported on self-forming nanoparticles for drug delivery consisting of a biodegradable polymer, namely, \"AB-type\" Lactosome<sup>®</sup> nanoparticles (AB-Lac particles)- highly loaded with hydrophobic B compounds, namely <i>o</i>-Carborane (Carb) or 1,2-dihexyl-<i>o</i>-Carborane (diC6-Carb), and the latter (diC6-Carb) especially showed the \"molecular glue\" effect. Here we present in vivo and ex vivo studies with human pancreatic cancer (AsPC-1) cells to find therapeutically optimal formulas and the appropriate treatment conditions for these particles. The biodistribution of the particles was assessed by the tumor/normal tissue ratio (T/N) in terms of tumor/muscle (T/M) and tumor/blood (T/B) ratios using near-infrared fluorescence (NIRF) imaging with indocyanine green (ICG). The in vivo and ex vivo accumulation of B delivered by the injected AB-Lac particles in tumor lesions reached a maximum by 12 h post-injection. Irradiation studies conducted both in vitro and in vivo showed that AB-Lac particles-loaded with either <sup>10</sup>B-Carb or <sup>10</sup>B-diC6-Carb significantly inhibited the growth of AsPC-1 cancer cells or strongly inhibited their growth, with the latter method being significantly more effective. Surprisingly, a similar in vitro and in vivo irradiation study showed that ICG-labeled AB-Lac particles alone, i.e., without any <sup>10</sup>B compounds, also revealed a significant inhibition. Therefore, we expect that our ICG-labeled AB-Lac particles-loaded with <sup>10</sup>B compound(s) may be a novel and promising candidate for providing not only NIRF imaging for a practical diagnosis but also the dual therapeutic effects of induced cancer cell death, i.e., \"theranostics\".</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 1","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11719788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Small Extracellular Vesicles Promote Axon Outgrowth by Engaging the Wnt-Planar Cell Polarity Pathway.","authors":"Samar Ahmad, Tania Christova, Melanie Pye, Masahiro Narimatsu, Siyuan Song, Jeffrey L Wrana, Liliana Attisano","doi":"10.3390/cells14010056","DOIUrl":"https://doi.org/10.3390/cells14010056","url":null,"abstract":"<p><p>In neurons, the acquisition of a polarized morphology is achieved upon the outgrowth of a single axon from one of several neurites. Small extracellular vesicles (sEVs), such as exosomes, from diverse sources are known to promote neurite outgrowth and thus may have therapeutic potential. However, the effect of fibroblast-derived exosomes on axon elongation in neurons of the central nervous system under growth-permissive conditions remains unclear. Here, we show that fibroblast-derived sEVs promote axon outgrowth and a polarized neuronal morphology in mouse primary embryonic cortical neurons. Mechanistically, we demonstrate that the sEV-induced increase in axon outgrowth requires endogenous Wnts and core PCP components including Prickle, Vangl, Frizzled, and Dishevelled. We demonstrate that sEVs are internalized by neurons, colocalize with Wnt7b, and induce relocalization of Vangl2 to the distal axon during axon outgrowth. In contrast, sEVs derived from neurons or astrocytes do not promote axon outgrowth, while sEVs from activated astrocytes inhibit elongation. Thus, our data reveal that fibroblast-derived sEVs promote axon elongation through the Wnt-PCP pathway in a manner that is dependent on endogenous Wnts.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 1","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11720052/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143055949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}