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Three-dimensional cell-cell interactions promote direct reprogramming of patient fibroblasts into functional and transplantable neurons

Kajtez, Janko LU orcid ; Laurin, Kerstin LU orcid ; Nilsson, Fredrik LU orcid ; Bruzelius, Andreas LU ; Cepeda-Prado, Efrain LU orcid ; Birtele, Marcella LU orcid ; Barker, Roger A. ; Herborg, Freja ; Ottosson, Daniella Rylander LU orcid and Storm, Petter LU orcid , et al. (2025) In Science Advances 11(23).
Abstract

Direct reprogramming of somatic cells into induced neurons (iNs) has become an attractive strategy for the generation of patient-specific neurons for disease modeling and regenerative neuroscience. To this end, adult human dermal fibroblasts (hDFs) present one of the most relevant cell sources. 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... (More)

Direct reprogramming of somatic cells into induced neurons (iNs) has become an attractive strategy for the generation of patient-specific neurons for disease modeling and regenerative neuroscience. To this end, adult human dermal fibroblasts (hDFs) present one of the most relevant cell sources. 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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Advances
volume
11
issue
23
article number
eadq7855
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • pmid:40479059
  • scopus:105008383335
ISSN
2375-2548
DOI
10.1126/sciadv.adq7855
language
English
LU publication?
yes
additional info
Publisher Copyright: Copyright © 2025 The Authors, some rights reserved.
id
64a1de16-f5dc-43c8-80ae-9e4f0bf17c0d
date added to LUP
2025-12-17 09:21:24
date last changed
2025-12-17 09:22:21
@article{64a1de16-f5dc-43c8-80ae-9e4f0bf17c0d,
  abstract     = {{<p>Direct reprogramming of somatic cells into induced neurons (iNs) has become an attractive strategy for the generation of patient-specific neurons for disease modeling and regenerative neuroscience. To this end, adult human dermal fibroblasts (hDFs) present one of the most relevant cell sources. 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.</p>}},
  author       = {{Kajtez, Janko and Laurin, Kerstin and Nilsson, Fredrik and Bruzelius, Andreas and Cepeda-Prado, Efrain and Birtele, Marcella and Barker, Roger A. and Herborg, Freja and Ottosson, Daniella Rylander and Storm, Petter and Fiorenzano, Alessandro and Habekost, Mette and Parmar, Malin}},
  issn         = {{2375-2548}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{23}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Advances}},
  title        = {{Three-dimensional cell-cell interactions promote direct reprogramming of patient fibroblasts into functional and transplantable neurons}},
  url          = {{http://dx.doi.org/10.1126/sciadv.adq7855}},
  doi          = {{10.1126/sciadv.adq7855}},
  volume       = {{11}},
  year         = {{2025}},
}