Frontiers in Cell and Developmental Biology最新文献

{"title":"CGRP-mediated neuro-vascular-pulp cell crosstalk is essential for dental pulp repair.","authors":"Zixin Wu, Junyang Chen, Yiming Zhao, Zhenjuan Zhou, Rui Lin, Wei Liu","doi":"10.3389/fcell.2026.1793692","DOIUrl":"https://doi.org/10.3389/fcell.2026.1793692","url":null,"abstract":"<p><strong>Introduction: </strong>The repair of dental pulp injury is the cornerstone of vital pulp therapy. Traditional research has predominantly focused on the roles of immune cells, vascular endothelial cells, and dental pulp stem cells, often overlooking the active regulatory functions of the sensory neural network. Sensory nerve fibers constitute nearly 40% of the dental pulp volume, and their released neuropeptides, such as calcitonin Gene-Related Peptide (CGRP), are hypothesized to coordinate the repair process via intercellular communication. This study aims to systematically elucidate the molecular mechanisms by which sensory nerves and their key neuropeptide, CGRP, regulate angiogenesis and the activation of stromal cells within the injured pulp microenvironment, thereby providing a theoretical basis for novel pulp regeneration strategies targeting neural signaling pathways.</p><p><strong>Methods: </strong>The cell-cell communication network in dental pulp was using single-cell transcriptome analysis (GSE197289, GSE274562, GSE280528). A series of in vitrocellular experiments, including qPCR, Western blot, immunofluorescence, scratch wound healing assay, and tube formation assay, were employed to evaluate the effects of CGRP on cell migration, angiogenesis, and mineralization. A mouse model of dentin-pulp injury was established, and the in vivoangiogenic changes were validated through intervention with the CGRP receptor antagonist BIBN4096BS. RNA sequencing was conducted to analyze the transcriptional reprogramming of human dental pulp cells (DPCs) induced by CGRP.</p><p><strong>Results: </strong>Single-cell communication analysis revealed intensive CGRP signaling interactions between sensory neurons, endothelial cells, and dental pulp cells. In vitroexperiments demonstrated that CGRP directly enhanced the tube-forming and migratory capabilities of human umbilical vein endothelial cells (HUVECs) and upregulated the expression of CD31/VEGFA. Furthermore, CGRP potentiated the mineralization of dental Pulp Stem Cells (DPSCs) via a paracrine mechanism. Concurrently, CGRP significantly accelerated the migration of DPCs, and the conditioned medium from CGRP-pretreated DPCs enhanced endothelial tube formation, a mechanism involving the upregulation of VEGFA and the activation of IL-17/TNF signaling pathways. In vivoexperiments confirmed that inhibition of CGRP signaling significantly reduced angiogenesis (CD31<sup>+</sup> signals) in the injured pulp area of mice.</p><p><strong>Conclusion: </strong>This study elucidates that the sensory neuropeptide CGRP drives a \"neuro-vascular-stromal cell\" collaborative network during pulp repair through dual pathways: directly activating endothelial cell function and indirectly modulating the paracrine profile of dental pulp cells (e.g., upregulating VEGFA), thereby promoting angiogenesis and stem cell differentiation. This discovery not only deepens the understanding of the self-repair mechanisms of denta","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1793692"},"PeriodicalIF":4.6,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13141303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835912","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":"Integrative transcriptomic analysis reveals miR-26a-5p downregulation and a potential predictive gene signature for the progression of metabolic liver disease.","authors":"Andrei Sorop, Alina-Veronica Ghionescu, Diana Larisa Ancuța, Maria-Gabriela Croitoru, Cristin Coman, Daniela Lixandru, Simona Olimpia Dima","doi":"10.3389/fcell.2026.1805025","DOIUrl":"https://doi.org/10.3389/fcell.2026.1805025","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction-associated steatotic liver disease (MASLD) is an important inducer of hepatocellular carcinoma (HCC). MicroRNAs are key regulators of tumorigenesis. Among these, miR-26a-5p is known to be associated with liver pathogenesis, yet its role in linking MASLD progression to HCC development remains incompletely understood.