Clinical and Translational Medicine
·
2025
·Vol. 15
·期 3
·e70250
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IF 6.8
Kaixiang Li,Runjiao Luo,Xindi Yu,Wei Dong,Guoliang Hao,Dan Hu,Ziyou Yu,Minglu Liu,Tingting Lu,Xiangying Wang,Xin Tang,Xinjun Lin,Huijing Wang,Wei Wang,Wei Fu
Mesenchymal stem cell therapy involves the secretion of various factors to regulate the local microenvironment in various of diseases. This therapy offers hope for treating acute myocardial infarction (MI), which poses a serious threat to human health. However, challenges such as low paracrine efficiency and poor cell survival persist due to the harsh post-infarction conditions, such as hypoxia. Recently, enhanced cell therapy, in which vascular endothelial growth factor A (VEGFA) and basic fibroblast growth factor (bFGF) are used as therapeutic agents to limit myocardial injury and simultaneously induce neovascularisation, has been recognised as a promising new strategy to improve the efficacy of cell therapy. Chemically synthetic modified messenger RNA (modRNA), a novel protein expression technology, enables safe, rapid, efficient and pulsatile expression of target proteins in vivo and in vitro settings. It has been widely applied in the fields of vaccine research and tissue regeneration. In this study, human adipose-derived stem cells (hADSCs) were transfected with VEGFA and bFGF modRNA to transiently overexpress these proteins before transplantation. This modification enhanced the paracrine effect of transplanted hADSCs and promoted stability in the vascular network at the transplantation site. Overexpression of VEGFA and bFGF in hADSCs not only inhibited apoptosis but also reduced ventricular remodelling and improved cardiac function and left ventricular conduction. Overall, the additive effects of VEGFA modRNA, bFGF modRNA and hADSCs hold promise for comprehensive cardiac repair post-MI and show substantial potential for treating ischemic heart diseases. Key points ModRNAs-transfected hADSCs exhibit pulsed and transient expression, enabling efficient production of functional VEGFA and bFGF proteins. Intracardiac injection of these engineered hADSCs leads to the enhancement of cardiac function and the improvement of electrical conduction. The hADSCs dual mainly exerts its effect on myocardial infarction by promoting stable vascular regeneration and suppressing cell apoptosis.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2024
·
IF 7.1
Wenjie Dai,Bo Xu,Liyang Ding,Zhen Zhang,Hong Yang,Tiantian He,Ling Liu,Xiuying Pei,Xufeng Fu
Primary ovarian insufficiency (POI) in younger women (under 40) manifests as irregular periods, high follicle-stimulating hormone (FSH), and low estradiol (E2), often triggered by chemotherapy. Though mesenchymal stem cell (MSC) therapy shows promise in treating POI, its exact mechanism remains unclear. This study reveals that human umbilical cord-derived MSCs (hUC-MSCs) can protect ovarian granulosa cells (GCs) from cyclophosphamide (CTX)-induced ferroptosis, a form of cell death driven by iron accumulation. CTX, commonly used to induce POI animal model, triggered ferroptosis in GCs, while hUC-MSCs treatment mitigated this effect, both in vivo and in vitro . Further investigations using ferroptosis and autophagy inhibitors suggest that hUC-MSCs act by suppressing ferroptosis in GCs. Interestingly, hUC-MSCs activate a protective antioxidant pathway in GCs via NRF2, a stress-response regulator. Overall, our findings suggest that hUC-MSCs improve ovarian function in CTX-induced POI by reducing ferroptosis in GCs. This study not only clarifies the mechanism behind the benefits of hUC-MSCs but also strengthens the case for their clinical use in treating POI. Additionally, it opens up a new avenue for protecting ovaries from chemotherapy-induced damage by regulating ferroptosis.
