Cited by 6Neurogenesis and neuroplasticity mechanismsNeuroinflammation and Neurodegeneration MechanismsNeuroscience and Neuropharmacology Research

Glial-restricted precursors stimulate endogenous cytogenesis and effectively recover emotional deficits in a model of cytogenesis ablation

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Martins-Macedo, Joana, Araújo, Bruna, Anjo, Sandra I., Silveira-Rosa, Tiago, Patrício, Patrícia, Alves, Nuno Dinis, Silva, Joana M., Teixeira, Fábio G. +6 more·2024·Molecular Psychiatry

Published version of a preprint

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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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
Venue
Molecular Psychiatry
Published
2024-03-07
Volume
29
Issue
7
Pages
2185-2198
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
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
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

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