Mucosal-associated invariant T (MAIT) cells, representing one of the most abundant subsets of unconventional T cells, have been shown to play a significant role in regulating immune responses. However, their immunoregula...Mucosal-associated invariant T (MAIT) cells, representing one of the most abundant subsets of unconventional T cells, have been shown to play a significant role in regulating immune responses. However, their immunoregulatory roles in the context of liver transplantation (LT) immunity remain largely undefined. To address this, we conducted single-cell RNA/TCR sequencing, flow cytometry, and multiplex immunohistochemical (mIHC) assays to identify the proportion and characteristics of CD8+ MAIT cells in humans and mice following liver transplantation. We found that CD8+ MAIT cells were prominently represented in the single-cell CD8 profiles of human transplanted livers, demonstrating strong signalling associations with macrophages, whilst the fractional populations of MAIT1 and MAIT17 were distinctly clustered. In parallel, the proportion of CD8+ MAIT cells was significantly elevated in mouse LT models, revealing a dynamic trend where percentages increased at 1 and 2 weeks post-transplant, peaking at 3 weeks. Furthermore, using established MR1 knockout (MR1KO) LT mice, we observed that mice lacking MAIT cells exhibited milder rejection responses, indicating that MR1 mediates rejection by influencing the remodelling of the TCR repertoire after transplantation. Collectively, our study reveals that MAIT cells play a critical role in LT rejection, as MR1KO alleviated inflammatory responses and mitigated rejection via TCR repertoire remodelling. By mapping the dynamic changes of MAIT cells throughout the rejection process, these findings lay the groundwork for further investigations into the role of these cells in transplant immunity.
Qiao Y, Sun Y, Huang Y
… +4 more, Meng Q, Lin X, Wei W, Tang X
Cell Prolif
· 2026 Jun · PMID 41804220
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The endoplasmic reticulum membrane protein complex (EMC) is an evolutionarily conserved multi-subunit complex. Due to its essential roles in protein biogenesis and quality control, the EMC has attracted considerable atte...The endoplasmic reticulum membrane protein complex (EMC) is an evolutionarily conserved multi-subunit complex. Due to its essential roles in protein biogenesis and quality control, the EMC has attracted considerable attention in recent years. In this review, we systematically explore the functions and disease-associated regulatory mechanisms of the EMC across various organ systems. We highlight the lung as a paradigmatic model for illustrating the 'molecular switch' function of EMC shaped by spatiotemporal and cell-type-specific contexts. Dysfunction of EMC contributes to pathologies and cancers of diverse organs, positioning EMC subunits as potential biomarkers and therapeutic targets. Despite considerable progress, our understanding of the molecular underpinnings of EMC in health and disease remains far from complete. Future efforts should aim to unravel the regulatory networks centered on EMC to harness their potential for cross-disease therapy development.
Obstructive nephropathy leads to renal fibrosis, and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) drives this macrophage-mediated process, but its mechanism remains unclear. This study investigated TREM2's ro...Obstructive nephropathy leads to renal fibrosis, and Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) drives this macrophage-mediated process, but its mechanism remains unclear. This study investigated TREM2's role in macrophage polarisation and renal fibrosis progression. In human fibrotic kidneys, TREM2 expression was significantly elevated and co-localised with macrophages. Unilateral ureteral obstruction (UUO) modelling in mice recapitulated this upregulation, accompanied by renal fibrosis, M2 macrophage polarisation and glomerular filtration rate (GFR) reduction. Trem2 deficiency (Trem2) significantly attenuated these pathological changes in UUO mice, preserving GFR. Separately, TREM2 inhibitory peptide sequence IA9 administration reduced renal fibrosis and M2 polarisation in UUO mice. In bone marrow-derived macrophages (BMDMs), Trem2 deficiency suppressed IL-4/IL-13-induced M2 polarisation, migration and β-catenin expression. Critically, lithium chloride (LiCl)-mediated β-catenin stabilisation rescued these impairments in Trem2 BMDMs. In conclusion, TREM2 promotes renal fibrosis by activating β-catenin signalling to drive profibrotic M2 macrophage responses, establishing TREM2 blockade as a therapeutic strategy for obstructive nephropathy.