</p><p><strong>Methods: </strong>Hepatic miR-26a-5p expression was quantified in the C57BL/6 mice with a 3-month high-carbohydrate diet (HCD). Public transcriptomic datasets with MASLD and HCC samples were analyzed to identify predicted miR-26a-5p downstream candidates upregulated in the above-mentioned diseases. Associations with tumor features were examined, and protein expression of β-catenin, c-MYC and EpCAM were evaluated after miR-26a-5p modulation.</p><p><strong>Results: </strong>Integrative bioinformatics identified miR-26a-5p as a candidate prognostic indicator for metabolic liver disease progression. <i>In vivo</i>, results confirmed that suppressed miR-26a-5p expression is a hallmark of diet-induced metabolic perturbation. Mechanistically, <i>in vitro</i> modulation of miR-26a-5p attenuated oncogenic signaling via the β-catenin/c-Myc/EpCAM axis, establishing its role as a tumor suppressor. Notably, <i>in silico</i> analysis of HCC tissues revealed that high miR-26a-5p levels correlate with enhanced antitumor immunity. Leveraging these insights, we constructed a transcriptional signature from miR-26a-5p downstream candidates and MASLD-HCC differentially expressed genes. This signature effectively stratifies MASLDpatients, discriminating molecular risk groups associated with progression to HCC.</p><p><strong>Conclusion: </strong>Integrating transcriptomic, clinical and experimental data suggests the role of miR-26a-5p, along with the MASLD-HCC gene signature (EpCAM, DTNA, and KPNA2), may serve as an early molecular indicator and mechanistic modulator of hepatocarcinogenesis, warranting further functional investigation.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1805025"},"PeriodicalIF":4.6,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835863","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":"Ubiquitin-proteasome system regulation of bone remodeling in postmenopausal osteoporosis.","authors":"Xiangqian Chen, Tong Zhao, Hailun Zhou, Qinghui Zeng, Hongkang Xu, Yulin Dai, Ming Yan","doi":"10.3389/fcell.2026.1788812","DOIUrl":"https://doi.org/10.3389/fcell.2026.1788812","url":null,"abstract":"<p><p>Postmenopausal osteoporosis (PMOP) is associated with declining estrogen levels, and this hormonal deficiency alters the physiological balance between bone formation and resorption. Substantial evidence indicates that protein homeostasis disorders play a significant role in the pathological process of PMOP. As the core system regulating protein homeostasis, the ubiquitin-proteasome system exerts crucial regulatory effects on bone metabolism under estrogen-deficient conditions. Abnormal activity of these ubiquitin-associated enzymes often leads to excessive degradation or abnormal accumulation of key regulatory proteins in bone metabolism, thereby exacerbating bone loss in PMOP. This review summarizes recent studies, focusing on how ubiquitin E3 ligases and deubiquitinating enzymes influence the function of osteoblasts and osteoclasts in PMOP. By synthesizing evidence from postmenopausal clinical samples and ovariectomized animal models, we further elucidate the specific roles of ubiquitin-related pathways in this disease. A deeper understanding of the mechanisms underlying UPS dysregulation in postmenopausal women holds promise for identifying novel molecular targets for future therapeutic strategies in PMOP.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1788812"},"PeriodicalIF":4.6,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835905","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":"Multi-omics insights into tumor grade progression in clear cell renal cell carcinoma: from molecular mechanisms to precision therapeutics.","authors":"Rajat Subhra Jena, Akhilesh Mishra","doi":"10.3389/fcell.2026.1815377","DOIUrl":"https://doi.org/10.3389/fcell.2026.1815377","url":null,"abstract":"<p><p>Clear cell renal cell carcinoma (ccRCC) can transition from indolent, low-grade lesions to high-grade, lethal disease through a layered cascade of genomic, epigenomic, metabolic, and immune remodeling. The initiating event in ∼90% of ccRCC is loss of chromosome 3p, enabling biallelic inactivation of VHL and frequent co-loss of chromatin regulators PBRM1, BAP1, and SETD2. The order and combination of genetic alterations shape distinct evolutionary trajectories in ccRCC. PBRM1 loss, observed in approximately 55% of cases, is linked to angiogenic, initially low-grade tumors that may later progress to higher-grade disease. In contrast, BAP1 loss (∼15%) drives early high-grade, inflammatory, immune-enriched phenotypes associated with aggressive behavior and worse prognosis. Progression is further shaped by structural