Systematic analysis of purified astrocytes after SCI unveils Zeb2os function during astrogliosis

Abstract

SUMMARY Spinal cord injury (SCI) is one of the most devastating neural injuries without effective therapeutic solutions. Astrocytes are the predominant component of the scar. Understanding the complex contributions of reactive astrocytes to SCI pathophysiologies is fundamentally important for developing therapeutic strategies. We have studied the molecular changes in the injury environment and the astrocyte-specific responses by astrocyte purification from injured spinal cords from acute to chronic stages. In addition to protein-coding genes, we have systematically analyzed the expression profiles of long non-coding RNAs (lncRNAs) (>200 bp), which are regulatory RNAs that play important roles in the CNS. We have identified a highly conserved lncRNA, Zeb2os , and demonstrated using functional assays that it plays an important role in reactive astrogliosis through the Zeb2os / Zeb2 / Stat3 axis. These studies provide valuable insights into the molecular basis of reactive astrogliosis and fill the knowledge gap regarding the function(s) of lncRNAs in astrogliosis and SCI.

Glial progenitor heterogeneity and key regulators revealed by single-cell RNA sequencing provide insight to regeneration in spinal cord injury

“…We have previously studied gene expression using RNA sequencing (RNA-seq) in both tissue sample and fluorescence-activated cell sorting (FACS)-purified GFAP-expressing cells from adult spinal cord using GFAP-Cre:R26-tdTomato (tdT) transgenic mouse model over a time course. 18 - 20 Although the global SCI RNA-seq analysis provided important information on the transcriptional profiles of the spinal cord and astrocyte lineage in general, these analyses did not define the diverse constituents of astrocyte-lineage cells and how they may be regulated after injury or contribute to regeneration. Interestingly, glial progenitors and neural stem cells (NSCs) can express astrocyte markers such as GFAP during development 21 - 24 ; however, the identities of GFAP-expressing progenitors in adult spinal cord have not been studied in detail.…”

Remodeling of astrocyte secretome in amyotrophic lateral sclerosis: uncovering novel targets to combat astrocyte-mediated toxicity

“…Meanwhile, it is increasingly recognized that astrocytes also secrete ncRNAs that are packaged within extracellular vesicles known as ADEVs. These ncRNAs, which include miRNAs and long non-coding RNAs (lncRNAs), have been reported to contribute to neurodegeneration, promoting astrogliosis [ 150 ] and degeneration of neuronal networks [ 123 ]. Deep sequencing approaches have accelerated the identification of RNA species that exist in ADEVs.…”

Transplanting neurofibromatosis-1 gene knockout neural stem cells improve functional recovery in rats with spinal cord injury by enhancing the mTORC2 pathway

“…SCI lesions are formed by three tissue compartments, fibrotic scars, astroglial scars, and viable neural tissue surrounding the border of the astroglial scar 32 . On the one hand, the astroglial scar limits the lesion; on the other hand, the existence of the astroglial scar obstructs the connection of rostral and caudal neurons 33 . In the present study, NSCs with NF-1 knockout differentiated into neurons, and neurofilament outgrowth was significantly enhanced.…”