Airway remodelling is a major contributor to persistent airflow limitation and irreversible lung function impairment in asthma, with epithelial-mesenchymal transition (EMT) serving as a key driver. However, the molecular...Airway remodelling is a major contributor to persistent airflow limitation and irreversible lung function impairment in asthma, with epithelial-mesenchymal transition (EMT) serving as a key driver. However, the molecular mechanisms controlling EMT in asthma epithelium remain incompletely elucidated. This study reported that integrin α5 (ITGA5) was markedly upregulated in asthma patients, house dust mite (HDM)-sensitised asthma mice, and transforming growth factor beta 1 (TGF-β1)-induced in vitro EMT models. Elevated ITGA5 expression correlated positively with reduced lung function, asthma severity and higher levels of EMT regulators (Fibronectin, N-cadherin, Vimentin) and was functionally linked to anoikis resistance. In TGF-β1-induced bronchial epithelial cells exhibiting anoikis resistance, quantitative proteomics revealed that ITGA5 promoted mesenchymal transition via the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway and negatively regulated anoikis. ITGA5 directly bound to PI3K in vitro, and ITGA5 knockdown reversed TGF-β1-induced EMT, inhibited the activation of the PI3K/Akt pro-survival pathway, and restored anoikis sensitivity. According to molecular docking, molecular dynamics simulation and in vivo and in vitro pharmacological assays, resveratrol (Res) and M200 were found to be potential ITGA5 inhibitors that successfully reduced EMT and anoikis resistance, thereby attenuating airway remodelling in asthma mice and offering promising drug candidates for ITGA5-targeted therapy.
Although Myo-Inositol/D-Chiro-Inositol (Ins) and berberine (BBR) have each shown beneficial effects in polycystic ovary syndrome (PCOS), their combined therapeutic potential has not been systematically evaluated. Here, w...Although Myo-Inositol/D-Chiro-Inositol (Ins) and berberine (BBR) have each shown beneficial effects in polycystic ovary syndrome (PCOS), their combined therapeutic potential has not been systematically evaluated. Here, we demonstrate that Ins/BBR exerts superior efficacy compared with single treatments by targeting multiple pathogenic pathways in PCOS. In a DHEA+HFD-induced mouse model, Ins/BBR restored systemic sex steroid balance, normalized LH/FSH ratio, and improved estrous cyclicity. It also reduced ovarian cysts and enhanced fertility, accompanied by partial normalization of steroidogenic enzyme expression. At the cellular level, Ins/BBR alleviated mitochondrial defects and broadly reprogrammed metabolic landscape in granulosa cells, in specific, restoring nucleotide pools and amino acid turnover and preventing abnormal long-chain fatty acid accumulation. Together, these findings provide preclinical evidence that Ins/BBR acts through coordinated endocrine, ovarian and metabolic mechanisms, supporting its promise as a safe and effective therapeutic strategy for PCOS.
Huntington's disease (HD) is an inherited neurodegenerative disease characterised by progressive degeneration of GABAergic medium spiny neurons (MSNs) in the striatum. Neural precursor cells (NPCs) derived from human ind...Huntington's disease (HD) is an inherited neurodegenerative disease characterised by progressive degeneration of GABAergic medium spiny neurons (MSNs) in the striatum. Neural precursor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) have been considered as a promising and scalable source for neuronal replacement and circuit restoration. In this study, we investigated the therapeutic effects of a clinical-grade, human leukocyte antigen (HLA)-homozygous iPSC line (YZWJ-s513) differentiated into NPCs (s513-NPCs) in a quinolinic acid (QA)-lesioned rat model of HD. Following intrastriatal transplantation, s513-NPCs not only survived for 12 weeks but also differentiated into neurons, astrocytes, and oligodendrocytes, while generating new DARPP32 GABAergic MSNs. Specifically, graft-derived neurons projected to the host globus pallidus, indicating structural integration into the striato-pallidal pathways. Additionally, NPC-transplanted rats exhibited significant motor recovery across multiple tasks for up to 12 weeks, accompanied by reduced striatal atrophy and ventricular enlargement. Histological findings also revealed attenuated astrogliosis and microgliosis, along with a shift toward an anti-inflammatory milieu. Collectively, these results demonstrate that transplantation of clinical-grade, HLA-homozygous iPSC-derived NPCs can provide both neuronal replacement and modulation of the diseased microenvironment, supporting their potential as a regenerative therapy for HD. Key quality attributes and release criteria supporting the clinical-grade characterisation of the cell product used in vivo are summarised in Table S1.
