Publications by authors named "Hongwei Ouyang"

97 Publications

Correction: H3K36 methyltransferase NSD1 regulates chondrocyte differentiation for skeletal development and fracture repair.

Bone Res 2021 Jul 26;9(1):34. Epub 2021 Jul 26.

Shanghai Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

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http://dx.doi.org/10.1038/s41413-021-00160-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313643PMC
July 2021

Light-induced osteogenic differentiation of BMSCs with graphene/TiO composite coating on Ti implant.

Colloids Surf B Biointerfaces 2021 Jul 20;207:111996. Epub 2021 Jul 20.

Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address:

Light-induced surface potential have been demonstrated as an effective bone marrow mesenchymal stem cells (BMSCs) osteogenic differentiation regulator. However, traditional bone repair implants almost were weak or no light-responsive. Fortunately, surface modification was a feasible strategy to realize its light functionalization for bone implants. Herein, a graphene oxide (GO)/titanium dioxide (TiO) nanodots composite coating on the surface of titanium (Ti) implant was constructed, and GO was reduced to reduced graphene oxide (rGO) with the method of UV-assisted photocatalytic reduction. After rGO deposited on the surface of TiO, a heterojunction formed at the interface of rGO and TiO. With visible light illumination, positive charges accumulated on the surface of rGO/TiO film, and performed as a positive surface potential change. The light-induced surface potential which was generated under proper light intensity is harmless to the cell adhesion and proliferation behavior, but presented a good BMSCs osteogenic differentiation promoting effect, and the activation of the voltage-gated calcium channels through surface potential and the promotion of the adsorption of osteogenic growth factors could be the reason. This work given a new insight of the modification for Ti implant with a light-induced surface potential, and shows potential application for bone regeneration on the clinical practice through light stimulation.
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http://dx.doi.org/10.1016/j.colsurfb.2021.111996DOI Listing
July 2021

Interplay of Forces and the Immune Response for Functional Tendon Regeneration.

Front Cell Dev Biol 2021 4;9:657621. Epub 2021 Jun 4.

Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Tendon injury commonly occurs during sports activity, which may cause interruption or rapid decline in athletic career. Tensile strength, as one aspect of tendon biomechanical properties, is the main parameter of tendon function. Tendon injury will induce an immune response and cause the loss of tensile strength. Regulation of mechanical forces during tendon healing also changes immune response to improve regeneration. Here, the effects of internal/external forces and immune response on tendon regeneration are reviewed. The interaction between immune response and internal/external forces during tendon regeneration is critically examined and compared, in relation to other tissues. In conclusion, it is essential to maintain a fine balance between internal/external forces and immune response, to optimize tendon functional regeneration.
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http://dx.doi.org/10.3389/fcell.2021.657621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213345PMC
June 2021

Mass cytometry and transcriptomic profiling reveal body-wide pathology induced by Loxl1 deficiency.

Cell Prolif 2021 Jul 9;54(7):e13077. Epub 2021 Jun 9.

Clinical Research Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Objective: The loss of LOXL1 expression reportedly leads to the prolapse of pelvic organs or to exfoliation syndrome glaucoma. Increasing evidence suggests that LOXL1 deficiency is associated with the pathogenesis of several other diseases. However, the characterization of the systemic functions of LOXL1 is limited by the lack of relevant investigative technologies.

Materials And Methods: To determine the functions of LOXL1, a novel method for body-wide organ transcriptome profiling, combined with single-cell mass cytometry, was developed. A body-wide organ transcriptomic (BOT) map was created by RNA-Seq of tissues from 17 organs from both Loxl1 knockout (KO) and wild-type mice.

Results: The BOT results indicated the systemic upregulation of genes encoding proteins associated with the immune response and proliferation processes in multiple tissues of KO mice, and histological and immune staining confirmed the hyperplasia and infiltration of local immune cells in the tissues of KO mice. Furthermore, mass cytometry analysis of peripheral blood samples revealed systemic immune changes in KO mice. These findings were well correlated with results obtained from cancer databases. Patients with tumours had higher Loxl1 mutation frequencies, and patients with Loxl1-mutant tumours showed the upregulation of immune processes and cell proliferation and lower survival rates.

Conclusion: This study provides an effective strategy for the screening of gene functions in multiple organs and also illustrates the important biological roles of LOXL1 in the cells of multiple organs as well as in systemic immunity.
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http://dx.doi.org/10.1111/cpr.13077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249785PMC
July 2021

H3K36 methyltransferase NSD1 regulates chondrocyte differentiation for skeletal development and fracture repair.

Bone Res 2021 Jun 7;9(1):30. Epub 2021 Jun 7.

