Abstract

The glutamate transporter 1 (GLT1) is upregulated during astrocyte development and maturation in vivo and is vital for astrocyte function. Yet it is expressed at low levels by most cultured astrocytes. We previously showed that maturation of human and mouse stem cell-derived astrocytes – including functional glutamate uptake – could be enhanced by fibroblast growth factor (FGF)1 or FGF2. Here, we examined the specificity and mechanism of action of FGF2 and other FGF family members, as well as neurotrophic and differentiation factors, on mouse embryonic stem cell-derived astrocytes. We found that some FGFs – including FGF2, strongly increased GLT1 expression and enhanced astrocyte proliferation, while others (FGF16 and FGF18) mainly affected maturation. Interestingly, BMP4 increased astrocytic GFAP expression, and BMP4-treated astrocytes failed to promote the survival of motor neurons in vitro. Whole transcriptome analysis showed that FGF2 treatment regulated multiple genes linked to cell division, and that the mRNA encoding GLT1 was one of the most strongly upregulated of all astrocyte canonical markers. Since GLT1 is expressed at reduced levels in many neurodegenerative diseases, activation of this pathway is of potential therapeutic interest. Furthermore, treatment with FGFs provides a robust means for expansion of functionally mature stem cell-derived astrocytes for preclinical investigation.

Details

Title
FGF family members differentially regulate maturation and proliferation of stem cell-derived astrocytes
Author
Savchenko, Ekaterina 1 ; Teku, Gabriel N 2   VIAFID ORCID Logo  ; Boza-Serrano, Antonio 3 ; Kaspar, Russ 1 ; Berns, Manon 1 ; Deierborg, Tomas 3 ; Lamas, Nuno J 4 ; Wichterle, Hynek 5 ; Rothstein, Jeffrey 6   VIAFID ORCID Logo  ; Henderson, Christopher E 7 ; Vihinen, Mauno 2   VIAFID ORCID Logo  ; Roybon, Laurent 1 

1  Department of Experimental Medical Science, BMC D10, Faculty of Medicine, Lund University, Lund, Sweden; MultiPark and Lund Stem Cell Center, Faculty of Medicine, Lund University, Lund, Sweden 
2  Department of Experimental Medical Science, Faculty of Medicine, BMC B13, Lund University, Lund, Sweden 
3  Department of Experimental Medical Science, Faculty of Medicine, BMC B11, Lund University, Lund, Sweden 
4  Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal, and ICVS/3B’s, PT Government Associate Laboratory, Braga/Guimarães, Portugal; Anatomic Pathology Service, Pathology Department, Hospital and University Center of Porto, Largo Professor Abel Salazar, Porto, Portugal 
5  Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia Translational Neuroscience Initiative, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, Neurology, and Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY, USA 
6  Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA 
7  Center for Motor Neuron Biology and Disease, Columbia Stem Cell Initiative, Columbia Translational Neuroscience Initiative, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, Neurology, and Neuroscience, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, New York, NY, USA; Department of Rehabilitation and Regenerative Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA; Target ALS Foundation, New York, NY, USA; Biogen Inc., Cambridge, MA, USA 
Pages
1-13
Publication year
2019
Publication date
Jul 2019
Publisher
Nature Publishing Group
e-ISSN
20452322
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41598-019-46110-1
ProQuest document ID
2251707169
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.