GENE
·
2023
·
IF 3.5
Jianping Zhang,Zhijun Cai,Fanzhe Feng,Yufeng Peng,Yi Cui,Yongiqing Xu
Background Rotator cuff tears (RCTs) are culprit of shoulder pain and dysfunction. Tendon-bone interface (TBI) mal-healing is an essential contributor to retear after RCTs. Consequently, present project was conducted to investigate the role of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes on TBI healing. Method Young BMSCs (Y-BMSCs) and Aged BMSCs (A-BMSCs) were isolated from Young (3-month-old) and old (24-month-old) SD rats, and their-derived exosomes (A-BMSCs-exo and Y-BMSCs-exo) were identified. RCTs model was established, and A-BMSCs-exo and Y-BMSCs-exo were injected at the rotator cuff using hydrogel as a vehicle. Pathological changes of TBI were observed by HE, Sirius Red and Oil Red O staining. Western blotting and RT-qPCR were applied to assess the expression of extracellular matrix (ECM)-, tendon cell (TCs)-, osteogenic-, tendon-derived stem cell (TDSCs)- and angiogenic-associated proteins and mRNAs in TBI. Result Y-BMSCs exhibited increased activity, osteogenic and lipogenic abilities than A-BMSCs. After A-BMSCs-exo and Y-BMSCs-exo treatment, TBI displayed massive sharpey’s fibers growing along the tendon longitudinally, and a collagen fiber-chondrocyte migration zone forming a typical tendon-noncalcified fibrocartilage-calcified fibrocartilage-bone structure. A-BMSCs-exo and Y-BMSCs-exo significantly upregulated the expression of collagen Col I/II/III, Aggrecan, TNMD, SCX, Runx2, OPN, CD45, Sox2, CD31 and VEGFR2 in TBI. In vitro , A-BMSCs-exo and Y-BMSCs-exo significantly enhanced the activity of TCs and TDSCs, TDSCs stemness, and reduced the osteogenic and lipogenic capacity of TDSCs. The effect of Y-BMSCs-exo was significantly stronger than that of A-BMSCs-exo. Conclusion BMSCs-derived exosomes facilitate ECM remodeling, osteogenic differentiation, angiogenesis, and stemness of TDSCs, thereby accelerating TBI healing in RCTs, with better outcomes using young individual-derived BMSCs.
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ACS Applied Materials & Interfaces
·
2025
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IF 8.2
Min Wu,Han Lin,Maofei Ran,Mengqing Li,Chengli Liu,Jinhua Piao,Peng Yu,Chengyun Ning,Cairong Xiao,Suijian Qi
The involvement of neurons in the peripheral nervous system is crucial for bone regeneration. Mimicking extracellular matrix cues provides a more direct and effective strategy to regulate neuronal activity and enhance bone regeneration. However, the simultaneous coupling of the intrinsic mechanical-electrical microenvironment of implants to regulate innervated bone regeneration has been largely neglected. Inspired by the mechanical and bioelectric properties of the bone microenvironment, this study constructed a mechanical-electrical coupling microenvironment (M-E) model based on barium titanate piezoelectric nanoarrays, which could effectively promote innervated bone regeneration. The study found that the mechanical microenvironment provided by the nanostructure, coupled with the electrical microenvironment provided by the piezoelectric properties, created a controllable M-E. In vitro cell experiments demonstrated that this coupled microenvironment activated Piezo2 and VGCC ion channels, promoted calcium influx in DRG neurons, and activated downstream PI3K-AKT and RAS pathways. This cascade of events led to the synthesis and release of CGRP in sensory nerves, ultimately enhancing the osteogenic differentiation of BMSCs. This work not only broadens the current understanding of biomaterials that mimic the bone extracellular matrix but also provides new insights into innervated bone regeneration.
研究领域:
生物材料学
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骨组织工程
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神经科学
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BIOMATERIALS
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2025
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IF 12.9
Danmei Li,Yixiang Wang,Guangxun Yuan,Feifei Zhou,Hongpu He,Xiangyu Du,Shuyu Liu,Wentao Gao,Xuxuan Fan,Zhiqin Liu,Binbin Ma,Zhenhan Deng,Shuai Li,Jian Xu
The restricted self-healing capacity of articular cartilage, combined with the inflammatory response and oxidative stress that follow injury, makes articular cartilage restoration a challenging therapeutic problem. We engineered an injectable porous microgel system (BMSC-Met@MGs) utilizing microfluidic technology comprising GelMA, CSMA, and PVA, which co-encapsulate bone marrow mesenchymal stem cells (BMSCs) and metformin via hydrogen-bonded sustained release. This structure uniquely integrates immune modulation (downregulation of MMP3/MMP13), antioxidation (clearance of reactive oxygen species and restoration of the mitochondrial membrane potential), and cartilage regeneration (upregulation of COL2A1) in vitro. Preliminary in vivo results suggest that BMSC-Met@MGs facilitated hyaline cartilage repair in rats. Our study introduced a comprehensive therapeutic approach with anti-inflammatory, antioxidant, and regenerative effects, marking the inaugural use of metformin in the repair of cartilage defects. This synergistic material/drug/cell method offers novel insights into cartilage repair.
