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However, iNs generated from adult hDFs using two-dimensional cultures are difficult to maintain in vitro and face challenges in survival upon transplantation into the adult brain, thus imposing constraints on biomedical applications of iN technology. Here, we present a platform for direct in vitro reprogramming of adult hDFs inside three-dimensional suspension microcultures (3D-iNs). We show that the 3D environment favors neuronal over fibroblast cellular identity to yield more robust conversion into functional neurons with extended culturing span. The 3D reprogramming approach also provides a platform for fusion into induced assembloids. 3D-iNs can be gently harvested and transplanted into the adult rodent brain to reproducibly generate neuron-rich grafts, thus eliminating a major bottleneck in the direct reprogramming field.<\/jats:p>","DOI":"10.1126\/sciadv.adq7855","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T13:58:24Z","timestamp":1749218304000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":17,"title":["Three-dimensional cell-cell interactions promote direct reprogramming of patient fibroblasts into functional and transplantable neurons"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9997-2325","authenticated-orcid":true,"given":"Janko","family":"Kajtez","sequence":"first","affiliation":[{"name":"Department of Experimental Medical Sciences, Wallenberg Neuroscience Center, Division of 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