DEVELOPMENTAL CELL
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2024
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IF 10.7
Xiaoxin Guo,Juanyu Zhou,La Yan,Xingzhu Liu,Yu Yuan,Jinbao Ye,Zehong Zhang,Haiou Chen,Yongxin Ma,Zhendong Zhong,Guanzheng Luo,Haiyang Chen
Peroxisome dynamics are crucial for intestinal stem cell (ISC) differentiation and gut regeneration. However, the precise mechanisms that govern peroxisome dynamics within ISCs during gut regeneration remain unknown. Using mouse colitis and Drosophila intestine models, we have identified a negative-feedback control mechanism involving the transcription factors peroxisome proliferator-activated receptors (PPARs) and SOX21. This feedback mechanism effectively regulates peroxisome abundance during gut regeneration. Following gut injury, the released free very long-chain fatty acids (VLCFAs) increase peroxisome abundance by stimulating PPARs-PEX11s signaling. PPARs act to stimulate peroxisome fission and inhibit pexophagy. SOX21, which acts downstream of peroxisomes during ISC differentiation, induces peroxisome elimination through pexophagy while repressing PPAR expression. Hence, PPARs and SOX21 constitute a finely tuned negative-feedback loop that regulates peroxisome dynamics. These findings shed light on the complex molecular mechanisms underlying peroxisome regulation in ISCs, contributing to our understanding of gut renewal and repair.
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ACS Central Science
·
2025
·
IF 10.4
Qifang Wu,Yingna Li,Yunyun Zhao,Ruifen Zhang,Jingyang Tong,Chunlei Ji,Yiming Zhao,Mingjiang Wu,Xiaosheng Jin,Dandan Wang,Haibin Tong,Liwei Sun,Fangbing Liu
Excessive fructose intake drives intestinal aging and impairs intestinal stem cell (ISC) function, yet effective therapeutic interventions remain elusive. Astragaloside IV (AS-IV), a natural saponin from Astragalus membranaceus, has been widely recognized for its antiaging, anti-inflammatory, and gut-protective properties. Here, we revealed that AS-IV alleviates fructose-induced intestinal metabolic senescence via direct inhibition of ketohexokinase (KHK), the key rate-limiting enzyme in fructose metabolism. Molecular docking and site-directed mutagenesis identified Asn261 and Ala226 as distinct binding sites for AS-IV on KHK, with Asn261 also serving as a critical catalytic residue that is essential for KHK activity. Mutation at Asn261 abolished KHK enzymatic function, reduced the accumulation of fructose-derived metabolites such as palmitic acid and ceramide, and thereby prevented fructose-induced ISC cycle arrest. AS-IV’s therapeutic efficacy was validated across Drosophila, murine intestinal organoids, and mice, where treatment consistently reversed high-fructose-induced intestinal metabolic senescence phenotypes, restored ISC proliferation, and preserved ISC homeostasis. These findings indicate that KHK is a previously unrecognized molecular target of AS-IV and reveal a conserved mechanism by which AS-IV modulates fructose metabolism to interfere with gut aging. Our results highlight its therapeutic potential in treating fructose-driven intestinal aging and associated metabolic disorders.
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REPRODUCTIVE TOXICOLOGY
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2025
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IF 2.8
Shiling Chen,Xiuying Lin,Lei Liu,Jianhua Fu,Xiaodan Lu,Chunxue Niu,Qilai Wang,HaiFeng Wei,Mengxue Wu,Munan Sun,Lixin Cao,Xuguang Mi,Yanqiu Fang
Estrogen plays a central role in promoting endometrial thickening during the menstrual cycle. In patients with a thin endometrium, endometrial cells exhibit reduced sensitivity to estrogen, contributing to female infertility. We established an endometrial stromal cell damage model using the estrogen antagonist raloxifene (RAL) and investigated the role and underlying mechanism of human umbilical cord mesenchymal stem cell–derived exosomes (hUCMSC-EXO) in repairing RAL-induced damage in human endometrial stromal cells (hEndoSCs). In this study, hEndoSCs were treated with RAL and subsequently cultured with hUCMSC-EXO. The results showed that hUCMSC-EXO restored the proliferative capacity of hEndoSCs, decreased endogenous reactive oxygen species production, and increased mitochondrial membrane potential. Mechanistic analysis indicated that hUCMSC-EXO activated intracellular autophagy, and that autophagy inhibition reversed the protective effects of hUCMSC-EXO on hEndoSCs. These findings suggest that hUCMSC-EXO may ameliorate endometrial injury associated with estrogen insensitivity.
