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PreprintCC BY-NC-NDbioRxiv

SALL1 and neural microenvironmental contextspecify identity of stem cell derived humanmicroglia-like cells

  • M. T. Nikolova
  • K. Freitag
  • R. Okamoto
  • A. Catellani
  • J. Hinke
  • N. A. Luginbuehl
  • H.-C. Lin
  • J. Kaindl
  • Z. He
  • P. Wahle
  • J. Rohland
  • L. Geirsdottir
4 more authors
  • J. G. Camp
  • B. Winner
  • I. Amit
  • B. Treutlein1
  1. 1Department of Biosystems Science and Engineering, ETH Zuerich, Basel, Switzerland
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Abstract

Microglia, the immune cells of the brain parenchyma, play a pivotal role in neurodevelopment and neuroprotection. Human stem cell-derived microglia-like cells (MGL) offer a valuable, human-relevant system to study microglia in vitro. However, their cell states and intercellular interactions within complex 3-dimensional (3D) tissue contexts in vitro remain underexplored. Here, we analyze the gene expression profiles of MGL generated by two differentiation protocols in conventional 2D cultures. We show that co-culture with neural organoids promotes a more mature, in vivo-like MGL phenotype but this signature is lost during long-term co-culture. By varying media compositions, we modulate 2D MGL states toward more active or more homeostatic identities, which may enhance the similarity to primary microglia identities upon subsequent co-culture. Moreover, forced expression of the microglial lineage regulator SALL1 shifts MGL away from a general myeloid state toward a more defined pre-microglial fate. SALL1 overexpression within a 3D neural organoid environment further amplifies the shift toward a homeostatic developmental microglia population. Collectively, our transcriptomic analysis delineates human MGL states in 2D and 3D contexts, refines existing differentiation protocols toward more authentic MGL, and establishes a framework to investigate the intricate microglia-neural tissue interplay.

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Cite

BibTeXRIS
BibTeX
@misc{nikolova2026sall1,
  title = {{SALL1 and neural microenvironmental contextspecify identity of stem cell derived humanmicroglia-like cells}},
  author = {M. T. Nikolova and K. Freitag and R. Okamoto and A. Catellani and J. Hinke and N. A. Luginbuehl and H.-C. Lin and J. Kaindl and Z. He and P. Wahle and J. Rohland and L. Geirsdottir and J. G. Camp and B. Winner and I. Amit and B. Treutlein},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.25.754357},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.25.754357v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - SALL1 and neural microenvironmental contextspecify identity of stem cell derived humanmicroglia-like cells
AU  - M. T. Nikolova
AU  - K. Freitag
AU  - R. Okamoto
AU  - A. Catellani
AU  - J. Hinke
AU  - N. A. Luginbuehl
AU  - H.-C. Lin
AU  - J. Kaindl
AU  - Z. He
AU  - P. Wahle
AU  - J. Rohland
AU  - L. Geirsdottir
AU  - J. G. Camp
AU  - B. Winner
AU  - I. Amit
AU  - B. Treutlein
PY  - 2026
DA  - 2026/09/25
PB  - bioRxiv
DO  - 10.64898/2026.09.25.754357
UR  - https://www.biorxiv.org/content/10.64898/2026.09.25.754357v1
AB  - Microglia, the immune cells of the brain parenchyma, play a pivotal role in neurodevelopment and neuroprotection. Human stem cell-derived microglia-like cells (MGL) offer a valuable, human-relevant system to study microglia in vitro. However, their cell states and intercellular interactions within complex 3-dimensional (3D) tissue contexts in vitro remain underexplored. Here, we analyze the gene expression profiles of MGL generated by two differentiation protocols in conventional 2D cultures. We show that co-culture with neural organoids promotes a more mature, in vivo-like MGL phenotype but this signature is lost during long-term co-culture. By varying media compositions, we modulate 2D MGL states toward more active or more homeostatic identities, which may enhance the similarity to primary microglia identities upon subsequent co-culture. Moreover, forced expression of the microglial lineage regulator SALL1 shifts MGL away from a general myeloid state toward a more defined pre-microglial fate. SALL1 overexpression within a 3D neural organoid environment further amplifies the shift toward a homeostatic developmental microglia population. Collectively, our transcriptomic analysis delineates human MGL states in 2D and 3D contexts, refines existing differentiation protocols toward more authentic MGL, and establishes a framework to investigate the intricate microglia-neural tissue interplay.
ER  -