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JOURNAL OF MOLECULAR HISTOLOGY
·
2021
·Vol. 53
·期 1
·119-131
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IF 2.611
Lin Wei,Chen Zhipeng,Mo Xiaoyi,Zhao Shengli,Wen Zhenxing,Cheung Wing Hoi,Fu Dan,Chen Bailing
The imbalance between osteogenic and adipogenic differentiation of Bone marrow-derived mesenchymal stem cells (BMSCs) is involved in the occurrence and development of osteoporosis (OP). Previous studies have indicated the potential of phosphatase and actin regulator 1 (Phactr1) in regulating osteogenic and adipogenic differentiation of BMSCs. The present study aims to investigate the function and mechanism of Phactr1 in regulating osteogenic and adipogenic differentiation of BMSCs. Herein, the expression of Phactr1 in bone and adipose tissue of OP rats was determined by immunohistochemical. BMSCs were subjected to osteogenic and adipogenic differentiation, and transfected with Phactr1 overexpression lentivirus, small interference RNA (siRNA) and KD025 (selective ROCK2 inhibitor). The relationship between Phactr1 and ROCK2 was detected by Co-IP experiment. The expression of Phactr1, Runx2, C/EBPα, RhoA and ROCK2 was detected by Western blot. Calcium nodule and lipid droplets were determined by alizarin red and Oil red O staining. Interestingly, Phactr1 increased in both bone and adipose tissue of OP rats. During osteogenic differentiation, Phactr1 decreased and active RhoA, ROCK2 increased, while overexpression Phactr1 inhibits the increase of Runx2. Phactr1 increased and active RhoA decreased, ROCK2 did not changed during adipogenic differentiation. While, Knockdown Phactr1 inhibits the increase of C/EBPα. Phactr1 and ROCK2 were combined in osteogenic differentiation, but not in adipogenic differentiation. By using KD025, the decrease of Phactr1 and increase of Runx2 were inhibited respectively in osteogenic differentiation. Meanwhile, when ROCK2 was inhibited, Phactr1, C/EBPα were significantly increased in adipogenic differentiation. These findings indicated that Phactr1 negatively regulates bone mass by inhibiting osteogenesis and promoting adipogenesis of BMSCs by activating RhoA/ROCK2.
研究领域:
生物学
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医学
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干细胞研究
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骨骼生物学
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Stem Cell Research & Therapy
·
2025
·Vol. 16
·期 1
·691
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IF 7.3
Gu Hongji,Liu Buhan,An Yue
Background Bone marrow mesenchymal stem cells (BMSCs) play a crucial role in bone repair and regeneration. The sirtuin family member sirtuin 5 (SIRT5) has been implicated in various cellular processes, including the regulation of osteogenic differentiation. This study aimed to investigate the role of SIRT5 in osteogenic differentiation of BMSCs and its impact on fracture healing. Methods BMSCs were characterized and induced to undergo osteogenic and adipogenic differentiation. The effects of SIRT5 modulation on osteogenic differentiation were assessed through alkaline phosphatase (ALP) staining, Alizarin Red S (ARS) staining, and osteogenic genes expression analysis. The role of SIRT5 in regulating bone morphogenetic protein 2 (BMP2) succinylation and stability was explored using Western blot, immunoprecipitation, and co-immunoprecipitation. A rat tibial fracture model was used to evaluate the in vivo effects of SIRT5 and BMP2 modulation on fracture healing, assessed by Micro-CT and histological analysis. Results SIRT5 overexpression enhanced osteogenic differentiation of BMSCs, as evidenced by increased ALP activity and mineralization. It also upregulated the expression of osteogenic markers such as osteopontin (OPN), runt-related transcription factor 2 (RUNX2), osterix (OSX), and BMP2. Conversely, SIRT5 knockdown inhibited these processes. Mechanistically, SIRT5 was found to regulate BMP2 succinylation, affecting its stability and function. In vivo, overexpression of SIRT5 in a rat tibial fracture model significantly improved bone volume fraction, trabecular number, and thickness, while reducing trabecular separation. The beneficial effects of SIRT5 overexpression were counteracted by BMP2 knockdown, highlighting the importance of BMP2 in mediating SIRT5’s actions on bone healing. Conclusion SIRT5 promotes osteogenic differentiation of BMSCs and enhances fracture healing by modulating BMP2 succinylation. These findings suggest that SIRT5 could be a potential therapeutic target for the treatment of bone fractures and other skeletal disorders.