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Journal of Materials Chemistry B
·
2024
·
IF 6.1
Fan Zhang,Liping Nan,Jia-Qi Fang,Lei Liu,Bo Xu,Xue-Han Jin,Shuhao Liu,Shengfu Liu,Kaihang Song,Zhijie Weng,Feng Chen,Jian-Guang Wang,Jun-Jian Liu
The Nerve Guide Conduit (NGC)offers a promising alternative to traditional methods for regenerating peripheral nerves. The efficacy of nerve regeneration and functional recovery is heavily dependent on the electrical, chemical, and physical properties of the NGC. A bionic Melt electrowriting (MEW) NGC loaded with Placental derived mesenchymal Stem Cells (PDMSCs) has been developed. Our study introduces a novel approach by utilizing Schwann cells induced from placental mesenchymal stem cells (PDMSCs), showcasing their potential in enhancing nerve regeneration when integrated with conductive nerve guidance conduits. Schwann cells (SCs) are crucial for nerve regeneration, and while various stem cells, including Bone Marrow Stromal Cells (BMSCs), have been investigated as sources of SCs for NGC loading, they are often limited by ethical concerns and restricted availability. PDMSCs, however, offer the advantages of widespread sourcing and the unique ability to differentiate into SCs, making them an attractive alternative for NGC applications. This NGC utilizes of an electrostatic direct writing technique employing Polycaprolactone (PCL) for the sheath and acrimped fiber scaffold made of polypyrrole (PPY) incorporating PDMSCs for itsinternal structure. The bionic PC-NGC loaded with PDMSCs, exhibits favorable characteristics including permeability, mechanical stability, and electrical conductivity. The PPY component effectively transmitsphysiological nerve signals, thereby promoting nerve regeneration, while the PDMSCs differentiateinto Schwann cells, creating a conducive environment for nerve regeneration. This research innovatively combines PDMSCs, known for their wide availability and SC differentiation potential, with a bionic NGC to enhance the treatment of peripheral nerve injuries (PNI). In vitro evaluations have confirmed the excellent biocompatibility of the materials used. Animal experiments usinga rat model with sciatic nerve injury demonstratedthat the PC-NGC significentlyfacilitated peripheral nerve regeneration. This was evidenced by improvements in axonal myelination, increased musclemass, enhanced sciatic nerve function index, and positive electrophysiologicalfindings. These outcomes arecomparable to those achieved through autologous transplantation. Characterized by its layered oriented fibers, the bionic PC-NGC integrates multi-scale and multifunctional biomaterials with PDMSCPDMSCs to effectively address peripheral nerve injuries (PNI). The useof thisprinted NGC stimulatesneuronal cell growth, thereby accelerating nerve regeneration. This innovative approach in tissue engineering presentsa promising clinical treatment strategy for PNI.
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ACS Applied Materials & Interfaces
·
2025
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IF 8.2
Xuezhong Cui,Jing Li,Yuemin Wang,Tong Sun,Jie Weng,Zhiqiang Li,Jianshu Li,Xingyu Chen
In recent decades, porous titanium (Ti) bone-engineered scaffolds have emerged as a promising biomaterial for bone defect repair due to their excellent biocompatibility and mechanical properties. However, the limited bioactivity on the surface of the porous scaffold hinders osteogenesis and osseointegration, thereby restricting its further application. In this study, we utilized surface-initiated atom transfer radical polymerization to prepare a zwitterionic poly[2-(methacryloyloxy)ethyl choline phosphate] (PMCP) modified bioactive coating on the surface of a 3D-printed porous Ti scaffold. Additionally, exosomes derived from bone mesenchymal stem cells (BMSCs) were introduced into the scaffold surface via specific interactions between choline phosphate and phosphatidylcholine (CP-PC) on exosomes. In vitro studies for ossification and transcriptome analysis have shown that the exosome bioactive coating on a Ti scaffold enhances the proliferation of BMSCs, their osteogenic activity, and the expression of osteogenic-related genes. Furthermore, in vivo study results from hard tissue sectioning and microcomputed tomography indicate that the bioactive Ti scaffold significantly promotes new bone formation after 4 and 12 weeks of implantation in rabbit femoral defects. Overall, this study showcases the potential of the exosome-based Ti scaffold to enhance osteogenic activity, offering a novel strategy for cell-free bone tissue regeneration with significant therapeutic implications.