Wang Z, Zhang Y, Xu Y
… +8 more, Yang M, Wei Y, Li Y, Yang T, Wang X, Yang C, Feng Q, Xing G
Cell Prolif
· 2026 May · PMID 41742733
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Diabetes mellitus (DM) is a metabolic disorder marked by persistent hyperglycemia (HG), resulting from abnormalities in insulin secretion or insulin resistance. This condition represents a major public health concern sin...Diabetes mellitus (DM) is a metabolic disorder marked by persistent hyperglycemia (HG), resulting from abnormalities in insulin secretion or insulin resistance. This condition represents a major public health concern since it causes multisystem complications, including microvascular diseases, macrovascular diseases, and neuropathy. Few effective therapies are currently available. Ferroptosis, an iron-dependent mode of regulated cell death triggered by lipid peroxidation (LPO), is intricately linked to the pathogenesis, progression, and complications of DM. It has been increasingly recognised as a key mechanism underlying peripheral insulin resistance and insulin deficiency resulting from β-cell dysfunction. In this study, we systematically summarised the primary regulatory mechanisms of ferroptosis and outlined current research advancements in mechanistic insights into its role in diabetic complications. Besides, we explored how inter-organelle interactions drive ferroptosis under diabetic conditions and play pathogenic effects in diabetes and its complications. Finally, we systematically reviewed the therapeutic drugs targeting ferroptosis from the perspectives of traditional Chinese medicine (TCM) and Western medicine, respectively. This interdisciplinary integrated overview may provide a theoretical basis for future clinical transformation.
Li Y, Mao L, Liang B
… +3 more, Xie L, Xiang W, Kee K
Cell Prolif
· 2026 Apr · PMID 41742712
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Human oocyte meiosis utilises a specialised translational control strategy to coordinate meiotic progression, mediated through dynamic regulation of mRNA stores. While germ cell-specific RNA-binding proteins (RBPs) are k...Human oocyte meiosis utilises a specialised translational control strategy to coordinate meiotic progression, mediated through dynamic regulation of mRNA stores. While germ cell-specific RNA-binding proteins (RBPs) are known to orchestrate this post-transcriptional programme, the mechanistic basis of RBP-mediated cell fate specification remains elusive. Here, we demonstrate that BOLL, a Deleted in Azoospermia (DAZ) family protein, forms protein aggregates during meiotic prophase to drive translational reprogramming in human oogenesis. We determined that BOLL enhances the translation efficiency of cell cycle regulators, as demonstrated by integrative translatome-transcriptome analysis combined with RNA immunoprecipitation sequencing. We also revealed the functional interaction network of BOLL with core translation machinery components through its conserved DAZ-containing domain. Crucially, we identified SDS-resistant protein aggregates as a structural signature of BOLL in human oocyte-like cells, demonstrated by semi-denaturing electrophoretic analysis. Using human foetal ovarian tissues and an hESC-derived oogenesis model, we delineate a paradigm wherein BOLL-containing aggregates exert spatiotemporal control over cell cycle genes during meiosis prophase. These findings reveal that protein aggregates of gametogenesis-specific RBPs constitute an evolutionarily conserved mechanism in mammalian reproductive regulation.