and copy-number events including, chromothripsis coupling 3p loss with 5q gain, and recurrent 9p and 14q losses and 8q gain further promote cell-cycle dysregulation, genomic instability, and metastatic competence. Functionally, VHL loss stabilizes HIF-2α, driving VEGF signaling and Carbonic Anhydrase IX (CA9) expression and coupling pseudohypoxia to metabolic reprogramming and redox protection (glutathione/SLC7A11). Proteogenomic and metabolomic studies further highlight nutrient addiction with GLUT1/ASCT2 upregulation and a stress-resistant metabolic shield linked to grade and therapy resistance. Single-cell and spatial atlases place these programs in anatomic setting. They show that invasive fronts with high epithelial-mesenchymal transition (EMT) activity co-localize with myeloid and regulatory T-cell niches dominated by IL-1β, NF-κB, IL-10, STAT3, and TGF-β, along with exhausted CD8⁺ T cells, thereby promoting immune escape and invasion. Integrating these layers yields mechanism-based biomarkers and therapeutic nodes for risk-adapted precision treatment.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1815377"},"PeriodicalIF":4.6,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835351","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 multifaceted roles of mesenchymal stem cell-derived exosomes in digestive system malignancies: mechanisms and therapeutic implications.","authors":"Boyu Li, Ziheng Cui, Yanhua Jin","doi":"10.3389/fcell.2026.1814232","DOIUrl":"https://doi.org/10.3389/fcell.2026.1814232","url":null,"abstract":"<p><p>Mesenchymal stem cell-derived exosomes (MSC-Exos) have emerged as key mediators of intercellular communication within the tumor microenvironment. However, a comprehensive synthesis of their paradoxical roles in digestive system tumors remains absent. This review provides an in-depth analysis of the molecular mechanisms by which MSC-Exos regulate tumor progression, with a focus on how they transfer specific non-coding RNAs and proteins to target cells, thereby modulating angiogenesis, epithelial-mesenchymal transition, immune evasion, and drug resistance. We highlight the functional heterogeneity of MSC-Exos in colorectal, liver, gastric, and pancreatic cancers, and examine how signals from the tumor microenvironment remodel their molecular cargo, establishing complex feedback loops. Furthermore, we discuss emerging translational frontiers, including the engineering of MSC-Exos as targeted drug delivery vehicles. By integrating mechanistic insights with clinical challenges, this review aims to elucidate the complex biology of MSC-Exos and pave new avenues for their application in precision oncology for digestive system tumors.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1814232"},"PeriodicalIF":4.6,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835910","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":"Multiple strategies, one mission: mesenchymal stromal cell-based mechanisms of action in osteoarthritis.","authors":"Maid Junuzović, Antonia Troillet, Janina Burk","doi":"10.3389/fcell.2026.1763344","DOIUrl":"https://doi.org/10.3389/fcell.2026.1763344","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a cross-species, multifactorial joint disease characterized by the progressive degeneration of articular cartilage, morphological remodeling of the subchondral bone, and inflammatory and fibrotic changes of the joint capsule. These alterations arise from chronic, often subclinical, inflammatory processes and dysregulated cellular homeostasis, leading to profound shifts in the cellular and extracellular composition of the joint organ. Although the mechanisms driving persistent inflammation are only partially understood, their impact on all joint-associated tissues is well-established. Mesenchymal stromal cells (MSCs) have gained increasing attention as therapeutic candidates for OA due to their immunomodulatory and potentially regenerative capacities. Increasing evidence indicates that MSCs exert their effects predominantly through indirect mechanisms, including paracrine signaling, the release of extracellular vesicles, mitochondrial transfer, and modulation of innate and adaptive immune responses. This review summarizes current insights into how these mechanisms may act within the articular microenvironment to attenuate cartilage degeneration and promote tissue repair in OA. Herein, we consider the effects of MSCs on different cell types and tissues within the joint, and highlight mitochondrial transfer as an emerging mechanism through which MSCs may regenerate and protect them, thereby contributing to the rescue of joint homeostasis.