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Cell Communication and Signaling
·
2024
·Vol. 22
·期 1
·1-22
·
IF 8.2
Wu Xiao,Tang Ying,Lu Xinxing,Liu Yigao,Liu Xu,Sun Qin,Wang Lu,Huang Wei,Liu Airan,Liu Ling,Chao Jie,Zhang Xiwen,Qiu Haibo
Background Acute respiratory distress syndrome (ARDS) is a severe and fatal disease. Although mesenchymal stem cell (MSC)-based therapy has shown remarkable efficacy in treating ARDS in animal experiments, clinical outcomes have been unsatisfactory, which may be attributed to the influence of the lung microenvironment during MSC administration. Extracellular vesicles (EVs) derived from endothelial cells (EC-EVs) are important components of the lung microenvironment and play a crucial role in ARDS. However, the effect of EC-EVs on MSC therapy is still unclear. In this study, we established lipopolysaccharide (LPS) - induced acute lung injury model to evaluate the impact of EC-EVs on the reparative effects of bone marrow-derived MSC (BM-MSC) transplantation on lung injury and to unravel the underlying mechanisms. Methods EVs were isolated from bronchoalveolar lavage fluid of mice with LPS - induced acute lung injury and patients with ARDS using ultracentrifugation. and the changes of EC-EVs were analysed using nanoflow cytometry analysis. In vitro assays were performed to establish the impact of EC-EVs on MSC functions, including cell viability and migration, while in vivo studies were performed to validate the therapeutic effect of EC-EVs on MSCs. RNA-Seq analysis, small interfering RNA (siRNA), and a recombinant lentivirus were used to investigate the underlying mechanisms. Results Compared with that in non-ARDS patients, the quantity of EC-EVs in the lung microenvironment was significantly greater in patients with ARDS. EVs derived from lipopolysaccharide-stimulated endothelial cells (LPS-EVs) significantly decreased the viability and migration of BM-MSCs. Furthermore, engrafting BM-MSCs pretreated with LPS-EVs promoted the release of inflammatory cytokines and increased pulmonary microvascular permeability, aggravating lung injury. Mechanistically, LPS-EVs reduced the expression level of isocitrate dehydrogenase 2 (IDH2), which catalyses the formation of α-ketoglutarate (α-KG), an intermediate product of the tricarboxylic acid (TCA) cycle, in BM-MSCs. α-KG is a cofactor for ten-eleven translocation (TET) enzymes, which catalyse DNA hydroxymethylation in BM-MSCs. Conclusions This study revealed that EC-EVs in the lung microenvironment during ARDS can affect the therapeutic efficacy of BM-MSCs through the IDH2/TET pathway, providing potential strategies for improving the therapeutic efficacy of MSC-based therapy in the clinic.
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Materials Today Bio
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2025
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IF 10.2
Jialu Weng,Yizhang Chen,Yuhan Zeng,Wenzhang Jin,Ying Ji,Wa Zhang,Shunfu Wang,Haobing Li,Meilin Yi,Xiaoying Niu,Xuchen Deng,Jiancheng Huang,Xiang Su,Lulu Chen
Diabetic wound healing is constrained by various factors, including chronic inflammation, sustained oxidative stress, impaired angiogenesis, and abnormal wound microenvironments. Exosomes derived from mesenchymal stem cells (MSC-exo) contain a wealth of bioactive substances that play a positive role in promoting diabetic wound healing. Plant-derived exosomes, as a novel therapeutic approach, are continuously being explored. Momordica charantia (MC) has been shown to possess blood glucose-lowering effects, and its exosomes are of significant relevance for treating diabetic wounds. However, direct application of exosomes to wounds faces challenges such as poor stability and short retention time, limiting their therapeutic effectiveness and clinical applicability. Encapsulating exosomes in hydrogels is an effective strategy to preserve their bioactivity. In this study, we fabricated a hydrogel loaded with MSC-exo and MC exosomes (MC-exo) by photopolymerization of methacrylated gelatin (GelMA) and dopamine (MEMC-Gel). The resulting MEMC-Gel exhibited favorable mechanical properties, adhesion, degradability, absorbency, and biocompatibility. In vitro, MEMC-Gel demonstrated the ability to resist inflammation, counter oxidative stress, promote fibroblast migration, support endothelial cell angiogenesis, and regulate macrophage polarization. In a diabetic mouse wound model, MEMC-Gel accelerated wound healing by inhibiting inflammation and oxidative stress, modulating macrophage immune responses and hyperglycemia within the microenvironment, promoting angiogenesis, and enhancing epithelialization. In conclusion, MEMC-Gel is an outstanding hydrogel dressing that synergistically promotes repair by loading MSC-exo and MC-exo, significantly accelerating diabetic wound healing through multiple mechanisms. This multifunctional hydrogel, based on exosomes from two different sources, provides an innovative therapeutic strategy for diabetic wound repair with broad clinical application potential.
