Advanced Science
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2025
·
IF 14.1
Zixuan Dong,Xiaobing Liu,Shichun Li,Xiaoling Fu
The aberrant cellular senescence in chronic wounds presents a significant barrier to healing. Mitochondrial dysfunction is critical in initiating and maintaining cellular senescence, underscoring therapeutic potential in restoring mitochondrial function by delivering healthy mitochondria to wound cells. However, approaches for delivering mitochondria to achieve optimized wound repair remain lacking. Herein, enucleated MSCs-derived microvesicles containing functional mitochondria (Mito@euMVs) via simple extrusion are developed. By controlling the size of microvesicles within a small micron-scale range, the mitochondrial encapsulation efficiency is optimized. Mito@euMVs effectively delivered mitochondria into fibroblasts and HUVECs, inhibiting and rejuvenating hyperglycemia-induced cellular senescence. To enhance the clinical applicability, soluble PVA microneedle patches for the transdermal Mito@euMVs delivery are utilized. In diabetic rats with pressure sores, the senescence-inhibiting and -rescuing properties of Mito@euMVs are further validated, along with their therapeutic efficacy, demonstrating their potential for chronic wound repair. Moreover, as a versatile delivery vehicle for mitochondria, Mito@euMVs hold promising for treating mitochondrial dysfunction and aging-related conditions.
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JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION
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2025
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IF 3.6
Zeyue Sun,Xiaojun Li,Xueheng Sun,Liuting Chen,Zihang Wang,Xin Feng,Luying Wang,Wenjie Jin,Xin Sun,Jiaju Lu
Bone regeneration is frequently impaired by excessive reactive oxygen species (ROS) and prolonged inflammation, which disrupt the immune microenvironment and hinder osteogenesis. The stimulator of interferon gene (STING) pathway is an innate immune pathway and a critical mediator of the inflammatory response, has been increasingly implicated in inflammatory bone loss and impaired repair. While STING inhibition represents a promising therapeutic strategy, its effective implementation within the bone microenvironment requires spatiotemporally controlled delivery. Here, we developed an injectable and photocrosslinkable hydrogel system (GMPP+H151) that integrates ROS-responsive scavenging with targeted STING inhibition to synergistically guide immune microenvironment remodeling and bone regeneration. The GMPP hydrogel was fabricated through dual crosslinking of phenylboronic acid (PBA)-modified gelatin (GelMA) and polyvinyl alcohol (PVA), endowing it with self-healing properties and ROS-scavenging capacity. H151, a small molecule inhibitor of STING, was caged by PBA chemistry for on-demand release under oxidative stress. The GMPP+H151 can significantly reduce ROS levels in macrophages and promote their phenotypic differentiation from M1 to M2 by suppressing the STING pathway, downregulating pro-inflammatory cytokines, and upregulating anti-inflammatory factors. Furthermore, it efficiently enhanced survival, spreading, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), leading to increased expression of alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), and osteocalcin (OCN). This study presents a smart, multifunctional hydrogel drug delivery system that integrates immunomodulation and osteoinduction, offering a promising strategy for promoting osteogenic differentiation and in situ bone defect repair.
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Journal of the American Heart Association
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2025
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IF 5.3
Siyao Chen,Xiaodong Zeng,Meifeng Wu,Jiade Zhu,Yijin Wu
BackgroundMyocardial fibrosis is a pathological hallmark of heart failure post infarction, emphasizing the need for innovative treatment strategies. This research assesses the antifibrotic potential of a sodium alginate (SA) hydrogel loaded with extracellular vesicles (EVs) from bone marrow mesenchymal stem cells and PAP (p38α antagonistic peptides), aiming to interfere with fibrosis‐inducing pathways in myocardial tissue after infarction.MethodsWe induced fibrosis in mouse cardiac fibroblasts through hypoxia and disrupted the Mapk14 gene to study its contribution to fibrosis. Mesenchymal stem cell‐derived EVs, loaded with PAP, were encapsulated in the SA hydrogel (EVs‐PAP@SA). The formulation was tested in vitro for its effect on fibrotic marker expression and cell behavior, and in vivo in a murine model of myocardial infarction for its therapeutic efficacy.ResultsMap k14 silencing showed a decrease in the fibrotic response of cardiac fibroblasts. Treatment with the EVs‐PAP@SA hydrogel notably reduced profibrotic signaling, increased cell proliferation and migration, and lowered apoptosis rates. The in vivo treatment with the hydrogel post myocardial infarction significantly diminished myocardial fibrosis and improved cardiac performance.ConclusionsThe study endorses the SA hydrogel as an effective vehicle for delivering mesenchymal stem cell‐derived EVs and PAP to the heart post myocardial infarction, providing a novel approach for modulating myocardial fibrosis and promoting cardiac healing.