研究领域:
分子生物学
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干细胞研究
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骨再生医学
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翻译后修饰
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COLLOIDS AND SURFACES B-BIOINTERFACES
·
2021
·
IF 5.268
Yiqian Huang,Wei Jing,Yechen Li,Qing Cai,Xiaoping Yang
Bone is an electrically responsive tissue, so electroactive materials that can deliver electrical cues to bone are helpful for enhancing regeneration under electrical stimulation (ES), and conductive materials are crucial in ES transmission to determine osteogenesis. Compared with polyesters, biodegradable polyorganophosphazenes (POPPs) show superiority in the field of bone tissue engineering thanks to their rich phosphorus/nitrogen contents, suggesting that the combination of POPPs-based conductive substrates with ES may achieve synergistic enhancements on osteogenesis. Herein, conductive composite films were fabricated by blending poly[(alanine ethyl ester)-(glycine ethyl ester)]phosphazene (PAGP) with carbon nanotubes (CNTs). After surface modification with polydopamine (PDA), bone marrow mesenchymal stromal cells (BMSCs) were cultured on the films under ES, using the cells cultured on conductive films composed of poly(L-lactide) (PLLA) and CNTs as controls. The BMSCs on PAGP/CNT films demonstrated significantly faster proliferation rates and stronger osteogenic differentiation potentials than those on PLLA/CNT films, while cell attachments on the two PDA-coated substrates were similar. Under appropriate ES, further increases in the expressions of osteogenic markers as alkaline phosphatase, collagen I and calcium deposition were identified in comparison with the cases without ES. The contributions of the osteocompatible POPPs, the substrate conductivity and the ES treatment to enhanced osteogenesis suggested new strategies for the design of bone repair materials.
研究领域:
材料科学
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生物医学工程
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组织工程
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生物材料
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高影响因子
Stem Cell Reviews and Reports
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2026
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IF 4.9
Lv Yan,Du Yongjun,Peng Zhi,Ma Chengjie,Li Zhenggang,Xu Rui,Hou Jianhong,Lu Sheng
Osteoporotic fracture is the most severe complication of osteoporosis, and impaired bone regeneration and delayed healing after fracture remain major clinical challenges. Extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (BMSCs) may play a critical role in promoting bone regeneration after osteoporotic fracture. Enhancing their osteogenic potential and elucidating the underlying mechanisms may contribute to accelerated fracture healing. In this study, resveratrol-stimulated BMSC-derived EVs (Res-EVs) were isolated using differential centrifugation combined with ultracentrifugation. We found that compared with EVs secreted by BMSCs under normal culture conditions (Nor-EVs), Res-EVs significantly enhanced BMSCs osteogenic differentiation capacity. Analysis of miRNA sequencing data identified miR-19a-3p as significantly downregulated and PC-3p-83,608 as significantly upregulated. The reliability of the sequencing data was validated by qPCR results. By transfecting BMSCs with inhibitor and mimic of miR-19a-3p, we found that miR-19a-3p was a negative regulator of osteogenic differentiation. Bioinformatics prediction and dual-luciferase reporter assays confirmed that miR-19a-3p directly targets Raf1. Western blot results indicated that miR-19a-3p regulates osteogenic differentiation of BMSCs by targeting Raf1. In vivo experiments further demonstrated that Res-EVs treatment enhanced repair at osteoporotic fracture sites and increased the expression of RUNX2 and RAF1. Collectively, these findings indicate that Res-EVs promote bone regeneration at osteoporotic bone defect sites in rats, with the miR-19a-3p/Raf1 axis representing a potential underlying mechanism.