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Scientific Reports
·
2025
·Vol. 15
·期 1
·1-13
·
IF 3.9
Chen Juanli,Wei Chuanfei,Zhang Yingchao,Chen Qingfa,Li Xuemei,Zhang Wei,Zhang Xiaoping,Han Fabin
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid beta (Aβ) plaques, leading to neuronal death. Notably, there are no therapeutically efficacious treatments for this disorder. This study investigates the neuroprotective mechanisms of curcumin. In vitro experiments demonstrated that curcumin significantly promoted the proliferation of neural stem cells (NSCs) derived from E16 mouse embryos. Additionally, in the APP/PS1 transgenic mouse model, curcumin improved cognitive function, as evidenced by a shorter escape latency and increased platform crossing frequency in the Morris water maze test and enhanced novel object recognition. Histological analysis showed that curcumin reduced Aβ accumulation in the hippocampal and cortical regions. Molecular studies revealed that curcumin upregulated the expression of BDNF and enhanced phosphorylation of CREB. Collectively, these findings indicate that curcumin exerts neuroprotective effects through multiple mechanisms, including promoting NSC proliferation, reducing Aβ accumulation, and the potential modulation of the BDNF-CREB signaling pathway.
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ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Lixin Ding,Qian Guo,Ya’nan Ren,Pei Wang,Yongxiang Pan,Jin Ding,Feng Wang,Zhi Yang,Hua Zhu
Extracellular vesicles (EVs) act as carriers that transfer molecules between donor and recipient cells, thereby altering the phenotype and function of the latter. EVs derived from mesenchymal stem cells (MSCs) inherit the homing ability of their parent cells to tumor sites. We speculate that MSC-derived EVs labeled with the isotope zirconium-89 ([89Zr]Zr) will accumulate within tumors and have the potential for tumor location via positron emission tomography (PET) imaging. Here, as a proof of concept, we used [89Zr]Zr-labeled human umbilical cord MSC (hucMSC)-derived EVs to characterize the homing of EVs to tumor regions via PET imaging. The uptake of [89Zr]Zr-DFO-hucMSC-EVs by 4T1, H292, and FaDu cells increased in a time-dependent manner. [89Zr]Zr-DFO-hucMSC-EVs were rapidly cleared from the blood circulation, showing a 2-phase exponential decay with a biodistribution half-life of 0.46 h and an elimination-phase half-life of 11.87 h. At 24 h postinjection, [89Zr]Zr-DFO-hucMSC-EVs were mainly distributed in the liver (10.39 ± 0.52%ID/g) and, to a lesser extent, in the spleen (9.87 ± 0.87%ID/g). PET imaging in tumor-bearing mouse models revealed persistently high tumor accumulation. The projected effective dose for an adult human female was low and was 0.084 mSv/MBq. There was no obvious normal tissue toxicity following the administration of excessive radioactivity. In summary, these studies demonstrate the potential feasibility of using the [89Zr]Zr-DFO-hucMSC-EV tracer for noninvasive visualization of tumor lesions.
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CARBOHYDRATE POLYMERS
·
2024
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IF 10.7
Tianyi Shao,Mingzhe Yan,Rui Liu,Yanming Zhang,Banghui Wang,Yifei Li,Yuxin Liu,Danxia Li,Lixin Jin,Bingcheng Yi,Qihui Zhou
Acellular cellulose-based biomaterials hold promising potential for treating bladder injuries. However, the compromised cellular state surrounding the wound impedes the complete reconstruction of the bladder. This necessitates the development of a bio-instructive cellulose-based biomaterial that actively controls cell behavior to facilitate effective bladder regeneration. To develop such an advanced cell-free scaffold, a bacterial cellulose (BC) substrate is elaborately modified through layer-by-layer assembly of heparin and collagen (H/C), followed by glutaraldehyde crosslinking, resulting in a biomimetic nanofibrous scaffold with optimized mechanical properties and reduced salt crystal deposition. Critically, the scaffold is functionalized with anti-CD29 antibodies, enabling selective in situ capture of urine-derived stem cells (USCs) without compromising their viability. The (H/C)-modified BC scaffold exhibits exceptional swelling and extracellular matrix-like architecture, which mirrors the natural bladder environment. Fluorescent immunostaining confirms uniform antibody grafting, confirming the efficacy of this modified biomaterial in attracting and retaining USCs. Overall, this study introduces a BC-based scaffold that has been innovatively modified with CD29, enabling the selective capture of USCs from urine. This innovative acellular biomaterial represents a promising acellular strategy to address the challenges posed by compromised cellular conditions during bladder reconstruction, offering a novel avenue for regenerative bladder therapies.
