Human Pluripotent Stem Cell-Derived Astrocyte Functionality Compares Favorably with Primary Rat Astrocytes.
| Autor: | Lendemeijer B; Department of Psychiatry, Erasmus University Medical Center, Rotterdam 3015 AA, The Netherlands.; Department of Psychiatry, Columbia University, New York, New York 10027.; Stavros Niarchos Foundation (SNF) Center for Precision Psychiatry & Mental Health, Columbia University, New York, New York 10027., Unkel M; Department of Psychiatry, Erasmus University Medical Center, Rotterdam 3015 AA, The Netherlands., Smeenk H; Department of Psychiatry, Erasmus University Medical Center, Rotterdam 3015 AA, The Netherlands., Mossink B; Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands., Hijazi S; Department of Psychiatry, Erasmus University Medical Center, Rotterdam 3015 AA, The Netherlands., Gordillo-Sampedro S; Department of Psychiatry, Erasmus University Medical Center, Rotterdam 3015 AA, The Netherlands., Shpak G; Department of Psychiatry, Erasmus University Medical Center, Rotterdam 3015 AA, The Netherlands., Slump DE; Department of Psychiatry, Erasmus University Medical Center, Rotterdam 3015 AA, The Netherlands., van den Hout MCGN; Department of Cell Biology, Center for Biomics, Erasmus University Medical Center, Rotterdam 3015AA, The Netherlands., van IJcken WFJ; Department of Cell Biology, Center for Biomics, Erasmus University Medical Center, Rotterdam 3015AA, The Netherlands., Bindels EMJ; Department of Hematology, Erasmus University Medical Center, Rotterdam 3015AA, The Netherlands., Hoogendijk WJG; Department of Psychiatry, Erasmus University Medical Center, Rotterdam 3015 AA, The Netherlands., Nadif Kasri N; Department of Human Genetics, Radboud University Medical Center, Nijmegen 6525GA, The Netherlands., de Vrij FMS; Department of Psychiatry, Erasmus University Medical Center, Rotterdam 3015 AA, The Netherlands.; ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus University Medical Center, Rotterdam 3015AA, The Netherlands., Kushner SA; Department of Psychiatry, Erasmus University Medical Center, Rotterdam 3015 AA, The Netherlands.; Department of Psychiatry, Columbia University, New York, New York 10027.; Stavros Niarchos Foundation (SNF) Center for Precision Psychiatry & Mental Health, Columbia University, New York, New York 10027. |
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| Jazyk: | angličtina |
| Zdroj: | ENeuro [eNeuro] 2024 Sep 13; Vol. 11 (9). Date of Electronic Publication: 2024 Sep 13 (Print Publication: 2024). |
| DOI: | 10.1523/ENEURO.0148-24.2024 |
| Abstrakt: | Astrocytes are essential for the formation and maintenance of neural networks. However, a major technical challenge for investigating astrocyte function and disease-related pathophysiology has been the limited ability to obtain functional human astrocytes. Despite recent advances in human pluripotent stem cell (hPSC) techniques, primary rodent astrocytes remain the gold standard in coculture with human neurons. We demonstrate that a combination of leukemia inhibitory factor (LIF) and bone morphogenetic protein-4 (BMP4) directs hPSC-derived neural precursor cells to a highly pure population of astroglia in 28 d. Using single-cell RNA sequencing, we confirm the astroglial identity of these cells and highlight profound transcriptional adaptations in cocultured hPSC-derived astrocytes and neurons, consistent with their further maturation. In coculture with human neurons, multielectrode array recordings revealed robust network activity of human neurons in a coculture with hPSC-derived or rat astrocytes [3.63 ± 0.44 min -1 (hPSC-derived), 2.86 ± 0.64 min -1 (rat); p = 0.19]. In comparison, we found increased spike frequency within network bursts of human neurons cocultured with hPSC-derived astrocytes [56.31 ± 8.56 Hz (hPSC-derived), 24.77 ± 4.04 Hz (rat); p < 0.01], and whole-cell patch-clamp recordings revealed an increase of postsynaptic currents [2.76 ± 0.39 Hz (hPSC-derived), 1.07 ± 0.14 Hz (rat); p < 0.001], consistent with a corresponding increase in synapse density [14.90 ± 1.27/100 μm 2 (hPSC-derived), 8.39 ± 0.63/100 μm 2 (rat); p < 0.001]. Taken together, we show that hPSC-derived astrocytes compare favorably with rat astrocytes in supporting human neural network activity and maturation, providing a fully human platform for investigating astrocyte function and neuronal-glial interactions. Competing Interests: The authors declare no competing financial interests. (Copyright © 2024 Lendemeijer et al.) |
| Databáze: | MEDLINE |
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