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1763344"},"PeriodicalIF":4.6,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13136253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147835582","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":"Emerging functions of m6A-modified circRNAs and their targeting strategies in lung cancer.","authors":"Haipeng Wang, Yixiao Yuan, Chongxin Li, Xiulin Jiang, Jin Wang","doi":"10.3389/fcell.2026.1794138","DOIUrl":"https://doi.org/10.3389/fcell.2026.1794138","url":null,"abstract":"<p><p>Lung cancer, especially non-small cell lung cancer (NSCLC), remains a leading cause of cancer-related morbidity and mortality worldwide, largely due to challenges in early diagnosis, pronounced tumor heterogeneity, and frequent therapeutic resistance. N6-methyladenosine (m6A), the most prevalent RNA epigenetic modification, participates in tumorigenesis and progression by regulating various aspects of RNA metabolism. Circular RNAs (circRNAs), characterized by their covalently closed loop structure and high stability, have emerged as important regulators of tumor proliferation, metastasis, and drug resistance. Increasing evidence indicates that m6A modification influences circRNA biogenesis, stability, and translational potential, while circRNAs can reciprocally modulate the m6A machinery or act as molecular scaffolds within m6A regulatory networks. In this mini-review, we summarize recent advances regarding m6A-modified circRNAs in lung cancer, with particular emphasis on their roles in tumor growth and metastasis, ferroptosis, cancer stem cell maintenance, resistance to radiotherapy, chemotherapy, and targeted therapy, metabolic reprogramming, and the tumor immune microenvironment. Additionally, we discuss the diagnostic and therapeutic potential of m6A-circRNA interactions. Finally, we highlight the need for future studies to elucidate the dynamic regulation and clinical translation of the m6A-circRNA axis, aiming to provide novel strategies for precision therapy in lung cancer.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1794138"},"PeriodicalIF":4.6,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147813131","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":"On the potential origin of the zygote-like cancer stem cell with a focus on fusion for cell rescue.","authors":"Cosmin Andrei Cismaru, Sergiu Chira, George Adrian Calin, Romana Netea-Maier, Ioana Berindan-Neagoe","doi":"10.3389/fcell.2026.1797239","DOIUrl":"https://doi.org/10.3389/fcell.2026.1797239","url":null,"abstract":"<p><p>Cancer is conventionally viewed as a disease of accumulated somatic mutation and epigenetic dysregulation leading to cell de-differentiation and uncontrolled proliferation. With few exceptions, malignant tumors develop from a single damaged cell. However, there is also strong evidence for the involvement of more than one cell in the initiation of oncogenesis. Oncogenic mutations may be insufficient by themselves to trigger oncogenesis as somatic cells harboring driver mutations are often seen in nonmalignant tissues. We review experimental evidence for the reactivation of embryonic genes, emergence of cancer stem cells, and therapy resistance by the developmental programme hijack via cell fusion. Furthermore, based on our previous findings on fetal-maternal microchimerism, in this hypothesis article we delve into the potential mechanisms of activation of the early totipotent program by unselective stem cell fusion for cell rescue, centering the primitive pluripotent stem cells residing in postnatal human tissues as potential pivotal drivers of tumorigenesis that could recapitulate incomplete stages of embryogenesis and cell migration after triggering nuclear reprogramming toward a totipotent zygote-like cancer stem cell state, potentially amenable to genomic instability, somatic mutation, defective histogenesis and tumor-host microchimerism.