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BMC MUSCULOSKELETAL DISORDERS
·
2024
·Vol. 25
·期 1
·1-10
·
IF 2.2
Lai Zhen,Li Mingming,Yang Xiaodong,Xian Zhenjie
Osteoporosis is caused by the imbalance of osteoblasts and osteoclasts. The regulatory mechanisms of differentially expressed genes (DEGs) in pathogenesis of osteoporosis are of significant and needed to be further investigated. GSE100609 dataset downloaded from Gene Expression Omnibus (GEO) database was used to identified DEGs in osteoporosis patients. KEGG analysis was conducted to demonstrate signaling pathways related to enriched genes. Osteoporosis patients and the human mesenchymal stem cells (hMSCs) were obtained for in vivo and in vitro resaerch. Lentivirus construction and viral infection was used to knockdown genes. mRNA expression and protein expression were detected via qRT-PCR and western blot assay separately. Alkaline phosphatase (ALP) activity detection, alizarin Red S (ARS) staining, and expression of bone morphogenetic protein 2 (BMP2), osteocalcin (OCN) and Osterix were evaluated to determine osteoblast differentiation capacity. UL-16 binding protein 1 (ULBP1) gene was upregulated in osteoporosis and downregulated in differentiated hMSCs. Knockdown of ULBP1 increased ALP activity, mineralization ability evaluated by ARS staining, expression of BMP2, OCN and Osterix in differentiated hMSCs. Furthermore, rescue experiment demonstrated that suppressed ULBP1 boosted osteoblast differentiation by activating TNF-β signaling pathway. Knockdown of ULBP1 gene could promoted osteoblast differentiation by activating TNF-β signaling pathway in differentiated hMSCs. ULBP1 may be a the Achilles’ heel of osteoporosis, and suppression of ULBP1 could be a promising treatment for osteoporosis.
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ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Tingjun Liu,Ziying You,Fangyuan Shen,Puying Yang,Junyu Chen,Shuhuai Meng,Chenglin Wang,Ding Xiong,Chengjia You,Zhenming Wang,Yu Shi,Ling Ye
Cranial bone defects remain a major clinical challenge, increasing patients’ life burdens. Tricarboxylic acid (TCA) cycle metabolites play crucial roles in facilitating bone tissue regeneration. However, the development of TCA cycle metabolite-modified biomimetic grafts for skull bone regeneration still needs to be improved. The mechanism underlying the release of TCA cycle metabolites from biomaterials in regulating immune responses and mesenchymal stem cell (MSC) fate (migration and differentiation) remains unknown. Herein, this work constructs biomimetic hydrogels composed of gelatin and chitosan networks covalently cross-linked by genipin (CGG hydrogels). A series of TCA cycle metabolite-coordinated CGG hydrogels with strong mechanical and antiswelling performances are subsequently developed. Remarkably, the citrate (Na3Cit, Cit)-coordinated CGG hydrogels (CGG-Cit hydrogels) with the highest mechanical modulus and strength significantly promote skull bone regeneration in rat and murine cranial defects. Mechanistically, using a transgenic mouse model, bulk RNA sequencing, and single-cell RNA sequencing, this work demonstrates that CGG-Cit hydrogels promote Gli1+ MSC migration via neutrophil-secreted oncostatin M. Results also indicate that citrate improves osteogenesis via enhanced histone H3K9 acetylation on osteogenic master genes. Taken together, the immune microenvironment- and MSC fate-regulated CGG-Cit hydrogels represent a highly efficient and facile approach toward skull bone tissue regeneration with great potential for bench-to-bedside translation.
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Journal of Translational Medicine
·
2024
·Vol. 22
·期 1
·1-19
·
IF 6.1
Qin Qian,Shan Zhiyan,Xing Lei,Jiang Yutong,Li Mengyue,Fan Linlin,Zeng Xin,Ma Xinrui,Zheng Danyang,Wang Han,Wang Hui,Liu Hao,Liang Shengjun,Wu Lijie,Liang Shuang
Autism spectrum disorder (ASD) is a multifaceted neurodevelopmental disorder predominant in childhood. Despite existing treatments, the benefits are still limited. This study explored the effectiveness of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) loaded with miR-137 in enhancing autism-like behaviors and mitigating neuroinflammation. Utilizing BTBR mice as an autism model, the study demonstrated that intranasal administration of MSC-miR137-EVs ameliorates autism-like behaviors and inhibits pro-inflammatory factors via the TLR4/NF-κB pathway. In vitro evaluation of LPS-activated BV2 cells revealed that MSC-miR137-EVs target the TLR4/NF-κB pathway through miR-137 inhibits proinflammatory M1 microglia. Moreover, bioinformatics analysis identified that MSC-EVs are rich in miR-146a-5p, which targets the TRAF6/NF-κB signaling pathway. In summary, the findings suggest that the integration of MSC-EVs with miR-137 may be a promising therapeutic strategy for ASD, which is worthy of clinical adoption.
