MOLECULAR MEDICINE
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2024
·Vol. 30
·期 1
·1-16
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IF 6
Zhang Yanbin,Bai Jing,Xiao Bin,Li Chunyan
Osteoporosis is characterized by reduced bone mass due to imbalanced bone metabolism. Exosomes derived from bone mesenchymal stem cells (BMSCs) have been shown to play roles in various diseases. This study aimed to clarify the regulatory function and molecular mechanism of BMSCs-derived exosomes in osteogenic differentiation and their potential therapeutic effects on osteoporosis. Exosomes were extracted from BMSCs. Bone marrow-derived macrophages (BMDMs) were cultured and internalized with BMSCs-derived exosomes. Real-time quantitative PCR was used to detect the expression of macrophage surface markers and tripartite motif (TRIM) family genes. BMDMs were co-cultured with human osteoblasts to assess osteogenic differentiation. Western blot was performed to analyze the ubiquitination of triggering receptor expressed on myeloid cell 1 (TREM1) mediated by TRIM25. An ovariectomized mice model was established to evaluate the role of TRIM25 and exosomes in osteoporosis. Exosomes were successfully isolated from BMSCs. BMSCs-derived exosomes upregulated TRIM25 expression, promoting M2 macrophage polarization and osteogenic differentiation. TRIM25 facilitated the ubiquitination and degradation of TREM1. Overexpression of TREM1 reversed the enhanced M2 macrophage polarization and osteogenic differentiation caused by TRIM25 overexpression. TRIM25 enhanced the protective effect of BMSCs-derived exosomes against bone loss in mice. These findings suggested that BMSCs-derived exosomes promoted osteogenic differentiation by regulating M2 macrophage polarization through TRIM25-mediated ubiquitination and degradation of TREM1. This mechanism might provide a novel approach for treating osteoporosis.
研究领域:
细胞生物学
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骨代谢
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干细胞研究
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巨噬细胞生物学
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疾病分子机制
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DOI
PubMed
高影响因子
Journal of Orthopaedic Surgery and Research
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2024
·Vol. 19
·期 1
·1-17
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IF 2.8
Zhang Yong,Huang Wenliang,Xiao Hongli,Ruan Shiqiang,Deng Jiang
Background With the rapid growth of the ageing population, chronic diseases such as osteoarthritis have become one of the major diseases affecting the quality of life of elderly people. The main pathological manifestation of osteoarthritis is articular cartilage damage. Alleviating and repairing damaged cartilage has always been a challenge. The application of cartilage tissue engineering methods has shown promise for articular cartilage repair. Many studies have used cartilage tissue engineering methods to repair damaged cartilage and obtained good results, but these methods still cannot be used clinically. Therefore, this study aimed to investigate the effect of incorporating nerve growth factor (NGF) into a silk fibroin (SF)/chitosan (CS) scaffold containing bone marrow-derived mesenchymal stem cells (BMSCs) on the repair of articular cartilage defects in the knees of rabbits and to explore the possible underlying mechanism involved. Materials and methods Nerve growth factor-loaded sustained-release microspheres were prepared by a double emulsion solvent evaporation method. SF/CS scaffolds were prepared by vacuum drying and chemical crosslinking. BMSCs were isolated and cultured by density gradient centrifugation and adherent culture. NGF-SF/CS-BMSC composites were prepared and implanted into articular cartilage defects in the knees of rabbits. The repair of articular cartilage was assessed by gross observation, imaging and histological staining at different time points after surgery. The repair effect was evaluated by the International Cartilage Repair Society (ICRS) score and a modified Wakitani score. In vitro experiments were also performed to observe the effect of different concentrations of NGF on the proliferation and directional differentiation of BMSCs on the SF/CS scaffold. Results In the repair of cartilage defects in rabbit knees, NGF-SF/CS-BMSCs resulted in higher ICRS scores and lower modified Wakitani scores. The in vitro results showed that there was no significant correlation between the proliferation of BMSCs and the addition of different concentrations of NGF. Additionally, there was no significant difference in the protein and mRNA expression of COL2a1 and ACAN between the groups after the addition of different concentrations of NGF. Conclusion NGF-SF/CS-BMSCs improved the repair of articular cartilage defects in the knees of rabbits. This repair effect may be related to the early promotion of subchondral bone repair.