Shanghai Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Chondrocyte differentiation is a critical process for endochondral ossification, which is responsible for long bone development and fracture repair. Considerable progress has been made in understanding the transcriptional control of chondrocyte differentiation; however, epigenetic regulation of chondrocyte differentiation remains to be further studied. NSD1 is a H3K36 (histone H3 at lysine 36) methyltransferase. Here, we showed that mice with Nsd1 deficiency in Prx1 mesenchymal progenitors but not in Col2 chondrocytes showed impaired skeletal growth and fracture healing accompanied by decreased chondrogenic differentiation. Via combined RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analysis, we identified sex determining region Y box 9 (Sox9), the key transcription factor of chondrogenic differentiation, as a functional target gene of NSD1. Mechanistically, NSD1 regulates Sox9 expression by modulating H3K36me1 and H3K36me2 levels in the Sox9 promoter region, constituting a novel epigenetic regulatory mechanism of chondrogenesis. Moreover, we found that NSD1 can directly activate the expression of hypoxia-inducible factor 1α (HIF1α), which plays a vital role in chondrogenic differentiation through its regulation of Sox9 expression. Collectively, the results of our study reveal crucial roles of NSD1 in regulating chondrogenic differentiation, skeletal growth, and fracture repair and expand our understanding of the function of epigenetic regulation in chondrogenesis and skeletal biology.
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http://dx.doi.org/10.1038/s41413-021-00148-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185073PMC
June 2021

A long-term retaining molecular coating for corneal regeneration.

Bioact Mater 2021 Dec 5;6(12):4447-4454. Epub 2021 May 5.

Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Corneal injuries will cause corneal surface diseases that may lead to blindness in millions of people worldwide. There is a tremendous need for biomaterials that can promote corneal regeneration with practical feasibility. Here we demonstrate a strategy of a protein coating for corneal injury regeneration. We synthesize an o-nitrosobenzaldehyde group (NB)-modified gelatin (GelNB), which could adhere directly to the corneal surface with covalent bonding to form a thin molecular coating. The molecular coating could avoid rapid clearance and provide a favorable environment for cell migration, thereby effectively accelerating corneal repair and regeneration. The histological structure of the regenerated cornea is more similar to the native cornea. This molecular coating can be used conveniently as an eye drop solution, which makes it a promising strategy for corneal regeneration.
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http://dx.doi.org/10.1016/j.bioactmat.2021.04.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114076PMC
December 2021

Advanced Strategies of Biomimetic Tissue-Engineered Grafts for Bone Regeneration.

Adv Healthc Mater 2021 07 5;10(14):e2100408. Epub 2021 May 5.

Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.

The failure to repair critical-sized bone defects often leads to incomplete regeneration or fracture non-union. Tissue-engineered grafts have been recognized as an alternative strategy for bone regeneration due to their potential to repair defects. To design a successful tissue-engineered graft requires the understanding of physicochemical optimization to mimic the composition and structure of native bone, as well as the biological strategies of mimicking the key biological elements during bone regeneration process. This review provides an overview of engineered graft-based strategies focusing on physicochemical properties of materials and graft structure optimization from macroscale to nanoscale to further boost bone regeneration, and it summarizes biological strategies which mainly focus on growth factors following bone regeneration pattern and stem cell-based strategies for more efficient repair. Finally, it discusses the current limitations of existing strategies upon bone repair and highlights a promising strategy for rapid bone regeneration.
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http://dx.doi.org/10.1002/adhm.202100408DOI Listing
July 2021

An Off-the-Shelf Tissue Engineered Cartilage Composed of Optimally Sized Pellets of Cartilage Progenitor/Stem Cells.

ACS Biomater Sci Eng 2021 03 28;7(3):881-892. Epub 2020 Sep 28.

Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China.

Articular cartilage focal lesion remains an intractable challenge in sports medicine, and autologous chondrocytes' implantation (ACI) is one of the most commonly utilized treatment modality for this ailment. However, the current ACI technique requires two surgical steps which increases patients' morbidity and incurs additional medical costs. In the present study, we developed a one-step cryopreserved off-the-shelf ACI tissue-engineered (TE) cartilage by seeding pellets of spheroidal cartilage stem/progenitor cells (CSPCs) on a silk scaffold. The pellets were developed through a hanging-drop method, and the incubation time of 1 day could efficiently produce spheroidal pellets without any adverse influence on the cell activity. The pellet size was also optimized. Under chondrogenic induction, pellets consisting of 40 000 CSPCs were found to exhibit the most abundant cartilage matrix deposition and the highest mRNA expression levels of SOX9, aggrecan, and COL2A1, as compared with pellets consisting of 10 000, 100 000, or 200 000 CSPCs. Scaffolds seeded with CSPCs pellets containing 40 000 cells could be preserved in liquid nitrogen with the viability, migration, and chondrogenic ability remaining unaffected for as long as 3 months. When implanted in a rat trochlear cartilage defect model for 3 months, the ready-to-use, cryopreserved TE cartilage yielded fully cartilage reconstruction, which was comparable with the uncryopreserved control. Hence, our study provided preliminary data that our off-the-shell TE cartilage with optimally sized CSPCs pellets seeded within silk scaffolds exhibited strong cartilage repair capacity, which provided a convenient and promising one-step surgical approach to ACI.
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http://dx.doi.org/10.1021/acsbiomaterials.9b01863DOI Listing
March 2021

Tracing cell-type evolution by cross-species comparison of cell atlases.