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Stem Cells Translational Medicine
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2025
·Vol. 14
·期 3
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IF 4.9
Zhao Zhi-Meng,Ding Jia-Ming,Li Yu,Wang Da-Chuan,Kuang Ming-Jie
Glucocorticoid-induced osteoporosis (GIOP), the most common cause of secondary osteoporosis, is characterized by significant bone loss, decreased bone quality, and increased fracture risk. The current treatments for GIOP have several drawbacks. Exosomes are vital for cellular processes. However, very few studies have focused on using human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-EXOs) for GIOP treatment. In vitro and in vivo dexamethasone was used to evaluate the therapeutic effects of hUCMSC-EXOs on GIOP. CCK-8 and EdU assays were used to evaluate cell viability and proliferation, respectively. We conducted an alkaline phosphatase activity assay, alizarin red staining, Western blotting, and real-time PCR to detect the effect on osteogenesis. TMT-labeled quantitative proteomic and bioinformatic analyses were performed. Furthermore, we performed Western blotting, immunofluorescence, reactive oxygen species assays, and lipid peroxidation assays to investigate the regulatory mechanism by which hUCMSC-EXOs affect cell proliferation and osteogenic differentiation. The in vivo effects of hUCMSC-EXOs were evaluated using micro-CT, hematoxylin, and eosin staining, and immunohistochemical staining. We found that hUCMSC-EXOs reversed the inhibitory effects of glucocorticoids on human bone marrow stromal cell (hBMSC) proliferation and osteogenic differentiation and demonstrated that hUCMSC-EXOs reversed GIOP via the PI3K/AKT signaling pathway, inhibiting lipid peroxidation in vitro and in vivo. HUCMSC-EXOs promote hBMSC osteogenesis through the PI3K/AKT signaling pathway, inhibit ferroptosis, and have therapeutic potential for GIOP in mice.
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Biomaterials Advances
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2025
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IF 6
Jiayu Chen,Qing Liu,Jiayang Wan,Qihua Cao,Zili Guo,Kaijia Tang,Xin Chen,Qilei Lou,Xiaodong Xu,Yong Fu,Xiaoqiang Jin,Songying Zhang,Xiaohua Yu,Chang Li
Natural products, especially phenolic components isolated from Traditional Chinese Medicine (TCM), were reported to exhibit significant osteogenic potential in treating bone defects. However, low bioavailability, short half-life, and high clearance rate in the body hindered their practical applications in many cases. To develop delivery technologies for a bioactive phenolic acid from Salvia miltiorrhiza ( Danshen ), salvianolic acid A (SAA), a sustained release system based on biocompatible extracellular matrix (ECM) meticulously modified with a Hydroxyapatite (HAP) mineralized coating was established. The SAA construction of such delivery system not only addressed the low bioavailability of TCM formulation for SAA by local sustained release of this molecule, but also remarkably promoted its bone healing outcomes by synergizing with calcium and phosphate ion release during SAA release period. This approach collectively had a synergistic effect of osteogenesis with SAA, thereby significantly enhanced the efficacy of SAA in promoting bone formation. The in vitro experimental results indicated that the SAA@MECM exhibited good biocompatibility and significantly enhances angiogenesis and osteogenic differentiation. By day 14, compared to the MECM group, the gene expression levels of Col I, ALP, Runx-2, and OCN in the SAA-H group increased by 1.8, 1.5, 1.5, and 2.0 times, respectively. This demonstrates the potential role of SAA in promoting the activity and differentiation of osteoblasts, highlighting its potential applications in bone tissue engineering. Leveraging such favorable feature of this system, SAA-loaded MECM demonstrated extraordinary bone healing capability in a rat calvarial defect model by showing successful bridging of the defects and large amount of new bone formation. Histological analysis further confirmed its outstanding osteogenic potential, while the dense distribution of micro vessels in the newly formed bone revealed the scaffold's remarkable potential in enhancing vascularization. This study might offer an innovative delivery strategy for enhancing the efficacy of natural phenolic acids through biomaterials.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2024