研究领域:
生物医学工程
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骨科
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组织工程
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再生医学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2023
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IF 10
Tingting Yang,Yunsheng Dong,Jinpeng Wan,Xiangsheng Liu,Yufei Liu,Jiaxing Huang,Jie Zhou,Hui Xiao,Lizong Tang,Yanying Wang,Shufang Wang,Hong Cai
Extracellular vesicles (EVs) play an important role in intercellular communication, and the function of EVs mainly depends on the state of source cells. To determine the effect of diabetic microenvironment on EVs secreted by bone marrow mesenchymal stem cells (BMSCs), this work explores the effect of normal glucose (5.5 m m ) cultured BMSCs derived EVs (NG-EVs) and high glucose (30 m m ) cultured BMSCs derived EVs (HG-EVs) in regulating the migration, proliferation and osteoblastic differentiation of BMSCs in vitro. In order to improve the bioavailability of EVs, this work constructs a sustained release system of polydopamine (PDA) functionalized 3D printing gelatin/hyaluronic acid/nano-hydroxyapatite (Gel/HA/nHAP) scaffolds (S/PDA) and verifies its function in the calvarial defect model of diabetic rats. This work confirms that both NG-EVs and HG-EVs can promote proliferation and migration, inhibit apoptosis and promote osteogenic differentiation, but the function of HG-EVs is weaker than that of NG-EVs. Therefore, EVs secreted by autologous cells of diabetic patients are not suitable for self-repair. This work hopes that the 3D printing scaffold designed for sustained-release EVs will provide a new strategy for acellular tissue engineering bone repair in diabetic patients.
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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细胞生物学
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材料科学
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PubMed
高影响因子
BIOMATERIALS
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2021
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IF 12.479
Anqi Liu,Dan Lin,Hanjiang Zhao,Long Chen,Bolei Cai,Kaili Lin,Steve GF Shen
Mesenchymal stem cell-derived exosomes (MSC-exos), with its inherent capacity to modulate cellular behavior, are emerging as a novel cell-free therapy for bone regeneration . Herein, focusing on practical applying problems, the osteoinductivity of MSC-exos produced by different stem cell sources (rBMSCs/rASCs) and culture conditions (osteoinductive/common) were systematically compared to screen out an optimized osteogenic exosome (BMSC-OI-exo). Via bioinformatic analyses by miRNA microarray and in vitro pathway verification by gene silencing and miRNA transfection, we first revealed that the osteoinductivity of BMSC-OI-exo was attributed to multi-component exosomal miRNAs (let-7a-5p, let-7c-5p, miR-328a-5p and miR-31a-5p). These miRNAs targeted Acvr2b/Acvr1 and regulated the competitive balance of Bmpr2/Acvr2b toward Bmpr-elicited Smad1/5/9 phosphorylation. On these bases, lyophilized delivery of BMSC-OI-exo on hierarchical mesoporous bioactive glass (MBG) scaffold was developed to realize bioactivity maintenance and sustained release by entrapment in the surface microporosity of the scaffold. In a rat cranial defect model, the loading of BMSC-OI-exo efficiently enhanced the bone forming capacity of the scaffold and induced rapid initiation of bone regeneration. This paper could provide empirical bases of MSC-exo-based therapy for bone regeneration and theoretical bases of MSC-exo-induced osteogenesis mechanism. The BMSC-OI-exo-loaded MBG scaffold developed here represented a promising bone repairing strategy for future clinical application.
研究领域:
生物医学工程
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组织工程
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再生医学
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分子生物学
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干细胞研究
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2024
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IF 10
Kaiqi Qin,Xinyue Huang,Shengfeng Wang,Jiachen Liang,Zengjie Fan
Repairing osteochondral (OC) defect presents a significant challenge due to the intricate structural requirements and the unpredictable differentiation pathways of bone marrow mesenchymal stem cells (BMSCs). To address this challenge, a novel biomimetic OC hydrogel scaffold is developed that features a structure of soft and hard components. This scaffold incorporates bilayer metal–organic frameworks (MOFs), specifically ZIF-67 in the upper layer and ZIF-8 in the lower layer, achieved through an in situ printing process. This configuration enables the spatial and temporal modulation of BMSC differentiation by controlling the release of Co 2 ⁺ and Zn 2 ⁺. The results demonstrate that the bilayer MOF hydrogels significantly outperform hydrogels that either lack MOFs or contain a single type of MOF in enhancing repair outcomes in rabbit models of knee OC defects. The improved regenerative efficacy is attributed to the distinct chondrogenic and osteogenic differentiation cues provided by the bilayer MOFs, effectively guiding BMSCs toward enhanced tissue regeneration. This customizable biomimetic OC hydrogel scaffold not only opens new avenues for innovative therapeutic strategies but also holds great promise for widespread clinical applications.
