{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T15:52:31Z","timestamp":1783007551662,"version":"3.54.5"},"reference-count":35,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,1,24]],"date-time":"2021-01-24T00:00:00Z","timestamp":1611446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81973606"],"award-info":[{"award-number":["81973606"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Mesenchymalstem cell (MSC)-based therapy is being increasingly explored in preclinical and clinical studies as a regenerative method for treating osteoarthritis (OA). However, the use of primary MSCs is hampered by a number of limitations, including donor heterogeneity and inconsistent cell quality. Here, we tested the therapeutic potential of embryonic stem cell-derived MSCs (ES-MSCs) in anOA rat model. ES-MSCs were generated and identified by morphology, trilineage differentiation and flow cytometry. Sprague Dawley rats were treated with either a single dose (106 cells\/rat) of ES-MSCs or with three doses spaced one week apart for each dose, starting at four weeks after anterior cruciate ligament transectionto induce OA. Cartilage quality was evaluated at 6 and 10 weeks after treatment with behavioral analysis, macroscopic examination, and histology. At sixweeks after treatment, the groups treated with both single and repeated doses of ES-MSCs had significantly better modified Mankin scores and International Cartilage Repair Society (ICRS) macroscopic scores in the femoral condyle compared to the control group. At 10 weeks after treatment, the repeated doses group had a significantly better ICRS macroscopic scores in the femoral condyle compared to the single dose and control groups. Histological analysis also showed more proteoglycan and less cartilage loss, along with lower Mankin scores in the repeated doses group. In conclusion, treatment with multiple injections of ES-MSCs can ameliorate OA in a rat model. TheES-MSCs have potential to be considered as a regenerative therapy for OA, and can provide an infinite cellular source.<\/jats:p>","DOI":"10.3390\/molecules26030604","type":"journal-article","created":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T09:59:40Z","timestamp":1611568780000},"page":"604","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Clinical-Grade Human Embryonic Stem Cell-Derived Mesenchymal Stromal Cells Ameliorate the Progression of Osteoarthritis in a Rat Model"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6966-3134","authenticated-orcid":false,"given":"Dan","family":"Xing","sequence":"first","affiliation":[{"name":"Arthritis Clinic &amp; Research Center, Peking University People\u2019s Hospital, Peking University, Beijing 100044, China"},{"name":"Arthritis Institute, Peking University, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Arthritis Clinic &amp; Research Center, Peking University People\u2019s Hospital, Peking University, Beijing 100044, China"},{"name":"Arthritis Institute, Peking University, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6346-4756","authenticated-orcid":false,"given":"Jun","family":"Wu","sequence":"additional","affiliation":[{"name":"National Stem Cell Resource Center, Institute of Zoology, Chinese Academy of Sciences, Beijing 100190, China"},{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Arthritis Clinic &amp; Research Center, Peking University People\u2019s Hospital, Peking University, Beijing 100044, China"},{"name":"Arthritis Institute, Peking University, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing 100084, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3584-6765","authenticated-orcid":false,"given":"Jiao Jiao","family":"Li","sequence":"additional","affiliation":[{"name":"School of Biomedical Engineering, Faculty of Engineering and IT, University of Technology Sydney, Ultimo, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Gao","sequence":"additional","affiliation":[{"name":"National Stem Cell Resource Center, Institute of Zoology, Chinese Academy of Sciences, Beijing 100190, China"},{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deng","family":"Yan","sequence":"additional","affiliation":[{"name":"National Stem Cell Resource Center, Institute of Zoology, Chinese Academy of Sciences, Beijing 100190, China"},{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Wang","sequence":"additional","affiliation":[{"name":"National Stem Cell Resource Center, Institute of Zoology, Chinese Academy of Sciences, Beijing 100190, China"},{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China"},{"name":"Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Hao","sequence":"additional","affiliation":[{"name":"National Stem Cell Resource Center, Institute of Zoology, Chinese Academy of Sciences, Beijing 100190, China"},{"name":"State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China"},{"name":"Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China"},{"name":"Savaid Medical School, University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhao","family":"Lin","sequence":"additional","affiliation":[{"name":"Arthritis Clinic &amp; Research Center, Peking