Cell Rep 2021 Mar;34(9):108803

Center for Stem Cell and Regenerative Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou 311121, China; Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Hangzhou 310058, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China; Stem Cell Institute, Zhejiang University, Hangzhou 310058, China. Electronic address:

Cell types are the basic building units of multicellular life, with extensive diversities. The evolution of cell types is a crucial layer of comparative cell biology but is thus far not comprehensively studied. We define a compendium of cell atlases using single-cell RNA-seq (scRNA-seq) data from seven animal species and construct a cross-species cell-type evolutionary hierarchy. We present a roadmap for the origin and diversity of major cell categories and find that muscle and neuron cells are conserved cell types. Furthermore, we identify a cross-species transcription factor (TF) repertoire that specifies major cell categories. Overall, our study reveals conservation and divergence of cell types during animal evolution, which will further expand the landscape of comparative genomics.
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http://dx.doi.org/10.1016/j.celrep.2021.108803DOI Listing
March 2021

Forecasting sensitive targets of the kynurenine pathway in pancreatic adenocarcinoma using mathematical modeling.

Cancer Sci 2021 Apr 20;112(4):1481-1494. Epub 2021 Feb 20.

Shenzhen Key Laboratory of Tissue Engineering, Shenzhen Laboratory of Digital Orthopedic Engineering, Guangdong Provincial Research Center for Artificial Intelligence and Digital Orthopedic Technology, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University, Health Science Center), Shenzhen, China.

In this study, a new mathematical model was established and validated to forecast and define sensitive targets in the kynurenine pathway (Kynp) in pancreatic adenocarcinoma (PDAC). Using the Panc-1 cell line, genetic profiles of Kynp molecules were tested. qPCR data were implemented in the algorithm programming (fmincon and lsqnonlin function) to estimate 35 parameters of Kynp variables by Matlab 2017b. All tested parameters were defined as non-negative and bounded. Then, based on experimental data, the function of the fmincon equation was employed to estimate the approximate range of each parameter. These calculations were confirmed by qPCR and Western blot. The correlation coefficient (R) between model simulation and experimental data (72 hours, in intervals of 6 hours) of every variable was >0.988. The analysis of reliability and predictive accuracy depending on qPCR and Western blot data showed high predictive accuracy of the model; R was >0.988. Using the model calculations, kynurenine (x3, a6), GPR35 (x4, a8), NF-kβp105 (x7, a16), and NF-kβp65 (x8, a18) were recognized as sensitive targets in the Kynp. These predicted targets were confirmed by testing gene and protein expression responses. Therefore, this study provides new interdisciplinary evidence for Kynp-sensitive targets in the treatment of PDAC.
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http://dx.doi.org/10.1111/cas.14832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019197PMC
April 2021

Atlas of Musculoskeletal Stem Cells with the Soft and Hard Tissue Differentiation Architecture.

Adv Sci (Weinh) 2020 Dec 22;7(23):2000938. Epub 2020 Oct 22.

Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province Zhejiang University School of Medicine Hangzhou 310058 China.

Although being of utmost importance for human health and mobility, stem cell identity and hierarchical organization of musculoskeletal progenitors remain largely unexplored. Here, cells from E10.5, E12.5, and E15.5 murine limbs are analyzed by high throughput single-cell RNA sequencing to illustrate the cellular architecture during limb development. Single-cell transcriptional profiling demonstrates the identity and differentiation architecture of musculoskeletal stem cells (MSSC), soft and hard tissue progenitors through expression pattern of musculoskeletal markers (scleraxis [], , , and ). This is confirmed by genetic in vivo lineage tracing. Moreover, single-cell analyses of Scx knockout mice tissues illustrates that regulates MSSC self-renewal and proliferation potential. A high-throughput and low-cost multi-tissues RNA sequencing strategy further provides evidence that musculoskeletal system tissues, including muscle, bone, meniscus, and cartilage, are all abnormally developed in Scx knockout mice. These results establish the presence of an indispensable limb Scx+Hoxd13+ MSSC population and their differentiation into soft tissue progenitors () and hard tissue progenitors (). Collectively, this study paves the way for systematically decoding the complex molecular mechanisms and cellular programs of musculoskeletal tissues morphogenesis in limb development and regeneration.
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http://dx.doi.org/10.1002/advs.202000938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710003PMC
December 2020

Classification of four distinct osteoarthritis subtypes with a knee joint tissue transcriptome atlas.

Bone Res 2020 Nov 12;8(1):38. Epub 2020 Nov 12.

Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

The limited molecular classifications and disease signatures of osteoarthritis (OA) impede the development of prediagnosis and targeted therapeutics for OA patients. To classify and understand the subtypes of OA, we collected three types of tissue including cartilage, subchondral bone, and synovium from multiple clinical centers and constructed an extensive transcriptome atlas of OA patients. By applying unsupervised clustering analysis to the cartilage transcriptome, OA patients were classified into four subtypes with distinct molecular signatures: a glycosaminoglycan metabolic disorder subtype (C1), a collagen metabolic disorder subtype (C2), an activated sensory neuron subtype (C3), and an inflammation subtype (C4). Through ligand-receptor crosstalk analysis of the three knee tissue types, we linked molecular functions with the clinical symptoms of different OA subtypes. For example, the Gene Ontology functional term of vasculature development was enriched in the subchondral bone-cartilage crosstalk of C2 and the cartilage-subchondral bone crosstalk of C4, which might lead to severe osteophytes in C2 patients and apparent joint space narrowing in C4 patients. Based on the marker genes of the four OA subtypes identified in this study, we modeled OA subtypes with two independent published RNA-seq datasets through random forest classification. The findings of this work contradicted traditional OA diagnosis by medical imaging and revealed distinct molecular subtypes in knee OA patients, which may allow for precise diagnosis and treatment of OA.
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http://dx.doi.org/10.1038/s41413-020-00109-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658991PMC
November 2020

The regulation of cartilage extracellular matrix homeostasis in joint cartilage degeneration and regeneration.

