Molecular signature of primate astrocytes reveals pathways and regulatory changes contributing to human brain evolution
Open accessPublished version of a preprint
Abstract
Astrocytes contribute to the development and regulation of the higher-level functions of the brain, the critical targets of evolution. However, how astrocytes evolve in primates is unsettled. Here, we obtain human, chimpanzee, and macaque induced pluripotent stem-cell-derived astrocytes (iAstrocytes). Human iAstrocytes are bigger and more complex than the non-human primate iAstrocytes. We identify new loci contributing to the increased human astrocyte. We show that genes and pathways implicated in long-range intercellular signaling are activated in the human iAstrocytes and partake in controlling iAstrocyte complexity. Genes downregulated in human iAstrocytes frequently relate to neurological disorders and were decreased in adult brain samples. Through regulome analysis and machine learning, we uncover that functional activation of enhancers coincides with a previously unappreciated, pervasive gain of "stripe" transcription factor binding sites. Altogether, we reveal the transcriptomic signature of primate astrocyte evolution and a mechanism driving the acquisition of the regulatory potential of enhancers.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Despite extensive studies in rodent models, the specific contributions of astrocytes to human pathology remain inadequately understood, partly due to species-specific differences.
“Despite extensive studies in rodent models, the specific contributions of astrocytes to human pathology remain inadequately understood, partly due to species-specific differences (17–20).”
From Varicose projection astrocytes: Conserved reactive cells in brain pathology (2026) · cites this paper as [20]
The Main section (p. 2) describes marked differences between rodent and primate astrocytes and says their evolutionary remodeling remains poorly understood. The Discussion (p. 9) says astrocyte malfunction contributes to brain disease. Neither passage says that extensive rodent-model research has left astrocytes’ specific contributions to human pathology inadequately understood because of species differences. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
UniProt: the Universal Protein Knowledgebase in 2023
The UniProt Consortium, Bateman, A., Martin, M.-J., Orchard, S., Magrane, M., Ahmad, S., Alpi, E., Bowler-Barnett, E. H., Britto, R., Bye-A-Jee, H., et al. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkac1052 · Cited by 7,210 · see citing works
Satterstrom, F. K., Kosmicki, J. A., Wang, J., Breen, M. S., De Rubeis, S., An, J.-Y., Peng, M., Collins, R., Grove, J., Klei, L., et al. (2020) · Cell · doi:10.1016/j.cell.2019.12.036 · Cited by 2,321 · see citing works
Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways
Chung, W.-S., Clarke, L. E., Wang, G. X., Stafford, B. K., Sher, A., Chakraborty, C., Joung, J., Foo, L. C., Thompson, A., Chen, C., et al. (2013) · Nature · doi:10.1038/nature12776 · Cited by 1,377 · see citing works
Gliotransmitters Travel in Time and Space
Araque, A., Carmignoto, G., Haydon, P. G., Oliet, S. H. R., Robitaille, R., & Volterra, A. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.007 · Cited by 1,308 · see citing works
The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal
Zhao, B., Tumaneng, K., & Guan, K.-L. (2011) · Nature Cell Biology · doi:10.1038/ncb2303 · Cited by 1,205 · see citing works
Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors
Allen, N. J., Bennett, M. L., Foo, L. C., Wang, G. X., Chakraborty, C., Smith, S. J., & Barres, B. A. (2012) · Nature · doi:10.1038/nature11059 · Cited by 764 · see citing works
Astrocyte function from information processing to cognition and cognitive impairment
Santello, M., Toni, N., & Volterra, A. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0325-8 · Cited by 737 · see citing works
Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC
Kucukdereli, H., Allen, N. J., Lee, A. T., Feng, A., Ozlu, M. I., Conatser, L. M., Chakraborty, C., Workman, G., Weaver, M., Sage, E. H., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1104977108 · Cited by 642 · see citing works
Topology of mammalian developmental enhancers and their regulatory landscapes