研究领域:
再生医学
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生物材料科学
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骨科
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DOI
PubMed
高影响因子
Materials Today Bio
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2025
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IF 10.2
Rong Xu,Hua Zhang,Yang Luo,Shiyi Pan,Chi Zhang,Xiaochuan Wu,Guofeng Zhang,Cuicui Su,Dongdong Xia
Bone tissue engineering utilizing magnetic anisotropic hydrogels (MAHs) loaded with bone marrow-derived stem cells (BMSCs) offers a promising strategy to enhance the regeneration of bone defects due to their mechanotransduction and osteoinductive properties. However, the application of MAHs as bioinks for creating personalized 3D scaffolds faces significant challenges. Bioprinting necessitates a rapid sol-gel transition to enable the ink to form stable structures, whereas anisotropic shaping requires the ink to remain in a sol state post-printing, allowing magnetic particles to assemble freely under magnetic induction. To overcome these challenges, we develop a biomimetic MAH that recapitulate the anisotropic structures of the bone using a continuous Liquid-in-Liquid bioprinting method combined with magnetic induction. The constructed MAHs feature uniformly aligned Fe 3 O 4 microfibers embedded within the bioprinted hydrogel filaments. These Fe 3 O 4 microfibers provide microscale geometric cues that promote the elongation and osteogenic bioactivity of BMSCs through biomechanical signaling pathways. The implantation of the MAHs loaded with BMSCs in a critical-sized cranial defect model effectively accelerates the healing of bone injuries by facilitating collagen matrix development and promoting neovascularization. This study introduces a novel approach in the development of MAHs and presents a promising candidate for applications in bone tissue engineering and repair.
研究领域:
组织工程学
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再生医学
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生物材料科学
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DOI
PubMed
高影响因子
Materials Today Bio
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2025
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IF 10.2
Qiumei Lan,Mengtian Fan,Fengmei Zhang,Qian Gong,Jiayan Zhong,Miao Yi,Qiqi Zeng,Jianqiang Chen,Yiming Pan,Nana Geng,Biao Kuang,Yu Du,Chuanrong Zhao,Deping Zeng,Chunliang Zhao,Zhen Li,Guixue Wang,Fengjin Guo
Bone regeneration remains a formidable challenging due to impaired energy metabolism and the limited osteogenic potential of transplanted stem cells. Mitochondrial homeostasis orchestrates osteogenesis, with mitophagy maintaining the metabolic rhythm essential for bone formation. However, the role of autophagy related gene 7(ATG7), a pivotal regulator of mitochondrial function, in bone regeneration remains elusive. In this study, we developed a ATG7-overexpressing bone marrow mesenchymal stem cells (ATG7-BMSCs) encapsulated within a thermoresponsive chitosan (CS) hydrogel, creating a biocompatible, living platform capable of adapting to physiological conditions. The hydrogel exhibited excellent injectability, physiological gelation at 37 °C, and prolonged biocompatibility, providing a favorable microenvironment for stem cell survival and proliferation. The system was evaluated through in vitro assays for mitochondrial function and osteogenic differentiation, as well as in vivo using rat cranial and femoral defect models. Mechanistically, ATG7 activation enhanced mitophagy, preserved mitochondrial integrity, reduced reactive oxygen species (ROS) accumulation, and reactivated oxidative phosphorylation via the PI3K-AKT signaling pathway, thereby reprogramming osteogenic metabolism and promoting differentiation. Conversely, ATG7 deficiency led to mitochondrial dysfunction, glycolytic dependence, and impaired bone formation. In vivo, the ATG7-BMSC@CS hydrogel markedly accelerated new bone formation and mineral density recovery while maintaining excellent injectability, biocompatibility, and systemic safety. Collectively, this study identifies ATG7-driven mitophagy as a critical regulator of osteogenic metabolism and bone formation, and establishes a smart, living hydrogel platform that seamlessly integrates metabolic reprogramming with stem cell delivery. This strategy provides a conceptual blueprint for next-generation, metabolism-oriented bone repair at the intersection of cell biology, biomaterials, and precision medicine.