The dysfunctional reconstitution of the intestinal barrier is pivotal in driving the initiation of inflammatory pathogenesis in Crohn's disease (CD), although the exact pathophysiology underlying this phenomenon has yet...The dysfunctional reconstitution of the intestinal barrier is pivotal in driving the initiation of inflammatory pathogenesis in Crohn's disease (CD), although the exact pathophysiology underlying this phenomenon has yet to be definitively characterised. This study aimed to investigate the role of the histone methyltransferase mixed lineage leukaemia 1 (MLL1) in the development of CD-like colitis and to elucidate the mechanism by which MLL1 promotes epithelial cell differentiation. Colonic tissue specimens from CD patients and TNBS-induced murine models were analysed to assess MLL1 expression dynamics. The functional impact of MLL1 on murine colitis modelling CD was systematically investigated through clinical symptom scoring, histopathological profiling and quantitative evaluation of intestinal barrier integrity. The role of MLL1 in promoting epithelial cell differentiation and repairing the intestinal barrier was investigated through immunofluorescence and western blotting. Additionally, potential mechanisms underlying the reparative effects of MLL1 on intestinal barrier function were explored. MLL1 expression was upregulated in colonic tissues from CD patients and TNBS-induced murine colitis models. In contrast, MLL1 suppression in the TNBS cohort attenuated mucosal inflammation and downregulated pro-inflammatory cytokine production (IL-1β, IL-6, TNF-α) within the colonic mucosa. Additionally, reduced MLL1 expression increased the differentiation capacity of intestinal epithelial cells, including goblet cells, absorptive cells and tuft cells, and promoted barrier function restoration in injured colons and lipopolysaccharide-stimulated colonic organoids. MLL1 downregulation activated the Gata4/Bmp4 signalling pathway, which may contribute to the reparative effects of MLL1 on intestinal barrier integrity. Downregulating MLL1 expression promotes intestinal epithelial cell differentiation by activating the Gata4/Bmp4 pathway. These findings elucidate a pathophysiological mechanism wherein MLL1 suppression potentiates intestinal barrier restoration, thereby attenuating colitis severity in murine models. The observed therapeutic efficacy positions MLL1 inhibition presents a novel strategy for CD management.
Zhang Y, Zhu Y, Jin M
… +8 more, Chen J, Yuan S, Yuan M, Sha Y, Liu Q, Wu W, Wang J, Ding X
Cell Prolif
· 2026 Apr · PMID 41730273
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Rutin directly binds to GSK3β, stabilising β-catenin and activating Wnt/β-catenin signalling to drive hair cycle.Rutin directly binds to GSK3β, stabilising β-catenin and activating Wnt/β-catenin signalling to drive hair cycle.
Although the role of retinoic acid (RA) signalling in odontogenesis is well established, its involvement in the repair of injured tooth germs remains unclear. To investigate this, we generated a Tg(scpp5:Dendra2-NTR) zeb...Although the role of retinoic acid (RA) signalling in odontogenesis is well established, its involvement in the repair of injured tooth germs remains unclear. To investigate this, we generated a Tg(scpp5:Dendra2-NTR) zebrafish line for labelling tooth germ cells and established a tooth germ injury model using the nitroreductase (NTR)/metronidazole (MTZ) system. We then modulated RA signalling by exogenous activation with RA, retinol, retinal, talarozole (TZ) or Tg(hsp70l:aldh1a2-p2a-mCherry; cryaa:venus), and by suppression with 4-diethylaminobenzaldehyde (DEAB) or Tg(hsp70l:dnRARAA-p2a-DsRed; cryaa:venus), to examine its function in tooth germ repair. Following targeted ablation of tooth germ cells, RA signalling was activated, with aldh1a2 showing the most pronounced upregulation. Exogenous RA promoted injury-induced tooth germ repair, whereas its precursors (retinol and retinal) had no significant effect on aldh1a2 expression or repair. Pharmacological inhibition of RA degradation with TZ enhanced repair, while dominant-negative inhibition of RA signalling impaired it. Furthermore, modulation of aldh1a2 revealed its essential role: inhibition with DEAB attenuated repair, whereas genetic activation facilitated tissue restoration. In summary, this study clarifies the regulatory role of RA signalling in tooth germ injury repair, offering a theoretical foundation and potential therapeutic targets for the treatment of injured tooth germs.