University People\u2019s Hospital, Peking University, Beijing 100044, China"},{"name":"Arthritis Institute, Peking University, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1016\/S0140-6736(12)61729-2","article-title":"Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990\u20132010: A systematic analysis for the Global Burden of Disease Study 2010","volume":"380","author":"Vos","year":"2012","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nrrheum.2014.44","article-title":"The individual and socioeconomic impact of osteoarthritis","volume":"10","author":"Hunter","year":"2014","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.berh.2014.02.001","article-title":"Pathogenesis of post-traumatic OA with a view to intervention","volume":"28","author":"Riordan","year":"2014","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.rehab.2016.04.003","article-title":"Surgical treatments for osteoarthritis","volume":"59","author":"Anract","year":"2016","journal-title":"Ann. Phys. Rehabil. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1007\/s00167-016-4089-y","article-title":"Non-surgical treatments for the management of early osteoarthritis","volume":"24","author":"Filardo","year":"2016","journal-title":"Knee Surg. Sports Traumatol. Arthrosc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/nrrheum.2010.159","article-title":"The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis","volume":"6","author":"Sellam","year":"2010","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1126\/science.284.5411.143","article-title":"Multilineage Potential of Adult Human Mesenchymal Stem Cells","volume":"284","author":"Pittenger","year":"1999","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"34","DOI":"10.4252\/wjsc.v2.i2.34","article-title":"Application of human umbilical cord blood-derived mesenchymal stem cells in disease models","volume":"2","author":"Kim","year":"2010","journal-title":"World J. Stem Cells"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1478-811X-9-12","article-title":"Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC","volume":"9","author":"Hass","year":"2011","journal-title":"Cell Commun. Signal."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"288","DOI":"10.4252\/wjsc.v6.i3.288","article-title":"Osteogenic potential: Comparison between bone marrow and adipose-derived mesenchymal stem cells","volume":"6","author":"Liao","year":"2014","journal-title":"World J Stem Cells"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/j.joca.2018.01.010","article-title":"Intra-articular injection of mesenchymal stem cells in treating knee osteoarthritis: A systematic review of animal studies","volume":"26","author":"Xing","year":"2018","journal-title":"Osteoarthr. Cartil."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1007\/s00296-017-3906-z","article-title":"Mesenchymal stem cells injections for knee osteoarthritis: A systematic overview","volume":"38","author":"Xing","year":"2017","journal-title":"Rheumatol. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1016\/j.joca.2012.06.003","article-title":"Mesenchymal stem cells secrete factors that inhibit inflammatory processes in short-term osteoarthritic synovium and cartilage explant culture","volume":"20","author":"Villafuertes","year":"2012","journal-title":"Osteoarthr. Cartil."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1111\/1756-185X.13834","article-title":"Intra-articular delivery of umbilical cord-derived mesenchymal stem cells temporarily retard the progression of osteoarthritis in a rat model","volume":"23","author":"Xing","year":"2020","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"963689720932142","DOI":"10.1177\/0963689720932142","article-title":"Intra-articular Injection of Cell-laden 3D Microcryogels Empower Low-dose Cell Therapy for Osteoarthritis in a Rat Model","volume":"29","author":"Xing","year":"2020","journal-title":"Cell Transplant."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s13075-016-0979-0","article-title":"Human embryonic stem cell-derived mesenchymal stromal cells ameliorate collagen-induced arthritis by inducing host-derived indoleamine 2,3 dioxygenase","volume":"18","author":"Galindo","year":"2016","journal-title":"Arthritis Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.stemcr.2014.08.005","article-title":"Human Bone Marrow Stromal Cells Lose Immunosuppressive and Anti-inflammatory Properties upon Oncogenic Transformation","volume":"3","author":"Rodriguez","year":"2014","journal-title":"Stem Cell Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1002\/stem.3016","article-title":"Concise review: Mesenchymal stem cells: From roots to boost","volume":"37","author":"Andrzejewska","year":"2019","journal-title":"Stem Cells"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1002\/sctm.17-0260","article-title":"Embryonic Stem Cell-Derived Mesenchymal Stem Cells (MSCs) Have a Superior Neuroprotective Capacity Over Fetal MSCs in the Hypoxic-Ischemic Mouse Brain","volume":"7","author":"Hawkins","year":"2018","journal-title":"Stem Cells Transl. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s13770-018-0165-3","article-title":"Human Embryonic Stem Cells-Derived Mesenchymal Stem Cells Reduce the Symptom of Psoriasis in Imiquimod-Induced Skin Model","volume":"16","author":"Kim","year":"2019","journal-title":"Tissue Eng. Regen. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1002\/jcp.29004","article-title":"Human umbilical cord mesenchymal stem cell-derived extracellular vesicles: A novel therapeutic paradigm","volume":"235","author":"Abbaszadeh","year":"2020","journal-title":"J. Cell. Physiol."},{"key":"ref_22","first-page":"163","article-title":"Human Embryonic Stem Cell-Derived Mesenchymal Progenitors: An Overview","volume":"690","author":"Hematti","year":"2010","journal-title":"Adv. Struct. Saf. Stud."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1038\/s41422-020-0354-1","article-title":"Immunity-and-matrix-regulatory cells derived from human embryonic stem cells safely and effectively treat mouse lung injury and fibrosis","volume":"30","author":"Wu","year":"2020","journal-title":"Cell Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hawker, G.A., Croxford, R., Bierman, A.S., Harvey, P.J., Ravi, B., Stanaitis, I., and Lipscombe, L.L. (2014). All-Cause Mortality and Serious Cardiovascular Events in People with Hip and Knee Osteoarthritis: A Population Based Cohort Study. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0091286"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1186\/s12967-019-1877-4","article-title":"Bone marrow donor selection and characterization of MSCs is critical for pre-clinical and clinical cell dose production","volume":"17","author":"Trivedi","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"D\u2019Arrigo, D., Roffi, A., Cucchiarini, M., Moretti, M., Candrian, C., and Filardo, G. (2020). Faculty Opinions recommendation of Secretome and extracellular vesicles as new biological therapies for knee osteoarthritis: A systematic review. J. Clin. Med., 8.","DOI":"10.3390\/jcm8111867"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.biologicals.2017.08.011","article-title":"Scientific considerations for the regulatory evaluation of cell therapy products","volume":"50","author":"Petricciani","year":"2017","journal-title":"Biologicals"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.joca.2015.12.018","article-title":"Not single but periodic injections of synovial mesenchymal stem cells maintain viable cells in knees and inhibit osteoarthritis progression in rats","volume":"24","author":"Ozeki","year":"2016","journal-title":"Osteoarthr. Cartil."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3604","DOI":"10.1002\/art.34626","article-title":"Antiinflammatory and chondroprotective effects of intraarticular injection of adipose-derived stem cells in experimental osteoarthritis","volume":"64","author":"Schelbergen","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/j.joca.2012.06.002","article-title":"Intra-articular injection of human mesenchymal stem cells (MSCs) promote rat meniscal regeneration by being activated to express Indian hedgehog that enhances expression of type II collagen","volume":"20","author":"Horie","year":"2012","journal-title":"Osteoarthr. Cartil."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e54","DOI":"10.1038\/emm.2013.94","article-title":"Mesenchymal stem cells: Environmentally responsive therapeutics for regenerative medicine","volume":"45","author":"Murphy","year":"2013","journal-title":"Exp. Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2147\/IJN.S54114","article-title":"Effect of self-assembled peptide\u2013mesenchymal stem cell complex on the progression of osteoarthritis in a rat model","volume":"9","author":"Kim","year":"2014","journal-title":"Int. J. Nanomed."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.vascn.2011.10.002","article-title":"Establishment of a novel objective and quantitative method to assess pain-related behavior in monosodium iodoacetate-induced osteoarthritis in rat knee","volume":"65","author":"Nagase","year":"2012","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1016\/j.joca.2007.05.005","article-title":"International Cartilage Repair Society (ICRS) and Oswestry macroscopic cartilage evaluation scores validated for use in Autologous Chondrocyte Implantation (ACI) and microfracture","volume":"15","author":"Raijmakers","year":"2007","journal-title":"Osteoarthr. Cartil."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1111\/j.1469-7580.2012.01513.x","article-title":"Investigating the potential value of individual parameters of histological grading systems in a sheep model of cartilage damage: The Modified Mankin method","volume":"221","author":"Moody","year":"2012","journal-title":"J. Anat."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/3\/604\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:14:49Z","timestamp":1760159689000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/3\/604"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,24]]},"references-count":35,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["molecules26030604"],"URL":"https:\/\/doi.org\/10.3390\/molecules26030604","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,24]]}}}