Biomaterials 2021 01 23;268:120555. Epub 2020 Nov 23.

Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, And Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, And Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China. Electronic address:

Osteoarthritis (OA) is a major cause of disability and socioeconomic loss worldwide. However, the current pharmacological approaches used to treat OA are largely palliative. Being the hallmark of OA, the cartilage extracellular matrix (ECM) destruction and abnormal homeostasis is gaining more attention as a therapeutic target in cartilage regeneration. Moreover, during the progression of OA, the cartilage ECM shows significant pathological alternations, which can be promising biomarkers in identifying the pathological stages of OA. In this review, we summarize the role of abnormal ECM homeostasis in the joint cartilage during OA. Furthermore, we provide an update on the cartilage ECM derived biomarkers and regenerative medicine therapies targeting cartilage ECM which includes preclinical animal models study and clinical trials.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120555DOI Listing
January 2021

Potential efficacy of dendritic cell immunomodulation in the treatment of osteoarthritis.

Rheumatology (Oxford) 2021 02;60(2):507-517

Shenzhen Key Laboratory of Tissue Engineering, Shenzhen Laboratory of Digital Orthopedic Engineering, Shenzhen Second People's Hospital, Shenzhen, China.

Dendritic cells (DCs) are a cluster of heterogeneous antigen-presenting cells that play a pivotal role in both innate and adaptive immune responses. Rare reports have discussed their role in OA immunopathogenesis. Recently, DCs derived from the synovial fluid of OA mice were shown to have increased expression of toll-like receptors. Moreover, from in vitro studies it was concluded that DCs derived from OA patients had secreted high levels of inflammatory cytokines. Likewise, a significant increase in CD123+BDCA-2 plasmacytoid DCs has been observed in the synovial fluid of OA patients. Furthermore, DCs have a peripheral tolerance potential and can become regulatory under specific circumstances. This could be exploited as a promising tool to eliminate immunoinflammatory manifestations in OA disease. In this review, the potential roles DCs could play in OA pathogenesis have been described. In addition, suggestions for the development of new immunotherapeutic strategies involving intra-articular injections of tolerogenic plasmacytoid DCs for treating OA inflammations have been made.
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http://dx.doi.org/10.1093/rheumatology/keaa745DOI Listing
February 2021

Advanced hydrogels for the repair of cartilage defects and regeneration.

Bioact Mater 2021 Apr 10;6(4):998-1011. Epub 2020 Oct 10.

Department of Orthopaedic Surgery, Second Affiliated Hospital & Zhejiang University-University of Edinburgh Institute & School of Basic Medicine, Zhejiang University School of Medicine, Hangzhou, China.

Cartilage defects are one of the most common symptoms of osteoarthritis (OA), a degenerative disease that affects millions of people world-wide and places a significant socio-economic burden on society. Hydrogels, which are a class of biomaterials that are elastic, and display smooth surfaces while exhibiting high water content, are promising candidates for cartilage regeneration. In recent years, various kinds of hydrogels have been developed and applied for the repair of cartilage defects or , some of which are hopeful to enter clinical trials. In this review, recent research findings and developments of hydrogels for cartilage defects repair are summarized. We discuss the principle of cartilage regeneration, and outline the requirements that have to be fulfilled for the deployment of hydrogels for medical applications. We also highlight the development of advanced hydrogels with tailored properties for different kinds of cartilage defects to meet the requirements of cartilage tissue engineering and precision medicine.
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http://dx.doi.org/10.1016/j.bioactmat.2020.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557878PMC
April 2021

An interleukin-4-loaded bi-layer 3D printed scaffold promotes osteochondral regeneration.

Acta Biomater 2020 11 29;117:246-260. Epub 2020 Sep 29.

School of Basic Medical Sciences, and Department of Orthopedic Surgery of the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China. Electronic address:

Multilayer scaffolds fabricated by 3D printing or other techniques have been used to repair osteochondral defects. However, it remains a challenge to regenerate the articular cartilage and subchondral bone simultaneously with higher performance. In the present study, we enhanced the repair efficiency of osteochondral defects by developing a bi-layer scaffold: an interleukin-4 (IL-4)-loaded radially oriented gelatin methacrylate (GelMA) scaffold printed with digital light processing (DLP) in the upper layer and a porous polycaprolactone and hydroxyapatite (PCL-HA) scaffold printed with fused deposition modeling (FDM) in the lower layer. An in vitro test showed that both layers supported cell adhesion and proliferation, as the lower layer promoted osteogenic differentiation and the upper layer with IL-4 relieved the negative effects of inflammation on murine chondrocytes, which were induced by interleukin-1β (IL-1β) and M1 macrophages. In a rabbit osteochondral defect repair model, the IL-4-loaded bi-layer scaffold group obtained the highest histological score (24 ± 2) compared to the nontreated (11 ± 1) and pure bi-layer scaffold (16 ± 1) groups after 16 weeks of implantation, which showed that the IL-4-loaded bi-layer scaffold promoted regeneration of both cartilage and subchondral bone with increased formation of neocartilage and neobone tissues. Thus, the IL-4-loaded bi-layer scaffold is an attractive candidate for repair and regeneration of osteochondral defects.
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http://dx.doi.org/10.1016/j.actbio.2020.09.039DOI Listing
November 2020

Sodium lactate promotes stemness of human mesenchymal stem cells through KDM6B mediated glycolytic metabolism.

