FGF family members differentially regulate maturation and proliferation of stem cell-derived astrocytes

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.

Protective Functions of Reactive Astrocytes Following Central Nervous System Insult

“…Fibroblast growth factors (FGFs) constitute a family of at least 20 secreted ligands with pleiotropic roles in the developing and mature CNS (192)(193)(194)(195)(196)(197)(198)(199)(200)(201)(202)(203). Most FGF receptors (FGFRs) can respond to multiple FGF ligands (e.g.…”

“…This notion is highlighted in a recent article by Duong et al (196), in which the authors report FGF8 to function as cell fate switch that controls the differentiation of radial glial cells in the SVZ into neurons or astrocytes. Additional studies have demonstrated that FGFs regulate astrocyte morphogenesis, maturation, and function in both health and disease (197)(198)(199). For instance, in remyelinating lesions of MS, FGF-1 may act as a promoter of remyelination by an indirect mechanism that involves the induction of CXCL8 and LIF expression in astrocytes (204).…”

Layer-By-Layer Fabrication of Large and Thick Human Cardiac Muscle Patch Constructs With Superior Electrophysiological Properties

“…An almost 70-fold increase in the expression level of elastin was observed from week 1 to week 2, followed by a decrease at week 4. One potential cause of this sharp decrease in the elastin expression level could be linked to bFGF production by the iECs in the engineered constructs (Savchenko et al, 2019). Previous studies have shown that free bFGF decreases the expression levels of elastin at the transcriptional level in culture (Rich et al, 1996).…”

Neuropsychiatric Symptoms of COVID-19 Explained by SARS-CoV-2 Proteins’ Mimicry of Human Protein Interactions

“…FGF family uses Ras/MAPK, PI3, and PLCγ pathways ( Diez Del Corral and Morales, 2017 ), through which it helps for neuroprotection, cell survival, and neural differentiation during embryonic development, it is also linked with epileptogenesis, mood disorders and autoimmunity in the brain ( Turner et al, 2016 ). Compared to other types of FGF, FGF 2 not only increases the cell survival, but they also help the maturation of the astrocytes and alter glutamate transport by the astrocytes through interaction with glutamate transporter 1 in mouse ( Savchenko et al, 2019 ). By this effect, they contribute to neuroprotection in two ways, increasing cell survival and avoiding excitotoxicity induced by accumulated glutamate.…”