Transient matrix remodeling during direct cell-fate reprogramming enables self-assembly of dense neuronal niches

Native tissues are characterized by high cellular density and continuous reciprocal interactions between cells and the extracellular matrix (ECM), yet recreating these features in vitro remains a major challenge. Current three-dimensional (3D) culture systems typically capture either dense cell-cell interactions or a defined ECM environment, but rarely both. Here, we introduce a strategy that exploits direct fibroblast-to-neuron reprogramming to decouple microenvironment formation from final cell identity. Human dermal fibroblasts were embedded in collagen microgels, where their intrinsic matrix-remodeling capacity drove rapid ECM compaction. Concurrently, the contractile fibroblasts were converted into induced neurons (iN), generating densely packed neuronal microcultures within a remodeled collagen matrix. This approach transforms a defining function of the starting cell type into a mechanism for engineering the microenvironment of the target cell type. The resulting iN-microgels combine high cell density, defined ECM composition, and tunable biophysical properties in a scalable microscale format. By coupling matrix remodeling with cell-fate conversion, our platform establishes a general framework for engineering tissue-like microenvironments and reveals how dynamic 3D extracellular contexts can be integrated into direct cell reprogramming.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-10-28
DOI
https://doi.org/10.64898/2026.10.27.762125
Primary Topic
Cellular Mechanics and Interactions
Type
preprint

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preprint

Transient matrix remodeling during direct cell-fate reprogramming enables self-assembly of dense neuronal niches

Malin Parmar, Jessica Giacomoni, Mette Habekost, David A. Weitz et al.
bioRxiv (Cold Spring Harbor Laboratory)
Cellular Mechanics and Interactions
preprint

Transient matrix remodeling during direct cell-fate reprogramming enables self-assembly of dense neuronal niches

Malin Parmar, Jessica Giacomoni, Mette Habekost, David A. Weitz, Emily B. Roloson, Daniella Rylander Ottosson, Andreas Bruzelius, Milan Finn Wesseler, Niels B. Larsen, Kerstin Laurin, Fredrik Nilsson, Janko Kajtez, Roger A. Barker, Pinelopi Apostolaki
preprint en

Abstract

Native tissues are characterized by high cellular density and continuous reciprocal interactions between cells and the extracellular matrix (ECM), yet recreating these features in vitro remains a major challenge. Current three-dimensional (3D) culture systems typically capture either dense cell-cell interactions or a defined ECM environment, but rarely both. Here, we introduce a strategy that exploits direct fibroblast-to-neuron reprogramming to decouple microenvironment formation from final cell identity. Human dermal fibroblasts were embedded in collagen microgels, where their intrinsic matrix-remodeling capacity drove rapid ECM compaction. Concurrently, the contractile fibroblasts were converted into induced neurons (iN), generating densely packed neuronal microcultures within a remodeled collagen matrix. This approach transforms a defining function of the starting cell type into a mechanism for engineering the microenvironment of the target cell type. The resulting iN-microgels combine high cell density, defined ECM composition, and tunable biophysical properties in a scalable microscale format. By coupling matrix remodeling with cell-fate conversion, our platform establishes a general framework for engineering tissue-like microenvironments and reveals how dynamic 3D extracellular contexts can be integrated into direct cell reprogramming.

bioRxiv (Cold Spring Harbor Laboratory)
University of Copenhagen (DK), Harvard University (US), Lund University (SE), University of Cambridge (GB), Technical University of Denmark (DK)
Innovationsfonden, National Institute for Health and Care Research, Department of Health and Social Care, European Commission, National Science Council, Lundbeckfonden, Novo Nordisk, Stiftelsen Olle Engkvist Byggmästare, Vetenskapsrådet, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Novo Nordisk Fonden, Parkinsonfonden, Horizon 2020 Framework Programme, NIHR Cambridge Biomedical Research Centre
Good health and well-being
Cellular Mechanics and Interactions
DOIOpen Access PDFOpenAlex
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