Ding S, Chen J, Li Z
… +6 more, Yu Y, Wang W, Liao Y, Yang J, Lu D, Fan Y
Cell Prolif
· 2026 Apr · PMID 41664583
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High altitude pulmonary hypertension (HAPH) is a complex disease featured by hypoxia-induced pulmonary vasoconstriction and remodelling of small pulmonary arterioles, which could lead to increased pulmonary pressures and...High altitude pulmonary hypertension (HAPH) is a complex disease featured by hypoxia-induced pulmonary vasoconstriction and remodelling of small pulmonary arterioles, which could lead to increased pulmonary pressures and right ventricular hypertrophy and eventually result in heart failure. The temporal trajectory of HAPH progression can be divided into three overlapping phases: hypoxic pulmonary arterioles vasoconstriction, hypoxic pulmonary arterioles remodelling and even right heart failure. Each phase is governed by distinct molecular engines and cellular effectors that translate hypoxia physiological adaption into irreversible cardiopulmonary dysfunction. This review describes the intricate cellular signalling networks involved in the pathogenesis of HAPH, integrating canonical pathways such as HIF, MAPK and BMP with emerging targets like Wnt/β-catenin, Notch, Hippo-YAP and IL-6. Inhibiting the HIF signalling pathway, modulating the MAPK pathway and suppressing the BMP, Wnt/β-catenin, Notch, Hippo-YAP and IL-6 pathways have shown potential in reducing vascular remodelling and right ventricular dysfunction. Despite encouraging progress, the clinical translation remains constrained by a lack of deeper understanding of the signalling networks in HAPH. A comprehensive understanding of these signalling pathways in HAPH may yield critical insights into the disease's pathogenesis and facilitate the development of targeted intervention strategies. Future research should focus on elucidating the molecular mechanisms underlying these pathways, exploring genetic and environmental interactions, validating intervention targets, developing biomarkers, utilising systems biology approaches and conducting clinical trials.
Long X, Tan D, Tao Q
… +4 more, Ye Q, Ye L, Li Q, Xiao J
Cell Prolif
· 2026 Apr · PMID 41635000
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Bone-related diseases (e.g., osteoporosis, osteoarthritis and fractures) exhibit a rising global incidence, imposing significant burdens on both quality of life and healthcare systems. Conventional therapeutic approaches...Bone-related diseases (e.g., osteoporosis, osteoarthritis and fractures) exhibit a rising global incidence, imposing significant burdens on both quality of life and healthcare systems. Conventional therapeutic approaches, including anti-resorptive drugs and surgical interventions, face limitations such as long-term medication requirements, adverse effects (e.g., bisphosphonate-related osteonecrosis of the jaw) and suboptimal efficacy. Bone marrow mesenchymal stromal cells (BMSCs) have emerged as a promising therapeutic alternative due to their accessibility, multi-lineage differentiation potential, immunomodulatory properties and homing capacity. However, challenges such as disease complexity, mechanistic heterogeneity and therapeutic inconsistency hinder their clinical translation. Recent advances in genetic engineering, preconditioning strategies, bone tissue engineering (e.g., three-dimensional [3D] scaffolding), extracellular vesicle-based therapies and epigenetic regulation (e.g., histone modification) have significantly enhanced the therapeutic effects of BMSCs. Furthermore, cutting-edge technologies like organoids and 3D bioprinting, which stem from advances in tissue engineering, offer novel avenues for clinical applications. Given these rapid developments, this review systematically summarises BMSC-based treatment strategies for bone-related diseases, discusses current challenges and outlines future directions to advance translational research.
Failure of timely bone regeneration compromises structural integrity and delays functional recovery; therefore immune regulation of the early repair microenvironment is crucial for successful healing. M1 (pro-inflammator...Failure of timely bone regeneration compromises structural integrity and delays functional recovery; therefore immune regulation of the early repair microenvironment is crucial for successful healing. M1 (pro-inflammatory) phenotype macrophages play pivotal roles in vascularisation during the early phase of bone regeneration and are typically activated by interferon-gamma (IFN-γ) or lipopolysaccharide (LPS) as well as by metabolite-derived signals. Lactate, a metabolite known to regulate a series of pathophysiological processes, has not yet been fully investigated for its specific immunomodulatory role in the microenvironment of bone injury healing. Our in vitro experiments demonstrated that lactate induced macrophage polarisation to the M1 phenotype and accelerated angiogenesis, with the HIF1α-NOD1-calcium influx axis identified as a key mediator. In vivo validation further confirmed the positive effects of lactate intervention in promoting vascularised bone regeneration at the early stage of injury. Thus, this study uncovers how lactate modulates immune response in association with M1 macrophages and indicates its potential as a therapeutic strategy for promoting vascularised bone healing.