·Vol. 25
·期 16
·8827
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IF 4.9
Chen Shen,Shan Yu,Xinyang Tan,Guanghua Luo,Zhengping Yu,Jiafei Ju,Lei Yang,Yuxuan Huang,Shuai Li,Rui Ji,Chunqing Zhao,Jichao Fang
Plants regulate the biosynthesis and emission of metabolic compounds to manage herbivorous stresses. In this study, as a destructive pest, the pre-infestation of rice striped stem borer (SSB,Chilo suppressalis) larvae on rice (Oryza sativa) reduced the subsequent SSB female adult oviposition preference. Widely targeted volatilomics and transcriptome sequencing were used to identify released volatile metabolic profiles and differentially expressed genes in SSB-infested and uninfested rice plants. SSB infestation significantly altered the accumulation of 71 volatile organic compounds (VOCs), including 13 terpenoids. A total of 7897 significantly differentially expressed genes were identified, and genes involved in the terpenoid and phenylpropanoid metabolic pathways were highly enriched. Correlation analysis revealed that DEGs in terpenoid metabolism-related pathways were likely involved in the regulation of VOC biosynthesis in SSB-infested rice plants. Furthermore, two terpenoids, (−)-carvone and cedrol, were selected to analyse the behaviour of SSB and predators. Y-tube olfactometer tests demonstrated that both (−)-carvone and cedrol could repel SSB adults at higher concentrations; (−)-carvone could simultaneously attract the natural enemies of SSB,Cotesia chilonisandTrichogramma japonicum, and cedrol could only attractT. japonicumat lower concentrations. These findings provide a better understanding of the response of rice plants to SSB and contribute to the development of new strategies to control herbivorous pests.
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JOURNAL OF AFFECTIVE DISORDERS
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2025
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IF 4.9
Siqi Sun,Jingtong Rong,Chao Wang,Ruiling Li,Honghan Zhang,Wei Wang,Hao Duan,Zhaowen Nie,Dan Xiang,Zhongchun Liu
Background Major depressive disorder (MDD) is a severe, and often treatment-resistant, psychiatric disorder. Mesenchymal stem cell-derived exosomes have been shown to be neuroprotective. Here we employed adipose-derived mesenchymal stem cell exosomes (ADSC-Exos) as a novel therapeutic approach for depressive-like behavior in mice and explored the underlying mechanisms. Methods ADSC-Exos were administered intranasally to mice subjected to chronic restraint stress to assess behavioral changes and neuroprotection in terms of apoptosis, AMPK-mTOR signaling, and NLRP3 pathway activation by western blotting, microglial activation by immunofluorescence, and changes in serum inflammatory factors by ELISA. The effects of ADSC-Exos were also studied in vitro in HT22 cells. Results ADSC-Exos significantly improved depressive-like behavior, anxiety-like behavior, and cognitive function in mice. ADSC-Exos had significant neuroprotective effects, including reducing neuronal apoptosis and promoting autophagy by activating AMPK-mTOR signaling, ultimately reducing neuroinflammation. In vitro, ADSC-Exos inhibited corticosterone-induced apoptosis, activated autophagy in an AMPK pathway-dependent manner, and inhibited NLRP3 inflammasome activation. Conclusion ADSC-Exos may be a potential treatment for MDD by alleviating depressive-like behaviors and protecting against tissue injury, possibly through activation of AMPK-mTOR signaling and inhibition of NLRP3 inflammasome-mediated neuroinflammation.
