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Engineering osteoarthritic cartilage model through differentiating senescent human mesenchymal stem cells for testing disease-modifying drugs

查看全文 作　　者：Ning [1,2,9]Wang;Yuchen [1,2]He;Silvia [3]Liu;Meagan [1,4]J.Makarcyzk;Guanghua [2]Lei;Alexander [5]Chang;Peter G [1,6]Alexander;Tingjun [1]Hao;Anne-Marie [1,7]Padget;Nuria de [8]Pedro;Tsapekos [8]Menelaos;Hang [1,4,6]Lin 高影响力作者 机构地区：[1]Department of Orthopaedic Surgery,University of Pittsburgh School of Medicine,Pittsburgh PA 15219,USA;[2]Department of Orthopedic Surgery,Xiangya Hospital,Central South University,Changsha 410008,China;[3]Department of Pathology,University of Pittsburgh School of Medicine,Pittsburgh PA 15219,USA;[4]Department of Bioengineering,University of Pittsburgh Swanson School of Engineering,Pittsburgh PA 15219,USA;[5]Department of Bioinformatics,University of Pittsburgh School of Medicine,Pittsburgh PA 15219,USA;[6]McGowan Institute for Regenerative Medicine,University of Pittsburgh School of Medicine,Pittsburgh PA 15219,USA;[7]Department of Biology,University of Pittsburgh Dietrich School of Arts and Science,Pittsburgh PA 15219,USA;[8]Department of Research B2B,Life Length SL,Madrid 28010,Spain;[9]Xiangya Third Hospital,Central South University,Changsha 410013,China高影响力机构 出　　处：《Science China(Life Sciences)》索引2022年第65卷第2期,共19页高影响力期刊 摘　　要：Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic medium.Results from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-MSCs.Interestingly,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis methods.Lastly,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics.The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage.The P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans. 关 键 词：OSTEOARTHRITIS MSC SENESCENCE cartilage tissue engineering disease-modifying OA drug senolytic
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