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Astrocyte metabolic programs diverge across primate evolution and are linked to species-specific neuronal development

  • Fred Gage
  • Sheila Steiner
  • Kaia Foster
  • Rebecca Chinn
  • Joshua Pratt
  • Sarah Fernandes
  • Amandeep Sharma
  • Renata Santos
  • Christian Metallo
  • Maria Marchetto
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Abstract

Humans are characterized by changes in neuronal development compared to non-human primates (NHPs), and metabolic changes are implicated in these species' differences. However, most research has focused on changes in the neurons and neural progenitor cells themselves, but astrocytes are crucial metabolic cells in the brain. Here, we identified a delayed onset of gliogenesis in human versus NHP organoid models. iPSC-derived astrocytes also revealed distinct metabolic profiles: NHP astrocytes exhibit increased serine and glycine synthesis, whereas human astrocytes show elevated lactate secretion, suggesting metabolic reprogramming of astrocytes across primate evolution. Astrocyte secretomes also differed, with human astrocyte secretomes enriched for axon-growth proteins. We then assessed the impact of these different species’ astrocyte secretomes on neuronal development. Conditioned media from NHPs as compared to humans led to increased electrophysiological activity and altered transcriptomic signatures of neuronal development in human neurons. Chemical PHGDH inhibition is consistent with a partial contribution of astrocytic serine/glycine metabolism to these species-specific effects. Together, these findings reveal a metabolic and secretory divergence between human and NHP astrocytes linked to species-specific neuronal development.

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Cite

BibTeXRIS
BibTeX
@misc{gage2026astrocyte,
  title = {{Astrocyte metabolic programs diverge across primate evolution and are linked to species-specific neuronal development}},
  author = {Fred Gage and Sheila Steiner and Kaia Foster and Rebecca Chinn and Joshua Pratt and Sarah Fernandes and Amandeep Sharma and Renata Santos and Christian Metallo and Maria Marchetto},
  howpublished = {Research Square},
  year = {2026},
  month = oct,
  doi = {10.21203/rs.3.rs-11133580/v1},
  url = {https://doi.org/10.21203/rs.3.rs-11133580/v1},
  note = {CC BY 4.0},
}
RIS
TY  - UNPB
TI  - Astrocyte metabolic programs diverge across primate evolution and are linked to species-specific neuronal development
AU  - Fred Gage
AU  - Sheila Steiner
AU  - Kaia Foster
AU  - Rebecca Chinn
AU  - Joshua Pratt
AU  - Sarah Fernandes
AU  - Amandeep Sharma
AU  - Renata Santos
AU  - Christian Metallo
AU  - Maria Marchetto
PY  - 2026
DA  - 2026/10/14
PB  - Research Square
DO  - 10.21203/rs.3.rs-11133580/v1
UR  - https://doi.org/10.21203/rs.3.rs-11133580/v1
AB  - Humans are characterized by changes in neuronal development compared to non-human primates (NHPs), and metabolic changes are implicated in these species' differences. However, most research has focused on changes in the neurons and neural progenitor cells themselves, but astrocytes are crucial metabolic cells in the brain. Here, we identified a delayed onset of gliogenesis in human versus NHP organoid models. iPSC-derived astrocytes also revealed distinct metabolic profiles: NHP astrocytes exhibit increased serine and glycine synthesis, whereas human astrocytes show elevated lactate secretion, suggesting metabolic reprogramming of astrocytes across primate evolution. Astrocyte secretomes also differed, with human astrocyte secretomes enriched for axon-growth proteins. We then assessed the impact of these different species’ astrocyte secretomes on neuronal development. Conditioned media from NHPs as compared to humans led to increased electrophysiological activity and altered transcriptomic signatures of neuronal development in human neurons. Chemical PHGDH inhibition is consistent with a partial contribution of astrocytic serine/glycine metabolism to these species-specific effects. Together, these findings reveal a metabolic and secretory divergence between human and NHP astrocytes linked to species-specific neuronal development.
SN  - 2693-5015
ER  -