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World Journal of Stem Cells
·
2025
·Vol. 17
·期 7
·104607
·
IF 3.6
Kun Wang,Wei Lin,Jun-Yong Han,Jin-Yan Chen,Rong-Hua Liu,Zhen Yu,Jing-Jun Jin
BACKGROUND Type 1 diabetes (T1D) results from the autoimmune-mediated loss of pancreatic β-cells. Current insulin therapies offer symptomatic relief but fall short of providing a definitive cure. Islet cell transplantation, while promising, faces limitations related to donor scarcity, procedural complexities, and the necessity for long-term immunosuppression. Consequently, there is an urgent need for innovative strategies aimed at β-cell regeneration. Patient-derived induced pluripotent stem cells (iPSCs), obtained from peripheral blood mononuclear cells (PBMCs) of T1D patients, hold great potential as a source of cells for therapeutic purposes. Therefore, the differentiation of T1D-iPSCs into functional pancreatic β-cells is a critical step toward effective β-cell replacement therapy. AIM To assess the potential of patient-derived T1D-β-like cells (differentiated from T1D-iPSCs reprogrammed from T1D-PBMCs) for restoring β-cell function in T1D. METHODS T1D-iPSCs were reprogrammed from T1D-PBMCs using an episomal vector-based approach. Pluripotency was confirmed by flow cytometry (FCM), quantitative real-time polymerase chain reaction, genomic stability analysis, and teratoma formation assays. Differentiation into pancreatic β-cells was optimized using triiodothyronine (T3), vitamin C (Vc), and an adenovirus (M3C) encoding pancreatic duodenal homeobox-1, neurogenin 3 ( Ngn3 ), and MAF bZIP transcription factor A ( MafA ). Following characterization of β-cell features by immunofluorescence, quantitative real-time polymerase chain reaction, and flow cytometry, therapeutic efficacy was assessed through blood glucose monitoring after transplantation under the renal capsule of streptozotocin-induced diabetic mice. RESULTS T1D-iPSCs were successfully generated from T1D-PBMCs. These cells exhibited the hallmark characteristics of pluripotent stem cells, including appropriate morphology, differentiation potential, genomic integrity, and expression of pluripotency-associated genes. Differentiation yielded insulin-positive (insulin + ) pancreatic β-like cells that, at the mRNA level, expressed key β-cell markers such as pancreatic duodenal homeobox-1, Ngn3 , MafA , NeuroD , glucagon-like peptide-1 receptor, Nkx6.1 , glucose transporter 2, and Kir6.2 . Notably, the T3 + Vc group displayed the lowest Ngn3 expression (1.31 ± 0.38 vs 1.96 ± 0.25 vs 2.51 ± 0.24, P < 0.01), while the M3C + T3 + Vc group exhibited the highest MafA expression (0.49 ± 0.11 vs 0.32 ± 0.06 vs 0.29 ± 0.08, P < 0.05). Both in vitro and in vivo assessments confirmed the insulin secretion ability of the generated β-like cells; however, they did not demonstrate appropriate modulation of insulin release in response to variations in extracellular glucose concentrations. CONCLUSION T1D-iPSCs derived from T1D-PBMCs can be differentiated into insulin + β-like cells, albeit with functional immaturity. These cells represent a potential source of seed cells for β-cell replacement therapy in T1D.
