Glial-restricted precursors stimulate endogenous cytogenesis and effectively recover emotional deficits in a model of cytogenesis ablation
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Abstract
Adult cytogenesis, the continuous generation of newly-born neurons (neurogenesis) and glial cells (gliogenesis) throughout life, is highly impaired in several neuropsychiatric disorders, such as Major Depressive Disorder (MDD), impacting negatively on cognitive and emotional domains. Despite playing a critical role in brain homeostasis, the importance of gliogenesis has been overlooked, both in healthy and diseased states. To examine the role of newly formed glia, we transplanted Glial Restricted Precursors (GRPs) into the adult hippocampal dentate gyrus (DG), or injected their secreted factors (secretome), into a previously validated transgenic GFAP-tk rat line, in which cytogenesis is transiently compromised. We explored the long-term effects of both treatments on physiological and behavioral outcomes. Grafted GRPs reversed anxiety-like deficits and demonstrated an antidepressant-like effect, while the secretome promoted recovery of only anxiety-like behavior. Furthermore, GRPs elicited a recovery of neurogenic and gliogenic levels in the ventral DG, highlighting the unique involvement of these cells in the regulation of brain cytogenesis. Both GRPs and their secretome induced significant alterations in the DG proteome, directly influencing proteins and pathways related to cytogenesis, regulation of neural plasticity and neuronal development. With this work, we demonstrate a valuable and specific contribution of glial progenitors to normalizing gliogenic levels, rescuing neurogenesis and, importantly, promoting recovery of emotional deficits characteristic of disorders such as MDD.
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Self-citationMachado-Santos, A. R., Loureiro‐Campos, E., Patrício, P., Araújo, B., Alves, N. D., Mateus‐Pinheiro, A., Correia, J. S., Morais, M., Bessa, J. M., Sousa, N., et al. (2022) · Cells · doi:10.3390/cells11030390 · Cited by 22 · see citing works
Self-citationMateus‐Pinheiro, A., Patrício, P., Alves, N. D., Martins‐Macedo, J., Caetano, I., Silveira‐Rosa, T., Araújo, B., Mateus‐Pinheiro, M., Silva‐Correia, J., Sardinha, V. M., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01287-8 · Cited by 21 · see citing works
Self-citationProwse, N. A., Dwyer, Z., Thompson, A., Fortin, T., Elson, K. I., Robeson, H., Fenner, B. M., & Hayley, S. P. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.112260 · Cited by 13 · see citing works
Treatment-Resistant Depression in Portugal: Perspective From Psychiatry Experts
Bessa, J. M., Carvalho, S., Cunha, I. B., Fernandes, M., Matos-Pires, A., Neves, R., Oliveira-Maia, A. J., Santos, S. G., & Santos, V. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.824919 · Cited by 13 · see citing works
Murano, T., Nakajima, R., Nakao, A., Hirata, N., Amemori, S., Murakami, A., Kamitani, Y., Yamamoto, J., & Miyakawa, T. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2106830119 · Cited by 13 · see citing works
Martins‐Macedo, J., Salgado, A. J., Gomes, E. D., & Pinto, L. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.09.030 · Cited by 11 · see citing works
Self-citationBook Review: The Rat Brain in Stereotaxic Coordinates
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Jeong, M., Jang, J., Oh, S.-J., Choe, Y., Park, J., Lee, J., Park, J., Lee, Y., Hwang, S., Kim, J. K., et al. (2020) · Research Square · doi:10.21203/rs.3.rs-92512/v1 · Cited by 2 · see citing works
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Stepenko, Y. V., Shmigerova, V. S., Kostina, D. A., Щеблыкина, О. В., Жернакова, Н. И., Solin, A., Koroleva, N. V., Марковская, В. А., Dudnikova, O. V., & Болгов, А. А. (2024) · Research Results in Pharmacology · doi:10.18413/rrpharmacology.10.492 · Cited by 4 · see citing works
Ribeiro, I., Silveira‐Rosa, T., Martins‐Macedo, J., Marques-Ferraz, L., Dourado, A. R., Martins-Ferreira, G., Farrugia, F., Rodrigues, A. J., Abrous, D. N., Alves, N. D., et al. (2025) · Neurobiology of Stress · doi:10.1016/j.ynstr.2025.100743 · Cited by 3 · see citing works
Self-citationFerreira, G. A. M., & Pinto, L. (2025) · Glia · doi:10.1002/glia.70031 · Cited by 2 · see citing works
Self-citationGlial Cells in Behavioral and Psychological Symptoms of Alzheimer’s Disease
Hasan, I., Tang, X., & Xu, J. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27104621 · Cited by 1 · see citing works
Sex Differences in Depression: Adult Cytogenesis as Potential Target for Precision Psychiatry
Rodrigues-Freitas, L., Pinto, L., & Canedo, T. (2026) · Cells · doi:10.3390/cells15121059
Self-citationAraújo, B., Caridade-Silva, R., Vilaça-Ferreira, A. C., Martins‐Macedo, J., Teixeira, C., Soares-Guedes, C., Summavielle, T., Svenningsson, P., Pinto, L., & Teixeira, F. G. (2026) · Research Square · doi:10.21203/rs.3.rs-10814574/v1
Self-citation
- Authors
- Martins-Macedo, J., Araújo, B., Anjo, S. I., Silveira-Rosa, T., Patrício, P., Alves, N. D., Silva, J. M., Teixeira, F. G., Manadas, B., Rodrigues, A. J., Lepore, A. C., Salgado, A. J., Gomes, E. D., & Pinto, L.
- Affiliations
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto (PT)
- Centro de Neurociências e Biologia Celular (PT)
- University of Minho (PT)
- Thomas Jefferson University (US)
- Corresponding author
- Pinto, Luísa
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2024-03-07
- Volume
- 29
- Issue
- 7
- Pages
- 2185-2198
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC11632613
- OpenAlex
- W4392562118
- Cited by
- 6
- References
- 102
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1
- FWCI
- 0.98
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Molecular Psychiatry (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- PubMed Central (submittedVersion, cc-by)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Funders
- U.S. Department of Health and Human Services (R01NS110385, R01NS079702)
- European Commission (100010434, 101003187, 2020 ‘, HORIZON2020, ID 100010434)
- Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona (UIDB/04539/2020, ID 100010434, 100010434)
- Nature
- Fundação para a Ciência e a Tecnologia (01-0145, 04539, POCI-01-0145, UIDP/04539/2020, UIDB/50026/2020, POCI-01-0145-FEDER-402-022125, 2022.02201.PTDC, ROTEIRO/0028/2013, UIDB/04539/2020 and UIDP/04539/2020, 100010434, UIDP/50026/2020, POCI-01-0145-FEDER-, POCI-01-, 2020.02855.CEECIND, CEECINST/00077/2018, UIDB/04539/2020, MC-18-2021, 10.54499, CT0003, PTDC/MED-NEU/4804/2020, MC-04/17, POCI‐01‐0145‐FEDER‐029206, UIDB/50026/2020 and UIDP/50026/2020, EXPL/BTM-TEC/1407/2021, CEECINST/00077/2018/CP1640/CT0003)
- National Institute of Neurological Disorders and Stroke (R01NS079702, R01NS110385)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- adult neurogenesis, gliogenesis, cytogenesis, dentate gyrus, cell transplantation, secretome, anxiety-like behavior, antidepressant-like effects, major depressive disorder, emotional deficits, hippocampus, proteome, neuroplasticity
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.
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