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Regenerative Therapy
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2025
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IF 3.5
Yude Hong,Zejia Feng,Yunlong Ge,Yuhang Xi,Bowen Zhang,Jianjie Wu,Tian Xia,Bowen Tang,Wei Wang,Jun Chen,Hua Wang,Hengjun Xiao
Background Neurogenic erectile dysfunction (ED) is a prevalent complication following radical prostatectomy in elderly patients, primarily resulting from the apoptosis of corpus cavernosum smooth muscle cells (CCSMCs) and the subsequent excessive fibrosis of the corpus cavernosum. Aim This study aimed to compare the therapeutic effects of exosomes derived from lentivirus-transfected miR-145 bone marrow mesenchymal stem cells (Exo-145) and unmodified BMSCs-derived exosomes (Exo) in aged rats with bilateral cavernous nerve injury (BCNI) and investigate the underlying mechanisms. Methods Twenty-four-month-old male rats were assigned to four groups, namely Sham, BCNI, Exo, and Exo-145. Three weeks after treatment, erectile function was assessed by measuring the maximal intracavernosal pressure to mean arterial pressure (ICP/MAP) ratio. Apoptosis and fibrosis were semi-quantitatively analyzed using TUNEL and Masson's trichrome staining, respectively. In vitro, CCSMCs were subjected to H 2 O 2 -induced oxidative stress, and the protective effects of Exo-145 were evaluated through flow cytometry and Western blot. Lastly, the targets and mechanisms of miR-145 were further validated using dual-luciferase reporter assays and rescue experiments. Results Exo-145 significantly outperformed Exo in restoring erectile function in aged BCNI rats, as evidenced by the significantly higher maximal ICP/MAP ratio, a marked reduction in TUNEL-positive cell count, and marked suppression of fibrosis in cavernous tissue. Moreover, Masson's trichrome staining displayed a substantial decrease in collagen deposition. In vitro, Exo-145 alleviated H 2 O 2 -induced apoptosis in CCSMCs by downregulating Cleaved Caspase-3 expression and Bax while concurrently upregulating Bcl-2 expression. TGFBR2 was identified as a direct target of miR-145 through dual-luciferase reporter assays, with its overexpression partially reversing the protective effects of Exo-145. Conclusion Exo-145 demonstrates superior efficacy compared to Exo in treating aged neurogenic ED by targeting TGFBR2 to alleviate apoptosis and fibrosis. It may represent a promising cell-free therapeutic option for neurogenic erectile dysfunction in elderly patients and could offer new perspectives for improving their prognosis.
研究领域:
男科学
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分子生物学
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干细胞研究
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老年医学
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CARBOHYDRATE POLYMERS
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2026
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IF 12.5
Xuehui Zhang,Jinming Yao,Wenjing Yan,Jing Chen,Yanru Xue,Xiaogang Wu,Weiyi Chen,Yanqin Wang,Qiang Zheng,Qiang Li
Natural trabecular bone is typically a complex 3D honeycomb-like material, which can influence the behavior of bone marrow mesenchymal stem cells (BMSCs), particularly their migration and differentiation direction. However, engineering such biomimetic hydrogels with an orthogonal anisotropic structure similar with trabecular bone via a universal and scalable manner still poses a great challenge. This study develops a cellulose nanofiber (CNF) reinforced composite hydrogel with an orthogonal anisotropic structure, which exhibits a highly aligned fibrous configuration and structural densification, endowing it with excellent mechanical properties and damage-tolerant architectures. Moreover, compared with the composite hydrogel with uniaxially anisotropic structure, this as-developed composite hydrogel with orthogonal anisotropic structure utilizes the interactions between rigid and flexible components to form an anisotropic network structure in orthogonal directions, mimicking the microscopic interactions between collagen fibers and proteoglycans in natural ECMs. It could not only facilitate the physical alignment and directional migration of BMSCs, but also enhance their proliferation and differentiation into osteoblasts. Overall, replicating the structure and properties of natural trabecular bone enhances insights into cellular mechanisms, but also improves the efficiency of bone regenerative medicine treatments.