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Reproductive Sciences
·
2025
·
IF 2.5
Qiu Yingying,Wei Xinjun,Cao Jian,Wang Jindan,Dou Qianru,Zhou Fangfang,Chen Xi,Liu Yongli,Wan Guiping,Huang Meihua,Li Zhenli,Gui Tao
Adenomyosis (AM), a gynecological disorder that severely affects female reproductive health. AM-associated macrophage (AAM) polarization-induced epithelial–mesenchymal transition (EMT) is a key driver of AM progression. In this study, we investigated the role and underlying mechanisms of endometrial mesenchymal stem cell (eMSC)-derived exosomes in regulating AAM polarization and the subsequent EMT of endometrial epithelial cells (EECs). In vitro coculture studies revealed that AM eutopic eMSCs markedly induced M2 macrophage polarization via exosomes and promoted EMT of EECs. Differentially expressed microRNAs (DE-miRNAs) between exosomes derived from normal eMSCs (N-eMSCs) and AM eutopic eMSCs (A-eMSCs) were identified using miRNA sequencing and miR-4669 was found to be the most significantly upregulated miRNA. Internalization of exosomal miR-4669 by macrophages induced their polarization toward the M2 phenotype and promoted the EMT of EECs. Mechanistic analysis using luciferase assay, mRNA sequencing, and rescue experiments revealed that miR-4669 induced M2 macrophage polarization via downregulation of DUSP6 and activation of MAPK/ERK signaling. The polarized M2 macrophages promoted the EMT of ISK cells via TGF-β1 secretion. In an AM xenograft mouse model, miR-4669 depletion inhibited AM progression by targeting the DUSP6/ERK1/2 pathway in macrophages. Overall, AM A-eMSC-derived exosomal miR-4669 facilitates M2 macrophage polarization by targeting the DUSP6/ERK signaling pathway, thereby promoting EMT of EECs via TGF-β1 secretion. These findings open avenues for developing novel preventive and therapeutic strategies for AM. Graphical
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BMC BIOTECHNOLOGY
·
2025
·Vol. 25
·期 1
·1-20
·
IF 3.4
Long Shengyu,Wang Wentong,Chen Yongcheng,Wang Zhihua,Duan Hao,Yuan Ping,Xu Yunrong,Li Denghui,Zhang Wan,Wang Weizhou,He Fei
Background The repair of bone defects remains a significant clinical challenge. Although magnesium (Mg)-based biomimetic scaffolds are widely utilized for bone defect repair, the release of Mg²⁺ ions often leads to an alkaline microenvironment, thereby adversely affecting bone regeneration. Regenerative medicine strategies that leverage the recruitment of endogenous bone marrow mesenchymal stem cells (BMSCs) offer a novel approach to treating bone defects.Methods In this study, we employed poly(L-lactic acid) (PLLA) and polyethylene glycol (PEG) as shell materials and nanomagnesium oxide (nMgO) combined with gelatin (G) as core materials to fabricate coaxial fibre membranes with a “core‒shell” structure via coaxial electrospinning technology. Additionally, we grafted the BMSC-affinitive peptide E7 (EPLQLKM) onto the fibres to achieve specific recruitment of endogenous BMSCs.Results Morphological and structural analyses confirmed the successful formation of the “core‒shell” structure of the fibre membranes. Grafting E7 peptides enhanced the hydrophilicity and mechanical properties of the fibre membranes and maintained pH stability in vitro. In vitro experiments demonstrated that the functionalized fibre membranes significantly promoted BMSC proliferation, migration, and osteogenic differentiation. When implanted into a rat cranial defect model, we observed the formation of new bone tissue and the repair of the bone defect.Conclusion sE7 peptide-functionalized coaxial fibre membranes effectively facilitated bone defect repair by promoting the recruitment and osteogenic differentiation of BMSCs, demonstrating substantial potential for tissue engineering applications.
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Small
·
2024
·
IF 13
Yan Shi,Shang Wang,Kai Wang,Ronghua Yang,Dewu Liu,Huaiwei Liao,Yuhan Qi,Keqing Qiu,Yanghong Hu,Huicai Wen,Kui Xu
Macrophage dysfunction is one of the primary factors leading to the delayed healing of diabetic wounds. Hypoxic bone marrow mesenchymal stem cells-derived exosomes (hyBMSC-Exos) have been shown to play an active role in regulating cellular function through the carried microRNAs. However, the administration of hyBMSC-Exos alone in diabetic wounds usually brings little effect, because the exosomes are inherently unstable and have a short retention time at the wounds. In this study, a multifunctional hydrogel based on gallic acid (GA) conjugated chitosan (Chi-GA) and partially oxidized hyaluronic acid (OHA) is prepared for sustained release of hyBMSC-Exos. The hydrogel not only exhibits needs-satisfying physicochemical properties, but also displays outstanding biological performances such as low hemolysis rate, strong antibacterial capacity, great antioxidant ability, and excellent biocompatibility. It has the ability to boost the stability of hyBMSC-Exos, leading to a continuous and gradual release of the exosomes at wound locations, ultimately enhancing the exosomes’ uptake efficiency by target cells. Most importantly, hyBMSC-Exos loaded hydrogel shows an excellent ability to promote diabetic wound healing by regulating macrophage polarization toward M2 phenotype. This may be because exosomal miR-4645-5p and antioxidant property of the hydrogel synergistically inhibit SREBP2 activity in macrophages. This study presents a productive approach for managing diabetic wounds.
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Stem Cells Translational Medicine
·
2025
·Vol. 14
·期 3
·
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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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 16
·8827
·
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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Biomaterials Advances
·
2025
·
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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