Biochem Biophys Res Commun 2020 11 3;532(3):433-439. Epub 2020 Sep 3.

Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China. Electronic address:

Mesenchymal stem cells (MSCs) are an important cell source for tissue homeostasis and repair due to their stemness characteristic. Lots of intrinsic signaling pathways have been reported to regulate MSC stemness, but the extrinsic signals such as sodium lactate, particularly in physiological conditions, are poorly understood. Herein, we evaluated the effect of sodium lactate on human MSC stemness regulation by examining colony-forming ability, energy metabolism, multi-lineage differentiation ability, and pluripotent gene and protein expression. The underlying mechanism was further investigated with gene knockdown as well as small molecule interference and rescue experiments. We found that: (1) low concentration (1 mM) of sodium lactate promoted the stemness of human MSCs; (2) the upregulation of glycolysis was responsible for the MSC stemness promotion; (3) lysine demethylase 6B (KDM6B) was the key regulator which mediated sodium lactate-induced glycolysis and human MSC stemness enhancement. This study indicated that sodium lactate played an important role in human MSC stemness maintenance in physiological conditions, which could be related to KDM6B mediated metabolic regulation. It would provide new insight into stem cell biology, and contribute to cell transplantation and tissue regeneration strategies.
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http://dx.doi.org/10.1016/j.bbrc.2020.08.061DOI Listing
November 2020

Rapid printing of bio-inspired 3D tissue constructs for skin regeneration.

Biomaterials 2020 11 14;258:120287. Epub 2020 Aug 14.

Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, And Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, And Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China. Electronic address:

It is still a challenge for existing bioprinting technologies to fabricate organs suitable for implantation, mainly due to the inability to recapitulate the organs' complex anatomical structures, mechanical properties, and biological functions. Additionally, the failure to create 3D constructs with interconnected microchannels for long-range mass transportation that limits the clinical applications of 3D printing technologies. Here, a new method was developed to print functional living skin (FLS) using a newly designed biomimetic bioink (GelMA/HA-NB/LAP) and digital light processing (DLP)-based 3D printing technology. The FLS possess interconnected microchannels that facilitates cell migration, proliferation and neo-tissue formation. The GelMA/HA-NB/LAP bioink, composed of gelatin methacrylate (GelMA), N-(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy) butanamide (NB) linked hyaluronic acid (HA-NB) and photo-initiator lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP). The bioink demonstrated its rapid gelation kinetics, tunable mechanical properties, good biocompatibility and tissue adhesion. The DLP-based 3D printing technology provides a rapid method to precisely position clusters of human skin fibroblasts (HSFs) and human umbilical vein endothelial cells (HUVECs) with high cell viability to form FLS. The FLS promotes skin regeneration and efficient neovascularization by mimicking the physiological structure of natural skin, and it can also be easily handled and implanted onto the wound site due to its strong mechanical and bio-adhesive properties. Moreover, in vivo study demonstrated that the living skin exhibited instant defense function and had superior performance in promoting dermal regeneration with skin appendages in large animals. This study provides a rapid and mass production method of functional living organs for future clinical applications.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120287DOI Listing
November 2020

Nanomaterial-based scaffolds for bone tissue engineering and regeneration.

Nanomedicine (Lond) 2020 08 19;15(20):1995-2017. Epub 2020 Aug 19.

Dr Li Dak Sum & Yip Yio Chin Center for Stem Cells & Regenerative Medicine & Department of Orthopedic Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.

The global incidence of bone tissue injuries has been increasing rapidly in recent years, making it imperative to develop suitable bone grafts for facilitating bone tissue regeneration. It has been demonstrated that nanomaterials/nanocomposites scaffolds can more effectively promote new bone tissue formation compared with micromaterials. This may be attributed to their nanoscaled structural and topological features that better mimic the physiological characteristics of natural bone tissue. In this review, we examined the current applications of various nanomaterial/nanocomposite scaffolds and different topological structures for bone tissue engineering, as well as the underlying mechanisms of regeneration. The potential risks and toxicity of nanomaterials will also be critically discussed. Finally, some considerations for the clinical applications of nanomaterials/nanocomposites scaffolds for bone tissue engineering are mentioned.
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http://dx.doi.org/10.2217/nnm-2020-0112DOI Listing
August 2020

The role of indoleamine 2,3 dioxygenase 1 in the osteoarthritis.

Am J Transl Res 2020 15;12(6):2322-2343. Epub 2020 Jun 15.

Shenzhen Key Laboratory of Tissue Engineering, Shenzhen Laboratory of Digital Orthopedic Engineering, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University, Health Science Center) Shenzhen 518035, P. R. China.