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高影响因子
JOURNAL OF CONTROLLED RELEASE
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2022
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IF 11.467
Zhi Zheng,Zheng Guo,Fengmin Zhong,Bin Wang,Li Liu,Wei Ma,Cui-yun Yu,Hua Wei
The efficacy of myocardial regeneration strategies for myocardial infarction (MI) is significantly compromised by the complex structure and microenvironment of the myocardium. Although tissue engineering strategies based on cell therapy and/or pro-angiogenesis can somewhat improve cardiac function, the lack of proper myocardial materials that can withstand sustained deformability and adaptable mechanical properties severely affects myocardial wall integrity, systolic-diastolic cycles, and regeneration. Herein, we developed an integrated single “all-in-one” in situ dual crosslinking conductive hydrogel with favorable treatment properties termed as MaHA/B-G-SH/Fe 3+ by ionic interactions and chemical covalency based on modified hyaluronic acid (HA), gelatin (G), and Fe 3+ . The resulting dual crosslinking dynamic hydrogel not only provides self-healing and mechanical properties adapted to the myocardial systolic-diastolic cycle with simultaneous electrical signal transmission to fibrous islands and normal tissue, but also leads to significant increase of the myocardial wall thickness very close to that of normal myocardium upon one single injection with complete degradation within 28 days. Notably, the hydrogel covalently conjugated with a tailored peptide sequence of GGR-KLT and encapsulated with bone mesenchymal stem cells (BMSCs) was further used for in situ injection in a rat MI model, which exhibited (i) efficient inhibition of excessive matrix degradation dependent on early MMP-2 expression, (ii) triggered on-demand release of KLT for at least 14 days and significant promotion of angiogenesis, and (iii) synergistic BMSCs considerably enhanced myocardial regeneration within 28 days. Taken together, the dual crosslinking conductive hydrogel-mediated synergistic peptide and cell therapy provides comprehensive recovery and regeneration of the structure and function of the injured myocardium, thus demonstrating great potential for clinical translations.
研究领域:
组织工程
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心血管医学
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再生医学
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生物医用材料
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干细胞治疗
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DOI
PubMed
高影响因子
Materials Today Bio
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2021
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IF 7.348
Luyu Wang,Dan Zhang,Yikun Ren,Shen Guo,Jinrui Li,Shanshan Ma,Minghao Yao,Fangxia Guan
Injectable hydrogel has the advantage to fill the defective area and thereby shows promise as therapeutic implant or cell/drug delivery vehicle for tissue repair. In this study, an injectable hyaluronic acid hydrogel in situ dual-enzymatically cross-linked by galactose oxidase (GalOx) and horseradish peroxidase (HRP) was synthesized and optimized, and the therapeutic effect of this hydrogel encapsulated with bone mesenchymal stem cells (BMSC) and nerve growth factors (NGF) for traumatic brain injury (TBI) mice was investigated. Results from in vitro experiments showed that either tyramine-modified hyaluronic acid hydrogels (HT) or NGF loaded HT hydrogels (HT/NGF) possessed good biocompatibility. More importantly, the HT hydrogels loaded with BMSC and NGF could facilitate the survival and proliferation of endogenous neural cells probably by neurotrophic factors release and neuroinflammation regulation, and consequently improved the neurological function recovery and accelerated the repair process in a C57BL/6 TBI mice model. All these findings highlight that this injectable, BMSC and NGF-laden HT hydrogel has enormous potential for TBI and other tissue repair therapy.