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Stem Cell Research & Therapy
·
2025
·Vol. 16
·期 1
·1-21
·
IF 7.3
Zhu Yanlin,Yang Yuhan,Lan Yuyan,Yang Zun,Gao Xiang,Zhou Jie
Background Diabetes mellitus (DM) and periodontitis have a bidirectional relationship, with each being a high-risk factor for the other. Prolonged hyperglycemia exacerbates periodontal inflammation and disrupts bone homeostasis. Pyruvate kinase M2 (PKM2), a key enzyme in glycolysis, is involved in metabolic reprogramming, but its role in osteogenesis under high-glucose (HG) inflammatory conditions remains largely unknown. This study aimed to investigate the effects of HG and inflammation on bone marrow mesenchymal stem cells (BMSCs) under indirect co-culture conditions and to explore how PKM2 regulates metabolism and mitochondrial function during osteogenic differentiation in HG inflammatory environments, elucidating its role in diabetic periodontitis (DP).Methods Expose BMSCs to conditioned medium (CM) collected from RAW264.7 cells stimulated with HG and/or lipopolysaccharide (LPS). BMSCs functionality was assessed using CCK8, EdU, Annexin V-PI apoptosis assay, alkaline phosphatase (ALP), and Alizarin Red S (ARS) staining. Metabolic characteristics were evaluated through Seahorse assays, lactate production, glucose uptake, and ATP measurements. Mitochondrial function was assessed via JC-1, and ROS staining, Mito-Tracker staining, and transmission electron microscopy (TEM). Gene and protein expression were analyzed by quantitative real-time PCR and western blotting. In vivo therapeutic effects of shikonin were validated via micro-CT and histological staining in a diabetic periodontitis mouse model.Results In vitro experiments demonstrated that HG inflammatory conditions impaired the survival of BMSCs, suppressed osteogenic differentiation, and induced metabolic reprogramming. This reprogramming was characterized by enhanced glycolysis, impaired oxidative phosphorylation (OXPHOS), abnormal upregulation of PKM2 expression, and mitochondrial dysfunction accompanied by morphological alterations. Shikonin effectively reversed these adverse effects by inhibiting PKM2 tetramerization, rescuing the loss of osteogenic function in BMSCs. The therapeutic potential of shikonin was confirmed in the diabetic periodontitis mouse model.Conclusion PKM2 impairs the osteogenesis of BMSCs by affecting metabolism and mitochondrial function, suggesting it as a potential therapeutic target for diabetic periodontitis.
研究领域:
细胞生物学
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代谢组学
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口腔医学
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COLLOIDS AND SURFACES B-BIOINTERFACES
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2024
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IF 5.4
Yang Xiang,Yuanhui Gao,Qiuhua Cheng,Zhongwen Lei,Xiaoyu Zhang,Yijun Yang,Jianquan Zhang
Bile duct injury presents a significant clinical challenge following hepatobiliary surgery, necessitating advancements in the repair of damaged bile ducts is a persistent issue in biliary surgery. 3D printed tubular scaffolds have emerged as a promising approach for the repair of ductal tissues, yet the development of scaffolds that balance exceptional mechanical properties with biocompatibility remains an ongoing challenge. This study introduces a novel, bio-fabricated bilayer bile duct scaffold using a 3D printing technique. The scaffold comprises an inner layer of polyethylene glycol diacrylate (PEGDA) to provide high mechanical strength, and an outer layer of biocompatible, methacryloylated recombinant collagen type III (rColMA) loaded with basic fibroblast growth factor (bFGF)-encapsulated liposomes (bFGF@Lip). This design enables the controlled release of bFGF, creating an optimal environment for the growth and differentiation of bone marrow mesenchymal stem cells (BMSCs) into cholangiocyte-like cells. These cells are instrumental in the regeneration of bile duct tissues, evidenced by the pronounced expression of cholangiocyte differentiation markers CK19 and CFTR. The PEGDA//rColMA/bFGF@Lip bilayer bile duct scaffold can well simulate the bile duct structure, and the outer rColMA/bFGF@Lip hydrogel can well promote the growth and differentiation of BMSCs into bile duct epithelial cells. In vivo experiments showed that the scaffold did not cause cholestasis in the body. This new in vitro pre-differentiated active 3D printed scaffold provides new ideas for the study of bile duct tissue replacement.
研究领域:
组织工程
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生物医学工程
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再生医学
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外科研究
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BIOMACROMOLECULES
·
2013
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IF 5.371
Yang Zhu,Zhengwei Mao,Changyou Gao
Gradient biomaterials can offer progressively changing signals to specific tissue interface, and thereby modulate the conjunction between different tissues. A linear density gradient of alendronate (Aln), a molecule that is capable of promoting osteogenic differentiation of bone mesenchymal stem cells (BMSCs), was created on an aminolyzed poly(ε-caprolactone) (PCL) membrane. X-ray photoelectron spectroscopy and quartz crystal microbalance with dissipation revealed the linear increase of the Aln amount as a function of the position on the PCL membrane. By contrast, the surface wettability and energy were kept unchanged. The surface-grafted Aln showed a stronger ability to induce the osteogenic differentiation of rat BMSCs than its counterpart in culture medium of the same amount, and the osteo-inductive culture medium. On the Aln-grafted gradient surface, the BMSCs showed gradient osteogenic differentiation as a function of membrane position in terms of cell morphology, alkaline phosphatase activity, calcium deposition, and the expression of osteogenesis marker proteins including collagen type I (COL I), Runt-related transcription factor 2 (Runx2), and osteocalcin (OCN).
研究领域:
生物材料
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干细胞生物学
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组织工程
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材料科学
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高影响因子
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