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Acta Biomaterialia
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2025
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IF 9.6
Mingye Chen,Junjie Tang,Binfa Liang,Gang Feng,Zefeng Deng,Simin Chen,Qing Sun,Jie Liu,Xian Chen
The increasing prevalence of refractory thin endometrium (TE) is a serious issue affecting women’s reproductive health. Human umbilical cord-derived mesenchymal stem cells (huMSCs) have shown therapeutic potential for TE. However, their clinical application is limited by poor cell retention, low survival rates, and unclear regenerative mechanisms. Here, we introduced an injectable 3D delivery system using clinically applicable collagen hydrogels to encapsulate huMSCs (Gel-huMSCs), offering a promising strategy for endometrial regeneration. We systematically optimized the physicochemical properties of the collagen hydrogels to enhance their efficacy in 3D stem cell culture. Our TE mouse model demonstrated that Gel-huMSCs effectively restore uterine function by increasing endometrial thickness, reconstructing immune homeostasis, promoting angiogenesis, and reversing fibrosis. Specifically, we observed significant upregulation of tissue regeneration-related genes ( Vegf, Cdh4 , and Foxa2 ) and downregulation of inflammatory response-related genes ( Mstn, Tnf, Trem1 , and Col4a3 ) in the endometrium after Gel-huMSCs therapy compared to the control group. These findings provide insights into the regenerative mechanism of Gel-huMSCs in improving endometrial repair in TE. Notably, our study confirmed the safety of Gel-huMSCs and their efficacy in enhancing fertility rates in TE treatment. In conclusion, these results suggest that Gel-huMSCs represent a promising and viable therapeutic strategy for stem cell-based treatment of TE in clinical applications. Statement of Significance Thin endometrium (TE) is a major contributor to infertility and adverse pregnancy outcomes. Human umbilical cord-derived mesenchymal stem cells (huMSCs) have shown therapeutic potential for TE, yet their clinical translation is limited by poor retention and an incomplete understanding of their regenerative mechanisms. Here, we have developed a thermosensitive injectable type I collagen hydrogel engineered to carry huMSCs (Gel-huMSCs). The hydrogel recapitulates key physicochemical and architectural features of the native endometrial extracellular matrix, preserving huMSC stemness and augmenting proliferation and angiogenesis in vitro . An AIEgen (DPTA-BT) was employed to label and track huMSCs in vivo . After intrauterine injection, Gel-huMSCs undergo controlled enzymatic degradation, gradually releasing viable cells that integrate into the endometrial epithelium and stroma. RNA sequencing of treated endometrial tissue has demonstrated significant up-regulation of genes associated with extracellular-matrix remodeling and angiogenesis, together with down-regulation of pro-inflammatory cytokine pathways. In a validated rat model of TE, Gel-huMSCs have been shown to increase endometrial thickness and restore fertility.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
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IF 3.322
Hao Li,Xue Gan,Lei Pan,Yuhua Zhang,Xintian Hu,Zhengbo Wang
Stem cell replacement therapy is considered a promising treatment for diseases of the central nervous system. Improving the ratio of surviving transplanted cells and the efficiency of differentiation into functional neuronal cells are the most important issues related to research on neuroregenerative medicine. Epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) have been reported to promote the proliferation and differentiation of neural stem cells (NSCs) in vitro , but whether they have the same effect in vivo is unclear. In this study, NSCs derived from rhesus monkey embryonic stem cells (ESCs) were resuspended in medium with or without EGF/bFGF and xenotransplanted into the rat striatum. No behavioral abnormalities or teratoma formation were observed in the recipient engrafted rats. GFP-labeled cells exhibited a higher survival rate and longer migration in the EGF/bFGF group than control group at 2 months after transplantation. Moreover, the percentages of Tuj1 + neurons and Map2 + neurons in the EGF/bFGF group were significantly higher than those in the control group, while the percentages of astrocytes and oligodendrocytes were significantly lower in the EGF/bGFG group than control group. These findings indicated that EGF/bFGF can promote protrusion of nerve fibers and the survival and neuronal differentiation of transplanted NSCs in the recipient brain, suggesting that EGF/bFGF has a potential application for stem cell therapy .