Ma Y, Chen Z, Liu B
… +18 more, Ding W, Duan R, Kong K, Xu Z, Li J, Ru J, Guo D, Wei X, Liu Y, Lin Z, Meng Y, Liu Y, Jiang L, Chen Z, Tuxun R, Tsai C, Liu C, Li T
Retinal neovascularisation (RNV) is manifested in various retinal pathological conditions, often leading to irreversible blindness. The oxygen-induced retinopathy (OIR) mouse model proves to be a useful tool for understa...Retinal neovascularisation (RNV) is manifested in various retinal pathological conditions, often leading to irreversible blindness. The oxygen-induced retinopathy (OIR) mouse model proves to be a useful tool for understanding RNV pathogenesis. In this model, retinal vascular phenotype undergoes two distinct stages: neovascular formation, followed by spontaneous regression. While microglial functions in the neovascular formation stage have been extensively studied, their behaviors and roles during regression remain unclear. In this study, we characterise the spatiotemporal dynamics and molecular heterogeneity of retinal microglia across both stages. During RNV formation, microglia exhibit an outer-to-inner and central-to-midperipheral migration pattern, whereas a reversed migration trend is observed during regression. We confirm a highly glycolytic microglia (HGM) subpopulation during RNV formation and demonstrate its pro-angiogenic role by targeting a highly expressed pyruvate kinase M2 (Pkm2), a crucial enzyme for glycolysis. Importantly, we find that microglia exhibit enhanced phagocytic activity during regression, constituting a distinct phagocytosis-associated microglia (PAM) subtype, expressing mannose receptor C-type 1 (Mrc1/CD206). Altogether, our findings reveal stage-specific microglial functional dynamics, providing novel insights into RNV pathogenesis and intervention.
Liver grafts from donation-after-cardiac-death (DCD) are vulnerable to ischemia-reperfusion injury, which compromises graft function after transplantation. Agrimoniin has been shown to possess antioxidant and anti-inflam...Liver grafts from donation-after-cardiac-death (DCD) are vulnerable to ischemia-reperfusion injury, which compromises graft function after transplantation. Agrimoniin has been shown to possess antioxidant and anti-inflammatory properties, making it a potential therapeutic agent for organ preservation. This study investigated whether supplementing agrimoniin to the University of Wisconsin (UW) cold storage solution protected liver grafts from DCD rats or cold preserved human liver cell lines (QSG-7701 and HepG2). Agrimoniin supplementation significantly reduced oxidative damage, alleviated ferroptosis, and mitigated liver injury by activating the Nrf-2 pathway, both in vivo and in vitro. These findings suggest that ferroptosis is a mediator in DCD liver injury, and agrimoniin, through its activation of the Nrf-2 pathway, may be an effective therapeutic agent for enhancing liver graft preservation and improving outcomes in DCD liver transplantation.
Xu HW, Chang SJ, Wang S
… +2 more, Liu XW, Wang SJ
Cell Prolif
· 2026 Jun · PMID 41531174
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Intervertebral disc degeneration (IDD) is a primary cause of low back pain, with the development of new blood vessels being a key pathological feature. Fibroblast activation protein-alpha (FAP-α), a member of the Type II...Intervertebral disc degeneration (IDD) is a primary cause of low back pain, with the development of new blood vessels being a key pathological feature. Fibroblast activation protein-alpha (FAP-α), a member of the Type II serine protease family, possesses dipeptidase and collagenase activities and is closely linked to angiogenesis. Bioinformatics and immunohistochemical analysis revealed elevated FAP-α expression and increased angiogenesis in degenerated cartilage endplate (CEP). Co-culture of FAP-α-silenced CEP cells or conditioned media with human umbilical vein endothelial cells (HUVECs) demonstrated a reduction in hypoxia-inducible factor-α (HIF-α) levels, vascular endothelial growth factor (VEGF)-A and PI3K/AKT phosphorylation, which impaired HUVEC migration and tube formation. Conversely, FAP-α overexpression enhanced angiogenesis via the PI3K/AKT/HIF-α/VEGF-A signalling pathway. In rats with IDD induced by lumbar instability, FAP-α inhibitors reduced angiogenesis and ossification of the CEP, thereby delaying IDD progression associated with CEP degeneration. Genetic deletion of FAP further slowed IDD progression. Collectively, these findings provide compelling evidence that FAP-α accelerates IDD by promoting angiogenesis, which disrupts disc homeostasis. Targeting FAP-α may offer a novel therapeutic approach for mitigating IDD.
