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Placenta\u2010derived multipotent stem cells (PMSCs) are considered an ideal source of Ins\u2010PC generation due to their immunomodulatory and differentiation properties. However, the cellular and molecular pathways underlying PMSC differentiation to Ins\u2010PCs have not been fully elucidated. In this study, PMSCs were isolated from human placenta and successfully differentiated into Ins\u2010PCs using miRNA\u2010181a mimics. Differentiated Ins\u2010PCs produced a significant amount of insulin and upregulation of C\u2010peptide, insulin, and MAFA expression, compared to undifferentiated control PMSCs. RNA sequencing and LC\u2010MS\/MS were performed to uncover the pathways involved in the Ins\u2010PC differentiation process. RNA sequencing revealed the transcriptional landscape of PMSC\u2010derived Ins\u2010PC differentiation. Pathway analysis identified important pathways involved in the differentiation process, including Notch and Wnt\/\u00df\u2010catenin, and so forth. Proteomics analysis further affirmed the presence of key insulin pathway\u2010related proteins involved in the differentiation of PMSCs into Ins\u2010PCs, including LEPR, STC2, MAP2K2, and so forth. Moreover, integrated transcriptomic and proteomic analyses further highlighted LEPR as a potential key regulator for Ins\u2010PC differentiation. These findings demonstrated the feasibility of generating Ins\u2010PCs from PMSCs and identified potential signaling pathways and regulators underlying Ins\u2010PC differentiation, supporting PMSCs as a promising stem cell source of cell\u2010based therapy for diabetes treatment.<\/jats:p>","DOI":"10.1002\/pmic.70120","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T13:21:27Z","timestamp":1775049687000},"page":"57-68","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling the Molecular Pathways of Insulin\u2010Producing Cells Derived From Placenta Multipotent Stem Cells via Multi\u2010Omics Analysis"],"prefix":"10.1002","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8183-9526","authenticated-orcid":false,"given":"Jie","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology Louisiana State University Health \u2010 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