de Laat, W., & Duboule, D. (2013) · Nature · doi:10.1038/nature12753 · Cited by 521 · see citing works
Repeated morphological evolution through cis-regulatory changes in a pleiotropic gene
Prud'homme, B., Gompel, N., Rokas, A., Kassner, V. A., Williams, T. M., Yeh, S.-D., True, J. R., & Carroll, S. B. (2006) · Nature · doi:10.1038/nature04597 · Cited by 507 · see citing works
An Efficient Platform for Astrocyte Differentiation from Human Induced Pluripotent Stem Cells
TCW, J., Wang, M., Pimenova, A. A., Bowles, K. R., Hartley, B. J., Lacin, E., Machlovi, S. I., Abdelaal, R., Karch, C. M., Phatnani, H., et al. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.06.018 · Cited by 435 · see citing works
Cholesterol and matrisome pathways dysregulated in astrocytes and microglia
TCW, J., Qian, L., Pipalia, N. H., Chao, M. J., Liang, S. A., Shi, Y., Jain, B. R., Bertelsen, S. E., Kapoor, M., Marcora, E., et al. (2022) · Cell · doi:10.1016/j.cell.2022.05.017 · Cited by 411 · see citing works
Comparative transcriptomics reveals human-specific cortical features
Jorstad, N. L., Song, J. H. T., Exposito-Alonso, D., Suresh, H., Castro-Pacheco, N., Krienen, F. M., Yanny, A. M., Close, J., Gelfand, E., Long, B., et al. (2023) · Science · doi:10.1126/science.ade9516 · Cited by 208 · see citing works
Gabriele, M., Vulto-van Silfhout, A. T., Germain, P.-L., Vitriolo, A., Kumar, R., Douglas, E., Haan, E., Kosaki, K., Takenouchi, T., Rauch, A., et al. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.05.006 · Cited by 163 · see citing works
Gain of CTCF-Anchored Chromatin Loops Marks the Exit from Naive Pluripotency
Pękowska, A., Klaus, B., Xiang, W., Severino, J., Daigle, N., Klein, F. A., Oleś, M., Casellas, R., Ellenberg, J., Steinmetz, L. M., et al. (2018) · Cell Systems · doi:10.1016/j.cels.2018.09.003 · Cited by 74 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 3
- [13]13. Kanton, S. et al. Organoid single-cell genomic atlas uncovers human-specific features of brain development. Nature (2019) doi:10.1038/s41586-019-1654-9. · DOI
- [35]35. Zintel, T., Pizzollo, J., Claypool, G. & Babbitt, C. Astrocytes drive divergent metabolic gene expression in humans and chimpanzees. bioRxiv (2020).
- [70]70. Verkhratsky, A., Arranz, A. M., Ciuba, K. & Pękowska, A. Evolution of neuroglia. Annals of the New York Academy of Sciences vol. 1518 Preprint at https://doi.org/10.1111/nyas.14917 (2022). · DOI
Cited by
Sorted by citations
Varicose projection astrocytes: Conserved reactive cells in brain pathology
Ciani, C., Pistorio, G., Giancola, S., Mearelli, M., Mongelli, F. E., Forouzeh, D., Campos Soares, L., Gonzalez Martin, M., Lichtenstein, M. E., Mio, L., et al. (2026) · Science Advances · doi:10.1126/sciadv.ady8204 · Cited by 4 · see citing works
Self-citation
- Authors
- Ciuba, K., Piotrowska, A., Chaudhury, D., Dehingia, B., Duński, E., Behr, R., Soroczyńska, K., Czystowska-Kuźmicz, M., Abbas, M., Bulanda, E., Gawlik-Zawiślak, S., Pietrzak, S., Figiel, I., Włodarczyk, J., Verkhratsky, A., Niedbała, M., Kaspera, W., Wypych, T., Wilczyński, B., & Pękowska, A.
- Affiliations
- Instytut Biologii Doświadczalnej im. Marcelego Nenckiego (PL)
- German Primate Center (DE)
- Medical University of Warsaw (PL)
- Institute of Psychiatry and Neurology (PL)
- Ikerbasque (ES)
- Medical University of Silesia (PL)
- University of Warsaw (PL)
- Corresponding author
- Pękowska, Aleksandra
- ORCID
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2025-03
- Volume
- 32
- Issue
- 3
- Pages
- 426-444.e14
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W4407135159
- Cited by
- 25
- References
- 15
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 2
- FWCI
- 6.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, other-oa)
- Funders
- European Molecular Biology Organization
- National Science Centre Poland
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- astrocytes, human brain evolution, primate evolution, induced pluripotent stem cell-derived astrocytes, transcription factor binding sites, regulome, gene expression signatures, chimpanzees, macaque, neurological disorders
- MeSH terms
- Animals, Astrocytes, Brain, Pan troglodytes, Biological Evolution, Humans, Macaca, Primates, Transcription Factors, Signal Transduction, Induced Pluripotent Stem Cells, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