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Nanoscale
·
2021
·Vol. 13
·期 19
·8998-9008
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IF 7.79
Xupeng Mu,Meng Zhang,Anhui Wei,Fei Yin,Yan Wang,Kebang Hu,Jinlan Jiang
Programmed cell death ligand 1 (PD-L1) blockade has achieved great success in cancer immunotherapy. PD-L1 siRNA can restore the immune anti-tumor activity of T cells by downregulating the level of PD-L1 on tumor cells, but the efficiency of PD-1/PD-L1 monotherapy is relatively low. Doxorubicin (DOX) can induce tumor cell apoptosis, and then increase the release of tumor antigen. But the expression of PD-L1 in tumor tissues treated with DOX will be enhanced adaptively. Therefore, DOX combination with PD-L1 siRNA can produce a good synergistic anti-tumor effect. In this study, stem cell membrane (SCM) camouflaged polydopamine nanoparticles carrying DOX and PD-L1 siRNA (PDA–DOX/siPD-L1@SCM) were constructed for targeting prostate cancer (PCa) bone metastases. PDA–DOX/siPD-L1@SCM NPs could effectively enhance blood retention and improve accumulation at tumor sites. In vitro and in vivo studies demonstrated that PDA–DOX/siPD-L1@SCM NPs showed excellent performance in synergistic chemoimmunotherapy for PCa bone metastases. Hence, this study provided an effective strategy for developing biomimetic multifunctional nanoparticles for PCa bone metastasis treatment.
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Frontiers in Cell and Developmental Biology
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2021
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IF 6.684
Albashari Abdullkhaleg Ali,He Yan,Albaadani Mohammed A.,Xiang Yangfan,Ali Jihea,Hu Fengting,Zhang Yuan,Zhang Keke,Luo Lihua,Wang Jianming,Ye Qingsong
Titanium modifications with different silver loading methods demonstrate excellent antibacterial properties. Yet pure silver nanoparticles with limited bioactive properties may delay regeneration of bone surrounding the dental implant. Therefore, loading silver with bioactive drugs on titanium surfaces seems to be a very promising strategy. Herein, we designed a silver (Ag) step-by-step cross-linking with the basic fibroblast growth factor (bFGF) by polydopamine (PDA) and heparin on titanium nanotube (TNT) as its cargo (TNT/PDA/Ag/bFGF) to improve the implant surface. Our results showed that TNT/PDA/Ag/bFGF significantly enhanced the osteogenic differentiation of dental pulp stem cells (DPSCs). It also showed an excellent effect in bacterial inhibition and a reduction of pro-inflammatory factors through inhibition of M1 macrophage activity. These results showed that bFGF cross-linked silver coating on TNTs presented good osteogenic differentiation and early anti-infiammatory and antibacterial properties. Together, this novel design on titanium provides a promising therapeutic for dental implants.
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European Review for Medical and Pharmacological Sciences
·
2017
·Vol. 21
·期 10
·2316-2328
·
IF 1.778
An G,Zhang WB,Ma DK,Lu B,Wei GJ,Guang Y,Ru CH,Wang YS
Objective To investigate the influence of VEGF/BMP-2 on the proliferation and osteogenic differentiation of rat bone mesenchymal stem cells BMSCs) on PLGA/gelatin composite scaffold. Materials and methods Randomly-oriented nanofibers with different ratios of Poly Lactic-co-Glycolic Acid (PLGA)/gelatin were produced through electrospinning. The mixture of nanofibers and BMSCs was pipetted onto the surface of the scaffolds, and BMSCs/PLGA/gelatin composite was obtained. The surface morphology, chemical structure, hydrophilicity and mechanical property of PLGA/gelatin nanofibers were revealed by scanning electron microscope. In vitro release kinetics of bone morphogenetic protein (BMP-2) and vascular endothelial growth factor (VEGF) were studied using ELISA kits. The cell adhesion, growth and proliferation of BMSCs on scaffolds were observed by scanning electron microscopy. The CCK-8 assay was used to evaluate the effects of VEGF/BMP-2 slow release system on the proliferation of BMSCs on scaffolds. RT-PCR was used to examine the activities of alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX-2), and osteocalcin (OCN). Results In each group of cells in the in-vitro experiment, through electron microscope scanning, fiber scaffolds were interconnected three-dimensional reticular structure, BMSCs firmly attached to the fiber surface and internal stent, cells experienced a long spindle, polygon change, and branch-like protrusions on the cell surface were connected. Under the electron microscope, cell proliferation curve and osteogenesis markers (ALP, RUNX-2, OCN) expression in the dual factor group on cell adhesion, proliferation and differentiation were much better than those of blank control group and single factor groups. Conclusions In the successfully constructed gelatin/PLGA nanofiber scaffold, VEGF and BMP-2 can be sequentially released, during which VEGF and BMP-2 can promote the adhesion, proliferation, and differentiation of BMSCs.
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