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Brain macrophages originate from primitive macrophages that arise from mesodermal cells in the yolk sac and play a role in brain development. Previously, we showed a reduced number of brain macrophages in Ts1Cje foetuses, a murine model of DS. However, the mechanism underlying this reduction in Ts1Cje embryos remains unknown. First, in this study, we identified that the reduced brain macrophages in Ts1Cje foetuses were microglia. This study further reports the low production of primitive macrophages from Ts1Cje mouse embryonic stem cells (Ts1Cje\u2010mESCs). Gene expression profiling in Ts1Cje\u2010mESC\u2010derived cells indicated the persistence of pluripotency, preference for endodermal differentiation, and suppression of mesodermal differentiation. Consistently, Ts1Cje\u2010mESC\u2010derived cells showed the disturbed expression of cytokine receptors and apoptosis, and a decreased number of primitive macrophages was confirmed in the Ts1Cje yolk sac. A human induced pluripotent stem cell line established from an individual with DS also showed lower primitive macrophage production relative to diploidized controls. Thus, our data indicate resistance to mesodermal differentiation and impaired production of primitive macrophages in DS, providing valuable insights into abnormalities in brain development associated with DS.<\/jats:p>","DOI":"10.1111\/imm.70070","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T06:27:42Z","timestamp":1764311262000},"page":"596-612","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preventing Differentiation Towards Primitive Macrophages in Stem Cells With Down Syndrome"],"prefix":"10.1111","volume":"177","author":[{"given":"Koki","family":"Harada","sequence":"first","affiliation":[{"name":"Joint Research Laboratory, Division of Integrated Pharmaceutical Sciences Kyoto Pharmaceutical University  Kyoto 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