Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Abstract

The function of astrocytes intertwines with the extracellular matrix, whose neuron and glial cell-derived components shape neuronal plasticity. Astrocyte abnormalities have been reported in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We compared human FXS and control astrocytes generated from human induced pluripotent stem cells and we found increased expression of urokinase plasminogen activator (uPA), which modulates degradation of extracellular matrix. Several pathways associated with uPA and its receptor function were activated in FXS astrocytes.Levels of uPA were also increased in conditioned medium collected from FXS hiPSCderived astrocyte cultures and correlated inversely with intracellular Ca 2+ responses to activation of L-type voltage-gated calcium channels in human astrocytes. Increased uPA augmented neuronal phosphorylation of TrkB within the docking site for the phospholipase-Cγ1 (PLCγ1), indicating effects of uPA on neuronal plasticity. Gene expression changes during neuronal differentiation preceding astrogenesis likely contributed to properties of astrocytes with FXS-specific alterations that showed specificity by not affecting differentiation of adenosine triphosphate (ATP)-responsive astrocyte Ulla-Kaisa Peteri and Juho Pitkonen contributed equally to this study.

Retinoic Acid Supplementation Rescues the Social Deficits in Fmr1 Knockout Mice

“…The biological process pathways enriched in the GO analysis were also found related to the FXS. For instance, extracellular structure plays a pivotal role in neurite outgrowth, neural connectivity, and synaptic plasticity (Cope and Gould, 2019;Peteri et al, 2021). Alterations in connected tissue and extracellular matrix (ECM) have been implied in the pathophysiological development of FXS (Ramírez-Cheyne et al, 2019).…”

Across Dimensions: Developing 2D and 3D Human iPSC-Based Models of Fragile X Syndrome

“…One group recently published a method to generate astrocytes with forebrain patterning from hPSCs (hASTRO) [ 144 ]. Using this method, the group found that the expression of urokinase plasminogen activator (uPA), a protease that regulates the degradation of the extracellular matrix, was increased in FXS hASTRO compared to control hASTRO [ 145 ]. Interestingly, the increase in uPA level was correlated with a reduced intracellular calcium response to depolarization in hASTRO [ 145 ], which is in contrast to the enhanced intracellular calcium release seen in FXS NPCs [ 63 ].…”

“…Using this method, the group found that the expression of urokinase plasminogen activator (uPA), a protease that regulates the degradation of the extracellular matrix, was increased in FXS hASTRO compared to control hASTRO [ 145 ]. Interestingly, the increase in uPA level was correlated with a reduced intracellular calcium response to depolarization in hASTRO [ 145 ], which is in contrast to the enhanced intracellular calcium release seen in FXS NPCs [ 63 ]. The authors stated that uPA signaling could play a role in modulating synaptic excitation/inhibition balance found to be altered in FXS [ 146 ].…”

Astrocytes regulate inhibition in Fragile X Syndrome

“…Human forebrain astrocytes were produced as described previously 91 from male FXS (HEL69.6, HEL70.3, HEL70.6, and HEL100.2) and control (HEL23.3, HEL24.3, HEL46.11, PO2/UEF-3A, and PO4/UEF-3B) human iPSC lines reported in several previous studies [92][93][94][95][96][97][98] . The research using human cells was approved by the Ethics Committee of the Hospital District of Helsinki and Uusimaa, Finland.…”