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1797239"},"PeriodicalIF":4.6,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147813146","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":"Neural-immune-cancer crosstalk in pancreatic cancer: mechanisms and clinical translation.","authors":"Wenjun Meng, Ping Yao, Manting Wang, Xinyue Pan, Jingzhang He, Yan Tie, Qinqin He, Rujun Zheng","doi":"10.3389/fcell.2026.1828946","DOIUrl":"https://doi.org/10.3389/fcell.2026.1828946","url":null,"abstract":"<p><p>Pancreatic cancer remains a persistently high mortality rate, with limited efficacy through traditional therapies, necessitating exploration of its pathogenesis from a new biological perspective. The tumor microenvironment plays a decisive role in the malignant progression of pancreatic cancer, and the nervous system, as a key component of the microenvironment, has an active and bidirectional interaction with tumor cells, known as the \"neuro-tumor interaction.\" Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is highly rich in neural components. The neuro-tumor interaction not only drives the unique neural infiltration of PDAC but also profoundly affects tumor proliferation, invasion, metastasis, immune escape, and pain perception. Recent studies have revealed that tumor cells, Schwann cells, cancer-associated fibroblasts, and immune cells form a \"perineural niche\" through neurotrophic factors, chemotactic axes, cell adhesion/extracellular matrix remodeling, and neurotransmitters, driving tripartite neural-immune-cancer interaction and providing targets for new therapeutic interventions. This review systematically summarized the key molecular and cellular mechanisms of neural-immune-cancer interactions in pancreatic cancer and specifically discussed several translational strategies, including neurotrophic factor blockade targeting NGF/TrkA and GDNF/RET, myeloid cell reprogramming targeting CXCR2/CXCL to improve T cell infiltration, and potential combination strategies that combine neuromodulatory drugs (e.g., β-blockers or CRGP antagonists) with immune checkpoint inhibitors. These strategies have shown feasibility in preclinical studies or PDAC models and warrant further validation in stratified clinical trials.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1828946"},"PeriodicalIF":4.6,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133089/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147813194","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":"New integrated three-interface conceptual model for clearance and immune surveillance in the human CNS.","authors":"José García-Cosamalón, Miguel Marchena, Vega Villar-Suárez, Luis Ley, Fernando de Castro","doi":"10.3389/fcell.2026.1785072","DOIUrl":"https://doi.org/10.3389/fcell.2026.1785072","url":null,"abstract":"<p><p>The central nervous system (CNS) lacks a classical lymphatic system and instead relies on cerebrospinal fluid (CSF) circulation for metabolic waste removal and for defense/immune surveillance. Recent research has consolidated the concept of an integrated glymphatic-lymphatic continuum (because of the relevant contribution of glial cells), where CSF acts as a central transport medium linking parenchymal exchange with meningeal lymphatic outflow. Within this framework, the glymphatic system supports CSF-interstitial fluid exchange, particularly during sleep, when vascular pulsatility enhances solute clearance. Translating insights from rodent systems to the human brain, however, requires explicit consideration of the subarachnoid space and CSF hydrodynamics as an intermediate interface that distributes CSF and modulates the balance between parenchymal influx and efflux toward dural lymphatics. We here propose a three-phase conceptual model comprising: (1) a microscale segment that includes perivascular spaces, the neuropil/interstitial compartment, glial elements, and aquaporin-mediated water transport; (2) a mesoscale segment centered on the arachnoid barrier and the subarachnoid CSF compartment, functioning as a distribution and exchange interface; and (3) a macroscale segment encompassing arachnoid granulations and dural meningeal lymphatic vessels as the principal egress pathways. To further support this with a clinical perspective, we review evolutionary adaptations that have resulted in more efficient fluid exchange between CSF reservoirs and the extracellular space of the human brain. This three-interface framework may improve diagnostic and therapeutic precision by recognizing that the distinct disorders, such as neurodegenerative proteinopathies, cerebral edema, hydrocephalus, or meningoencephalitis, preferentially disrupt specific interfaces across scales.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1785072"},"PeriodicalIF":4.6,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13131100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147813134","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}