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Mesenchymal stem cells (MSCs) have immunomodulatory properties for psoriasis, but the therapeutic efficacies varied, and the molecular mechanisms were unknown. In this study, we improved the efficacy by enhancing the immunomodulatory effects of umbilical cord\u2013derived MSCs (UC-MSCs). UC-MSCs stimulated by TNF-\u03b1 and IFN-\u03b3 exhibited a better therapeutic effect in a mouse model of psoriasis. Single-cell RNA sequencing revealed that the stimulated UC-MSCs overrepresented a subpopulation expressing high tryptophanyl-tRNA synthetase 1 (WARS1). WARS1-overexpressed UC-MSCs treat psoriasis-like skin inflammation more efficiently than control UC-MSCs by restraining the proinflammatory macrophages. Mechanistically, WARS1 maintained a RhoA-Akt axis and governed the immunomodulatory properties of UC-MSCs. Together, we identify WARS1 as a master regulator of UC-MSCs with enhanced immunomodulatory capacities, which paves the way for the directed modification of UC-MSCs for escalated therapeutic efficacy.<\/jats:p>","DOI":"10.4049\/jimmunol.2300752","type":"journal-article","created":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T09:24:17Z","timestamp":1718011457000},"page":"257-267","source":"Crossref","is-referenced-by-count":3,"title":["Single-Cell RNA Sequencing Identifies WARS1+ Mesenchymal Stem Cells with Enhanced Immunomodulatory Capacity and Improved Therapeutic Efficacy"],"prefix":"10.1093","volume":"213","author":[{"given":"Xiangxiao","family":"Li","sequence":"first","affiliation":[{"name":"Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]},{"name":"Department of Biochemistry and Molecular Cell Biology, State Key Laboratory of Systems 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Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Fan","sequence":"additional","affiliation":[{"name":"Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wu","sequence":"additional","affiliation":[{"name":"Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinping","family":"Jin","sequence":"additional","affiliation":[{"name":"Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Deng","sequence":"additional","affiliation":[{"name":"Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyao","family":"Xu","sequence":"additional","affiliation":[{"name":"Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6936-7570","authenticated-orcid":false,"given":"Xuxu","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of 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