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

Molecular Psychiatry (2024)Cite this article

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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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Fig. 1: Characterization of GRPs at P5, both in vitro and in vivo (post transplantation).
Fig. 2: GFAP-tk rat model characterization and experimental timeline.
Fig. 3: Effects of GRP and secretome treatments on behavior and generation of new cells in GFAP-tk rats.
Fig. 4: Analysis of the proteins significantly altered between GRPs or Secretome treatments and GFAP-tk sham animals.
Fig. 5: Analysis of the proteins altered between groups in the dDG region.
Fig. 6: Analysis of the proteins altered between groups in the vDG region.

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All data generated or analyzed during this study are included in this published article (and its Supplementary Data files).

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Acknowledgements

We would like to thank Prof. Itzhak Fisher for providing the transgenic rats to isolate GRPs and Prof. Jonathan Flint for providing the GFAP-tk rat line. L.P. was funded by the Portuguese Foundation for Science and Technology (FCT, 2020.02855.CEECIND, CEECINST/00077/2018/CP1640/CT0003 and https://doi.org/10.54499/2022.02201.PTDC). This work was funded by Nature Research Award for Driving Global Impact – 2019 Brain Sciences (to L.P.). A.J.S. received funding from Prémios Santa Casa Neurociências – Prize Melo e Castro for Spinal Cord Injury Research (MC-04/17; MC-18-2021), and from FCT (POCI-01-0145-FEDER-029206). A.J.R. was funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 101003187), by “La Caixa” Foundation (ID 100010434), under the agreement LCF/PR/HR20/52400020, as well as by FCT, under the scope of the project https://doi.org/10.54499/PTDC/MED-NEU/4804/2020 (ENDOPIO). This work has been also funded by National funds, through the FCT – project UIDB/50026/2020 and UIDP/50026/2020. A.C.L. was supported by the National Institute of Neurological Disorders and Stroke (R01NS079702, R01NS110385) and the Yant Family Spinal Cord Regeneration Fund. S.I.A. was funded by FCT (2021.04378.CEECIND and EXPL/BTM-TEC/1407/2021). B.M. was funded by The National Mass Spectrometry Network (POCI-01-0145-FEDER-402-022125 Ref.ROTEIRO/0028/2013) and FCT (UIDB/04539/2020 and UIDP/04539/2020).

Author information

Author notes

  1. These authors jointly supervised this work: António J. Salgado, Eduardo D. Gomes, Luísa Pinto.

Authors and Affiliations

  1. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal

    Joana Martins-Macedo, Bruna Araújo, Tiago Silveira-Rosa, Patrícia Patrício, Nuno Dinis Alves, Joana M. Silva, Ana J. Rodrigues, António J. Salgado, Eduardo D. Gomes & Luísa Pinto

  2. ICVS/3B’s—PT Government Associate Laboratory, Braga/Guimarães, Portugal

    Joana Martins-Macedo, Bruna Araújo, Tiago Silveira-Rosa, Patrícia Patrício, Nuno Dinis Alves, Joana M. Silva, Ana J. Rodrigues, António J. Salgado, Eduardo D. Gomes & Luísa Pinto

  3. Center for Translational Health and Medical Biotechnology Research (TBIO), School of Health (ESS), Polytechnic of Porto, Porto, Portugal

    Joana Martins-Macedo, Bruna Araújo, Fábio G. Teixeira & Eduardo D. Gomes

  4. I3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135, Porto, Portugal

    Joana Martins-Macedo, Bruna Araújo, Fábio G. Teixeira & Eduardo D. Gomes

  5. CNC—Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Sandra I. Anjo & Bruno Manadas

  6. Institute for Interdisciplinary Research, University of Coimbra (IIIUC), Coimbra, Portugal

    Sandra I. Anjo & Bruno Manadas

  7. Centre for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal

    Sandra I. Anjo & Bruno Manadas

  8. Department of Neuroscience, Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA

    Angelo C. Lepore

Authors
  1. Joana Martins-Macedo
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  2. Bruna Araújo
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  3. Sandra I. Anjo
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  4. Tiago Silveira-Rosa
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  5. Patrícia Patrício
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  6. Nuno Dinis Alves
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  7. Joana M. Silva
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  8. Fábio G. Teixeira
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  9. Bruno Manadas
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  10. Ana J. Rodrigues
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  11. Angelo C. Lepore
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  12. António J. Salgado
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  13. Eduardo D. Gomes
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  14. Luísa Pinto
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Contributions

JMM, BA, TSR and PP maintained the GFAP-tk colony, induced the model, performed genotyping and collected wellbeing measures. ACL isolated and provided the GRPs. JMM and EDG conducted all behavioral tests, in vitro experiments and immunohistochemical experiments, performed the analyses and interpreted the results. BA assisted in the immunohistochemical experiments and analyses. SIA performed the proteome experiments. SIA, FGT, JMS, NDA and BM analyzed and interpreted the proteome data. JMM, EDG, AJS and LP designed the study, planned the experiments and wrote the manuscript. JMM, EDG, AJS, AJR, BA, ACL and LP edited the manuscript.

Corresponding author

Correspondence to Luísa Pinto.

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The authors declare no competing interests.

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Martins-Macedo, J., Araújo, B., Anjo, S.I. et al. Glial-restricted precursors stimulate endogenous cytogenesis and effectively recover emotional deficits in a model of cytogenesis ablation. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02490-z

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  • DOI: https://doi.org/10.1038/s41380-024-02490-z

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