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EXPERIMENTAL CELL RESEARCH
·
2025
·
IF 3.5
Yongna Zhu,Xiang Ge,Zhi Chen,Tingting Chen,Yue Wu,Hebao Wen,Zeyu He,Caiyun Ma
Stem cells from the apical papilla (SCAPs) show strong odontogenic ability and can form root dentin. However, the underlying mechanisms that control the odontogenic differentiation of SCAPs in an inflammatory environment need further exploration. In the present study, we explored the regulatory role of METTL3 in the differentiation of SCAPs originating from tooth with apical periodontitis. Stem cells from the apical papilla derived from healthy teeth (SCAPs) and teeth with apical periodontitis (AP-SCAPs) were successfully isolated and cultured. The expressions of tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6) were higher in AP-SCAPs. A decrease in METTL3 expression accompanied the decreased osteo-/odontogenic differentiation ability of AP-SCAPs. Exploring the role of METTL3 on the osteo-/odontogenic differentiation of AP-SCAPs revealed that overexpression of METTL3 upregulated the odontogenic ability of AP-SCAPs. However, silencing METTL3 exerted the opposite effect. Overexpression of METTL3 suppressed the expression of TNF-α and IL-6 in AP-SCAPs, whereas knockdown of METTL3 in these cells enhanced TNF-α and IL-6 expression. METTL3 regulates the osteo-/odontogenic differentiation of SCAPs and modulates their inflammatory response. Furthermore, overexpression of METTL3 upregulated the methylation level, mRNA, and protein expression of nuclear factor-IC (NFIC) during mineralization induction. NFIC silencing attenuated osteo-/odontogenic differentiation of METTL3-overexpressed AP-SCAPs. In conclusion, METTL3-mediated-m6A upregulated the odontogenic differentiation of AP-SCAPs via NFIC. This paper elucidates a novel mechanism regulating the odontogenic differentiation of AP-SCAPs, and METTL3 may be a new target for regenerative endodontic treatment.
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Materials Today Bio
·
2025
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IF 10.2
Jinming Li,Qingxin Zhao,Jiani Sun,Hao Zeng,Anli Yang
Spatiotemporally precise control of mesenchymal stem cells (MSCs) differentiation remains an unmet challenge in regenerative medicine. Herein, we report a near-infrared (NIR)-responsive platform that integrates upconversion nanoparticle (UCNP)-functionalized substrates with host-guest photoresponsive chemistry (β-cyclodextrin/arylazopyrazole-RGD) to NIR spatiotemporally orchestrate MSCs adhesion, spreading, and lineage commitment with spatiotemporal precision. The UCNPs convert 808 nm NIR light into localized UV emissions, dynamically modulating azobenzene-cyclodextrin interactions and thereby tuning surface RGD ligand density via photoisomerization. Under low NIR intensities (0–0.5 W/cm 2 ), augmented integrin-RGD binding drives robust focal adhesion assembly, actin cytoskeletal tension, nuclear YAP translocation, and osteogenic differentiation, as evidenced by 2–3 fold upregulation of BMP2, RUNX2, and ALP. Conversely, high-intensity NIR (1–2 W/cm 2 ) induces RGD detachment, leading to suppressed cytoskeletal contractility and nuclear Lamin A/C expression, consequent cytoplasmic YAP retention, and activation of PPARγ-mediated adipogenesis, marked by 4–5 fold induction of PPARγ, C/EBPα, and FABP4. Most importantly, in vivo murine studies validate the platform's capacity for non-invasive, light-guided spatiotemporal regulation of MSCs adhesion, spreading, YAP signaling, and lineage specification (osteogenic vs. adipogenic), wherein differentiation thresholds (e.g., 1 W/cm 2 ) correspond to clinically safe NIR exposure limits. This opto-material hybrid system effectively decouples photochemical stimulation to program MSC fate via mechanotransduction pathways, thereby providing a translatable strategy for the design of intelligent biomaterials towards personalized tissue regeneration.
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