Dynamics of reactive astrocytes fosters tissue regeneration after cuprizone‐induced demyelination

Abstract

Demyelination in the central nervous system (CNS) is a hallmark of many neurodegenerative diseases such as multiple sclerosis (MS) and others. Here, we studied astrocytes during de‐ and remyelination in the cuprizone mouse model. To this end, we exploited the ribosomal tagging (RiboTag) technology that is based on Cre‐mediated cell type‐selective HA‐tagging of ribosomes. Analyses were performed in the corpus callosum of GFAP‐Cre+/−Rpl22HA/wt mice 5 weeks after cuprizone feeding, at the peak of demyelination, and 0.5 and 2 weeks after cuprizone withdrawal, when remyelination and tissue repair is initiated. After 5 weeks of cuprizone feeding, reactive astrocytes showed inflammatory signatures with enhanced expression of genes that modulate leukocyte migration (Tlr2, Cd86, Parp14) and they produced the chemokine CXCL10, as verified by histology. Furthermore, demyelination‐induced reactive astrocytes expressed numerous ligands including Cx3cl1, Csf1, Il34, and Gas6 that act on homeostatic as well as activated microglia and thus potentially mediate activation and recruitment of microglia and enhancement of their phagocytotic activity. During early remyelination, HA‐tagged cells displayed reduced inflammatory response signatures, as indicated by shutdown of CXCL10 production, and enhanced expression of osteopontin (SPP1) as well as of factors that are relevant for tissue remodeling (Timp1), regeneration and axonal repair. During late remyelination, the signatures shifted towards resolving inflammation by active suppression of lymphocyte activation and differentiation and support of glia cell differentiation. In conclusion, we detected highly dynamic astroglial transcriptomic signatures in the cuprizone model, which reflects excessive communication among glia cells and highlights different astrocyte functions during neurodegeneration and regeneration.

Ursolic acid attenuates cuprizone-induced alteration in cortical ceramide synthase-2, sphingomyelin synthase-1, and serine palmitoyl transferase-1 expression in rodent model of multiple sclerosis

“…In the present study, CPZ caused oxidative stress, astrocytopathy, microgliosis, oligodendropathy, neuroin ammation, and neurodegeneration in the mouse cortical tissue. Schröder et al (2023) suggested that CPZ causes astrocytopathy, neuroin ammation, and neurodegeneration in rodent corpus callosum (Schröder et al, 2023). In another study, it has been documented that CPZ also caused microgliosis in addition to astrocytopathy, neuroin ammation, and neurodegeneration in the corpus callosum of rodents (Mohamadi & Borhani-Haghighi, 2023).…”

Progressive lifespan modifications in the corpus callosum following a single juvenile concussion in male mice monitored by diffusion MRI

“…Functional role of these morphological changes in astrocytes in response to brain injury and whether these changes are linked to a specific inflammatory state remain unknown. The modulation of myelin dysfunction/repair by astrocytes has not been studied in TBI but research in multiple sclerosis models have observed a dynamic communication between glia and suggests an avenue of future research (Schroder, Mulenge et al 2023).…”

Stem cell therapies: a new era in the treatment of multiple sclerosis

“…Moreover, astrocytes have been shown to play multiple roles in the injury and repair processes of MS ( 166 ). Kerkering et al differentiated iPSCs derived from BMS patients into NSCs, further differentiating them into BMS patient-specific neurons and astrocytes.…”