Human oligodendrocyte progenitor cells mediate synapse elimination through TAM receptor activation
Oligodendrocyte progenitor cells (OPCs) have been implicated in synaptic remodelling in animal models, but the underlying mechanisms and their relevance to human brain development remain unclear. Here, we generate a human multi-lineage forebrain organoid model in which OPCs, together with microglia, form close contacts with synapses and spontaneously internalize synaptic material. Single-nucleus transcriptomic profiling with unbiased cell-cell communication analysis identifies the growth arrest-specific gene 6 (GAS6)-TYRO3, AXL, and MERTK (TAM) receptor axis as a key signalling pathway, with neurons and microglia expressing GAS6 and a subset of OPCs expressing AXL. Further, dose-dependent pharmacological inhibition of TAM receptors demonstrates the importance of AXL, and targeted reduction of AXL expression in OPCs impairs synaptic uptake. These findings reveal a role for GAS6-AXL signalling in driving synaptic internalisation by AXL+ OPCs during early human brain development.
Authors
- Eszter Molnár
- Marja Koskuvi (ORCID: https://orcid.org/0000-0002-1646-9992)
- Samudyata Samudyata (ORCID: https://orcid.org/0000-0002-1062-2626)
- Sandra Ceccatelli (ORCID: https://orcid.org/0000-0002-9367-8480)
- Raj Bose (ORCID: https://orcid.org/0009-0008-4039-862X)
- Martin Schalling (ORCID: https://orcid.org/0000-0001-5011-2922)
- Carl M. Sellgren (ORCID: https://orcid.org/0000-0001-9103-2785)
- Jari Koıstınaho (ORCID: https://orcid.org/0000-0001-6559-1153)
- Jari Tiihonen (ORCID: https://orcid.org/0000-0002-0400-6798)
- Sohvi Ohtonen (ORCID: https://orcid.org/0000-0003-4674-6484)
- Susmita Malwade (ORCID: https://orcid.org/0000-0002-6756-018X)
- Asimenia Gkogka (ORCID: https://orcid.org/0009-0001-7892-0769)
Institutions
- Karolinska University Hospital (SE)
- University of Helsinki (FI)
- University of Eastern Finland (FI)
- Niuvanniemi Hospital (FI)
- Stockholm County Council (SE)
- Karolinska Institutet (SE)
- Stockholm Health Care Services (SE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-05
- DOI
- https://doi.org/10.1038/s41467-025-66521-1
- Citations
- 1
- Primary Topic
- Neurogenesis and neuroplasticity mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.32
Funders
- Hjärnfonden
- Karolinska Institutet
- Stockholms Läns Landsting
- Vetenskapsrådet
- Uppsala Universitet
- Uppsala Multidisciplinary Center for Advanced Computational Science