研究领域:
生物医学工程
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神经科学
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组织工程
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干细胞治疗
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DOI
PubMed
高影响因子
Biomaterials Science
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2023
·Vol. 11
·期 8
·2924-2934
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IF 6.6
Zhaoyi Wang,Wangbei Cao,Fanghui Wu,Xiurong Ke,Xinyu Wu,Tong Zhou,Jun Yang,Guojing Yang,Cheng Zhong,Zhongru Gou,Changyou Gao
Osteochondral tissue involves cartilage, calcified cartilage and subchondral bone. These tissues differ significantly in chemical compositions, structures, mechanical properties and cellular compositions. Therefore, the repairing materials face different osteochondral tissue regeneration needs and rates. In this study, we fabricated an osteochondral tissue-inspired triphasic material, which was composed of a poly(lactide-co-glycolide) (PLGA) scaffold loaded with fibrin hydrogel, bone marrow stromal cells (BMSCs) and transforming growth factor-β1 (TGF-β1) for cartilage tissue, a bilayer poly(L-lactide-co-caprolactone) (PLCL)-fibrous membrane loaded with chondroitin sulfate and bioactive glass, respectively, for calcified cartilage, and a 3D-printed calcium silicate ceramic scaffold for subchondral bone. The triphasic scaffold was press-fitted into the osteochondral defects in rabbit (cylindrical defects with a diameter of 4 mm and a depth of 4 mm) and minipig knee joints (cylindrical defects with a diameter of 10 mm and a depth of 6 mm). The μ-CT and histological analysis showed that the triphasic scaffold was partly degraded, and significantly promoted the regeneration of hyaline cartilage after they were implanted in vivo. The superficial cartilage showed good recovery and uniformity. The calcified cartilage layer (CCL) fibrous membrane was in favor of a better cartilage regeneration morphology, a continuous cartilage structure and less fibrocartilage tissue formation. The bone tissue grew into the material, while the CCL membrane limited bone overgrowth. The newly generated osteochondral tissues were well integrated with the surrounding tissues too.
研究领域:
组织工程学
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再生医学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2025
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IF 8.5
Guanrong Li,Renhao Ni,Zheyuan Shi,Haijiao Mao,Yang Luo,Xu Cao,Chi Zhang,Yuetian Liu,Zhanping Jin,Jun Chen,Jun Fu,Hua Zhang,Yingchun Zhu
Hydrogel-based cartilage tissue engineering (HCTE) offers a promising strategy for the regeneration of articular cartilage. However, the effectiveness of current HCTE is hindered by the low efficiency of stem cell transplantation and insufficient chondrogenic differentiation. Here, we develop a mechanically optimized and biochemically sustained biomaterial system that integrates a dynamic hydrazone/covalent dual-crosslinked hyaluronan (HA) hydrogel with kartogenin (KGN)-loaded poly(lactic- co -glycolic acid) microspheres to facilitate stem cell chondrogenesis and repair articular cartilage. This composite hydrogel features excellent injectability and self-healing behavior, allowing for minimally invasive implantation while protecting cell viability. The tunable viscoelasticity of the hydrogel enhances focal adhesion formation in bone-marrow mesenchymal stem cells (BMSCs), promoting their spreading, proliferation, and aggregation. Furthermore, the combined effects of hydrogel viscoelasticity and sustained KGN release markedly promote the expression of cartilage-specific genes and the secretion of extracellular matrix components through the integrin-mediated Hippo signaling pathway and KGN-mediated TGF-β signaling pathway. This dual-stimuli hydrogel embedded with BMSCs significantly promotes the regeneration of articular cartilage in rabbit models. Overall, the designed KGN composite dynamic HA-based hydrogel enables highly effective transplantation and promotes efficient chondrogenesis of stem cells, providing a promising approach for stem cell therapy and cartilage regeneration.
研究领域:
组织工程学
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再生医学
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DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
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2025
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IF 5.5
Wenliao Chang,Peipei Lu,Shuxiang Li,Jinghua Xiang,Jiachen Liu,Yimin Wang,Lei Zhang,Han Sun
Currently, bone defects remain a major challenge in clinical treatment. Recruiting target cells at the defect site and inducing them to differentiate into bone tissue are effective treatment methods. In previous studies, we used the CD271 antibody to construct bone marrow mesenchymal stem cell (BMSC) recruitment microspheres for the treatment of bone defects. However, the osteoconductivity of the microspheres themselves was poor, and the system lacked osteoinductivity, which affected the repair efficiency. In this study, we prepared submillimeter-sized porous chitosan (CS) microspheres through process optimization, and the BMSCs were able to directly adhere and proliferate on their surfaces. After the bioconjugation of the CD271 antibody, bone morphogenetic protein-2 (BMP-2) was further loaded onto the pore structure of microspheres to obtain the injectable microspheres with BMSC recruitment and osteogenic differentiation induction functions. Microspheres could efficiently recruit BMSCs through the combined action of the CD271 antibody and BMP-2 and further induce the recruited BMSCs, differentiating into osteoblasts through BMP-2, which ultimately exhibited promising bone regeneration ability in rats. We expect that the novel functional microspheres have great potential in biomedical applications for in situ treatment of bone defects.
研究领域:
生物医学工程
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组织工程
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再生医学
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）