Osteoarthritis (OA) is a chronic degenerative joint disease and a leading cause of disability. It involves articular cartilage destruction and a whole joint inflammation. In spite of OA pathogenesis is still unclear, new studies on the OA pathophysiological aetiology and immunomodulation therapy continuously achieve significant advances with new concepts. Here, we focus on the indoleamine-2,3-dioxygenase1 (IDO1) activity in the osteoarthritis (OA), which is one of the noticeable enzymes in the synovial fluid of arthritis patients. It was recognized as an essential mediator of autoreactive B and T cell responses in rheumatoid arthritis (RA) and an interesting therapeutic target against RA. However, the role IDO1 plays in the OA pathogenesis hasn't been discussed. The new OA experimental analysis evidenced IDO1 overexpression in the synovial fluid of OA patients, and recent studies reported that IDO1 metabolites were found higher in the OA synovial fluid than RA and spondyloarthropathies (SpA) patients. Moreover, the positive relation of IDO1 metabolites with OA pain and joint stiffness has been confirmed. Thus, the IDO1 plays a pivotal role in the pathogenesis of OA. In this review, the role IDO1 plays in the OA pathogenesis has been deeply discussed. It could be a promising target in the immunotherapy of OA disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344072PMC
June 2020

Targeted pathological collagen delivery of sustained-release rapamycin to prevent heterotopic ossification.

Sci Adv 2020 May 29;6(18):eaay9526. Epub 2020 Apr 29.

Dr. Li Dak Sum-Yip Yio Chin Center for Stem Cells and Regenerative Medicine and Department of Orthopedic Surgery of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Heterotopic ossification (HO) in connective tissues like tendons and ligaments severely damages tissue structure. The pathogenesis of HO remains unclear but may involve mTOR. The results presented here indicate that tendon stem/progenitor cells do not undergo osteochondrogenic differentiation when mTOR signaling is inactivated by gene knockout or rapamycin (RAPA) treatment. Meanwhile, it is necessary to deliver RAPA to the injured sites and avoid disturbing the normal tendon. A RAPA delivery system, developed using collagen hybrid peptide (CHP) to modify the surface of poly(lactic--glycolic acid) (PLGA) nanoparticles, targeted RAPA specifically to pathological tendon collagen. The CHP-PLGA-RAPA nanoparticles showed excellent pathological collagen affinity, sustained-release ability, and bioactivity. In a mouse model of tendon HO, CHP-PLGA-RAPA nanoparticles specifically bound to pathological tendon and strongly suppressed HO progression. The mTOR signaling pathway appears to be a viable therapeutic target for tendon HO, and CHP-PLGA nanoparticles may be valuable for the treatment of tendon-related diseases.
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http://dx.doi.org/10.1126/sciadv.aay9526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239699PMC
May 2020

The influence of sample size and gender composition on the meta-analysis conclusion of platelet-rich plasma treatment for osteoarthritis.

J Orthop Translat 2020 May 15;22:34-42. Epub 2019 Nov 15.

Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China.

Objective: The magnitude of the therapeutic effects of intra-articular injection of platelet-rich plasma (PRP) on osteoarthritis (OA) is still under debate. The goal of this study that was a systematic review of randomised controlled trials ​of PRP injections for the treatment of OA was to elucidate the therapeutic efficacy of PRP.

Methods: Electronic databases of PubMed, CENTRAL, EMBASE, EBSCO, ClinicalTrials.gov, and International Clinical Trials Registry Platform ​were searched from inception to June 2018 for RCTs that compared PRP injections to controls in patients with OA. A random-effects approach was used to compile data and subgroups according to trial size (large trials versus small trials), patient profile (age and gender), and PRP preparation method was performed.

Results: Thirty trials met the inclusion criteria and were analysed. All results had unexplained statistical heterogeneity. Patients treated with PRP compared with control showed statistically relevant pain relief and function improvement at short term (standardised mean difference [SMD] ​= ​-0.62, 95% confidence interval [CI]: -0.98 to -0.27,  ​= ​0.0006, SMD ​= ​-0.74, 95% CI: -1.11 to 0.36,  ​= ​0.0001, respectively), medium term (SMD ​= ​-0.53, 95% CI: -0.83 to -0.23,  ​= ​0.0006, SMD ​= ​-0.50, 95% CI: -0.75 to -0.25,  ​= ​0.0006), and long term (SMD ​= ​-0.69, 95% CI: -1.08 to -0.30,  ​= ​0.0006, SMD ​= ​-0.68, 95% CI: -0.1.09 to -0.27,  ​= ​0.001, respectively). A subgroup analysis of the data from large trials and from trials composed of less than 50% female patients revealed that therapeutic effects of the treatment are insignificant.

Conclusions: According to the currently available data, PRP injections are beneficial for pain relief and function improvement in patients with OA. This meta-analysis, however, demonstrated that the efficacy of PRP is related to sample size and gender composition. Thus, more randomised controlled trials of high quality and larger patient size, also including gender aspects, are required to understand this phenomenon.

The Translational Potential Of This Article: The translation potential of this meta-analysis is that provided another perspective to analyse the treatment effect of PRP for OA. In future research, phenotypes subpopulation and gender difference of OA patient should be considered for PRP treatment.
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http://dx.doi.org/10.1016/j.jot.2019.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231962PMC
May 2020

Tissue-Adhesive Paint of Silk Microparticles for Articular Surface Cartilage Regeneration.