Cell Prolif
· 2026 Mar · PMID 41521070
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Brain organoids have become an essential platform for studying human neural development and neurological disorders. Yet, one major limitation of conventional brain organoids is their lack of vascular structures. This def...Brain organoids have become an essential platform for studying human neural development and neurological disorders. Yet, one major limitation of conventional brain organoids is their lack of vascular structures. This deficiency restricts organoid size, contributes to necrotic core formation, and hampers their functional maturation. Introducing vascularization offers a compelling solution-it enhances nutrient delivery, supports neurogenesis, and fosters the development of interfaces that resemble the blood-brain barrier (BBB). In this review, we explore how vascularization enhances the structural and physiological relevance of brain organoids and its growing significance in disease modelling and therapeutic screening. We examine current methodologies for engineering vascularized brain organoids (vBOs), including co-culturing with endothelial cells (ECs), transcriptional programming, tissue fusion techniques, microfluidic perfusion systems, and 3D bioprinting. These strategies vary in complexity, scalability, and the extent to which they achieve vascular integration. Functionally, vBOs demonstrate improved oxygen diffusion, enhanced synaptic development, and more robust barrier properties. Such advances enable modelling of complex neurovascular conditions like stroke, glioblastoma, and BBB dysfunction. Moreover, vBOs are emerging as valuable tools in developmental studies and personalised medicine, supporting patient-derived modelling and large-scale drug testing in BBB-relevant contexts. Despite these advances, replicating the structural complexity, functionality, and long-term stability of native vasculature remains challenging. We discuss current limitations and highlight innovative approaches, including the use of next-generation biomaterials and dynamic perfusion technologies. Ultimately, vBOs mark a significant step towards creating physiologically accurate in vitro models of the human brain-offering new opportunities for neuroscience research, drug development, and regenerative medicine.
Xie M, Liu Q, Xiong Z
… +4 more, Li J, Jin R, Lian L, Li Z
Cell Prolif
· 2026 Jun · PMID 41482641
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This study elucidates the critical role of macrophage-myofibroblast transition (MMT) in the pathogenesis of intestinal fibrosis in Crohn's disease (CD). Through analysis of stricturing intestinal tissues from CD patients...This study elucidates the critical role of macrophage-myofibroblast transition (MMT) in the pathogenesis of intestinal fibrosis in Crohn's disease (CD). Through analysis of stricturing intestinal tissues from CD patients and TNBS-induced CD mouse models, we demonstrated that TGF-β1 activates the MAPK signalling pathway to induce MMT in macrophages (Mø), resulting in increased expression of α-SMA and collagen production. Importantly, these MMT-derived myofibroblasts secrete CCL17, which recruits CCR4 regulatory T cells (Tregs) to fibrotic lesions, creating a pro-fibrotic microenvironment. Further investigation showed that the adoptive transfer of Mø exacerbated fibrosis in CD mice, whilst Mø depletion attenuated this process. Therapeutically, adipose-derived mesenchymal stromal cells-derived extracellular vesicles (AMSC-sEVs) could effectively deliver MFGE8 to inhibit MAPK activation, thereby suppressing MMT and reducing CCL17-mediated Treg recruitment. Treatment with AMSC-sEVs significantly improved intestinal fibrosis in CD mice, as evidenced by reduced collagen deposition and improved histological scores, whereas MFGE8 knockdown in AMSC-sEVs diminished these protective effects. These findings not only establish MMT as a key mechanism driving CD-associated intestinal fibrosis through the CCL17-CCR4 axis but also highlight AMSC-sEVs as a promising cell-free therapeutic strategy targeting this pathological process.