ACS Appl Mater Interfaces 2020 May 12;12(20):22467-22478. Epub 2020 May 12.

Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.

Current biomaterials and tissue engineering techniques have shown a promising efficacy on full-thickness articular cartilage defect repair in clinical practice. However, due to the difficulty of implanting biomaterials or tissue engineering constructs into a partial-thickness cartilage defect, it remains a challenge to provide a satisfactory cure in joint surface regeneration in the early and middle stages of osteoarthritis. In this study, we focused on a ready-to-use tissue-adhesive joint surface paint (JS-Paint) capable of promoting and enhancing articular surface cartilage regeneration. The JS-Paint is mainly composed of -(2-aminoethyl)-4-(4-(hydroxymethyl)-2-methoxy-5-nitrosophenoxy) butanamide (NB)-coated silk fibroin microparticles and possess optimal cell adhesion, migration, and proliferation properties. NB-modified silk fibroin microparticles can directly adhere to the cartilage and form a smooth layer on the surface via the photogenerated aldehyde group of NB reacting with the -NH groups of the cartilage tissue. JS-Paint treatment showed a significant promotion of cartilage regeneration and restored the smooth joint surface at 6 weeks postsurgery in a rabbit model of a partial-thickness cartilage defect. These findings revealed that silk fibroin can be utilized to bring about a tissue-adhesive paint. Thus, the JS-Paint strategy has some great potential to enhance joint surface regeneration and revolutionize future therapeutics of early and middle stages of osteoarthritis joint ailments.
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http://dx.doi.org/10.1021/acsami.0c01776DOI Listing
May 2020

"All-in-One" Gel System for Whole Procedure of Stem-Cell Amplification and Tissue Engineering.

Small 2020 04 5;16(16):e1906539. Epub 2020 Mar 5.

Department of Orthopaedic Surgery, Second Affiliated Hospital and Zhejiang University-University of Edinburgh Institute and School of Basic Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.

Microsphere (MS)-based systems provides great advantages for cell expansion and transplantation due to their high surface-to-volume ratio and biomimetic environment. However, a MS-based system that includes cell attachment, proliferation, passage, harvest, cryopreservation, and tissue engineering together has not been realized yet. An "all-in-one" gel MS-based system is established for human adipose-derived mesenchymal stem cells (hADSCs), realizing real 3D culture with enhanced expansion efficiency and simplified serial cell culture operations, and construction of macrotissues with uniform cell distribution and specific function. A 3D digital light-processing technology is developed to fabricate gel MSs in an effective way. The printed MSs present a suitable environment with rough surface architecture and the mechanical properties of soft tissues, leading to high cell viability, attachment, proliferation, activity, and differentiation potential. Further, convenient standard operation procedures, including cell passage, detachment, and cryopreservation, are established for cell culture on the gel MSs. Finally, hADSCs-loaded gel MSs form macrotissues through a "bottom-up" approach, which demonstrates the potential applications for tissue engineering. These findings exhibit the feasibility and beauty of "all-in-one" stem cell culture and tissue engineering system.
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http://dx.doi.org/10.1002/smll.201906539DOI Listing
April 2020

High-Resolution Dissection of Chemical Reprogramming from Mouse Embryonic Fibroblasts into Fibrocartilaginous Cells.

Stem Cell Reports 2020 03 20;14(3):478-492. Epub 2020 Feb 20.

Department of Orthopaedic Surgery, Second Affiliated Hospital and Zhejiang University-University of Edinburgh Institute and School of Basic Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Sports Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou 310058, China. Electronic address:

Articular cartilage injury and degeneration causing pain and loss of quality-of-life has become a serious problem for increasingly aged populations. Given the poor self-renewal of adult human chondrocytes, alternative functional cell sources are needed. Direct reprogramming by small molecules potentially offers an oncogene-free and cost-effective approach to generate chondrocytes, but has yet to be investigated. Here, we directly reprogrammed mouse embryonic fibroblasts into PRG4+ chondrocytes using a 3D system with a chemical cocktail, VCRTc (valproic acid, CHIR98014, Repsox, TTNPB, and celecoxib). Using single-cell transcriptomics, we revealed the inhibition of fibroblast features and activation of chondrogenesis pathways in early reprograming, and the intermediate cellular process resembling cartilage development. The in vivo implantation of chemical-induced chondrocytes at defective articular surfaces promoted defect healing and rescued 63.4% of mechanical function loss. Our approach directly converts fibroblasts into functional cartilaginous cells, and also provides insights into potential pharmacological strategies for future cartilage regeneration.
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http://dx.doi.org/10.1016/j.stemcr.2020.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066361PMC
March 2020

Rab5a activates IRS1 to coordinate IGF-AKT-mTOR signaling and myoblast differentiation during muscle regeneration.

Cell Death Differ 2020 08 12;27(8):2344-2362. Epub 2020 Feb 12.

Department of Biochemistry and Molecular Biology and Department of Orthopaedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.

Rab5 is a master regulator for endosome biogenesis and transport while its in vivo physiological function remains elusive. Here, we find that Rab5a is upregulated in several in vivo and in vitro myogenesis models. By generating myogenic Rab5a-deficient mice, we uncover the essential roles of Rab5a in regulating skeletal muscle regeneration. We further reveal that Rab5a promotes myoblast differentiation and directly interacts with insulin receptor substrate 1 (IRS1), an essential scaffold protein for propagating IGF signaling. Rab5a interacts with IRS1 in a GTP-dependent manner and this interaction is enhanced upon IGF-1 activation and myogenic differentiation. We subsequently identify that the arginine 207 and 222 of IRS1 and tyrosine 82, 89, and 90 of Rab5a are the critical amino acid residues for mediating the association. Mechanistically, Rab5a modulates IRS1 activation by coordinating the association between IRS1 and the IGF receptor (IGFR) and regulating the intracellular membrane targeting of IRS1. Both myogenesis-induced and IGF-evoked AKT-mTOR signaling are dependent on Rab5a. Myogenic deletion of Rab5a also reduces the activation of AKT-mTOR signaling during skeletal muscle regeneration. Taken together, our study uncovers the physiological function of Rab5a in regulating muscle regeneration and delineates the novel role of Rab5a as a critical switch controlling AKT-mTOR signaling by activating IRS1.
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http://dx.doi.org/10.1038/s41418-020-0508-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370222PMC
August 2020

[Correlation between histone methylation level and pathological development of osteoarthritis].

Zhejiang Da Xue Xue Bao Yi Xue Ban 2019 Dec;48(6):682-687

Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China.

Osteoarthritis is the most common degenerative cartilage disease. A large number of studies have shown the close association between epigenetics and osteoarthritis. Histone methylation is a type of epigenetic modification, and the link between histone methylation and osteoarthritis has also been revealed. In this article, we summarize the correlation between methylation levels of different histones and osteoarthritis in an attempt to explore the changes and regulation mechanisms of histone methylation in osteoarthritis. It has been shown that there are possible relations between the methylation levels of different amino acids on histone H3 and the pathological development of osteoarthritis; specifically, the rise of methylation level at the lysine 4 would aggravate the pathological development of osteoarthritis, while the the pattern of lysine 9 and 27 would be the opposite. These results indicate the possible existence of a complex network of histone methylation modifications. And the specific regulation of histone methylation levels in different positions may delay or prevent the occurrence and development of osteoarthritis.
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December 2019

Targeting downstream subcellular YAP activity as a function of matrix stiffness with Verteporfin-encapsulated chitosan microsphere attenuates osteoarthritis.

Biomaterials 2020 02 26;232:119724. Epub 2019 Dec 26.

School of Basic Medical Sciences and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, China; China Orthopedic Regenerative Medicine Group (CORMed), Hangzhou, China. Electronic address:

Changes in the stiffness of chondrocyte extracellular matrix (ECM) are involved in the pathological progression of osteoarthritis (OA). However, the downstream responses of cartilage ECM stiffness are still unclear. YAP (Yes-associated protein) has been extensively studied as a mechanotransducer, we thus hypothesized that by targeting the downstream molecule activity of ECM stiffness could maintain chondrocyte phenotype and prevent cartilage degeneration in OA. Here, we showed that human cartilage matrix stiffened during pathological progression of OA, and the chondrocyte YAP activity was associated with ECM stiffness. We then mimicked the physiological and pathological stiffness of human cartilage by using PDMS-based substrates, and found that YAP was activated in chondrocytes seeded on stiff substrate, gradually losing their phenotype. In addition, it was observed that YAP was also significantly activated in mice OA development, and conditional knockout (cKO) of YAP in mice preserved collagen II expression and protected cartilage from degeneration in the OA model. Furthermore, intra-articular injection of YAP-selective inhibitor, Verteporfin, significantly maintained cartilage homeostasis in mice OA model. This study indicates that the application of mechanotransducer-targeted drugs could be a potential therapeutic approach for cartilage repair in OA.
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http://dx.doi.org/10.1016/j.biomaterials.2019.119724DOI Listing
February 2020

Ezh2 Ameliorates Osteoarthritis by Activating TNFSF13B.

J Bone Miner Res 2020 05 3;35(5):956-965. Epub 2020 Feb 3.

Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Epigenetic regulation is highly correlated with osteoarthritis (OA) development, whereas its role and detailed mechanisms remain elusive. In this study, we explored the expression of EZH2, an H3K27me3 transferase, in human OA cartilages and its roles in regulating OA pathogenesis. Here, we found EZH2 was highly expressed in both mice and human OA cartilage samples by using histological analysis and RNA sequencing (RNA-Seq). The medial meniscectomy (MMx) OA model results indicated the conditional knockout of Ezh2 deteriorated OA pathological conditions. Furthermore, we showed the positive role of Ezh2 in cartilage wound healing and inhibition of hypertrophy through activating TNFSF13B, a member of the tumor necrosis factor superfamily. Further, we also indicated that the effect of TNFSF13B, increased by Ezh2, might boost the healing of chondrocytes through increasing the phosphorylation of Akt. Taken together, our results uncovered an EZH2-positive subpopulation existed in OA patients, and that EZH2-TNFSF13B signaling was responsible for regulating chondrocyte healing and hypertrophy. Thus, EZH2 might act as a new potential target for OA diagnosis and treatment. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3952DOI Listing
May 2020
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