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RNA-Seq analysis after spinal cord injury in lamprey reveals distinct transcriptional responses during functional recovery in spinal cord and brain

ABSTRACT: The lamprey is a vertebrate that, unlike mammals, achieves spontaneous recovery after spinal cord transection. Despite anatomical, physiological, and behavioral data on spinal cord regeneration in lamprey, the molecular mechanisms underlying this capacity are largely unknown. To address this, we used RNA-Seq to obtain transcriptional profiles from uninjured animals and at 10 time points ranging from 6 hours to 12 weeks post injury. Overall, 4208 (spinal cord) and 3788 (brain) transcripts are differentially expressed (DE). Complex intraspinal and supraspinal responses were induced acutely and occurred even at chronic phases of recovery. Leveraging functional data for mammalian homologs of DE genes (via Enrichr) permitted identification of enriched conserved genes and pathways. These included genes and pathways induced after mammalian peripheral nerve injury, such as those associated with regeneration, immune function, cell growth, proliferation and cell death. For example, ATF3, a transcription factor implicated in mammalian peripheral nerve regeneration, is highly expressed and enriched in lamprey spinal cord and brain after SCI. Other homologs of regeneration-associated genes that are differentially expressed after SCI include members of the WNT, HDAC, SOX, SMAD, KLF, and JUN families. This study provides the first comprehensive view of transcriptional responses during successful anatomical and functional recovery from spinal cord injury in lamprey, and reveals unexpectedly large changes in transcription in the brain, which is quite distant from the spinal lesion site. Gene expression patterns associated with functional recovery in lamprey may be useful in guiding studies aimed at modulating mammalian responses to SCI.

ORGANISM(S): Petromyzon marinus

PROVIDER: GSE95686 | GEO | 2018/03/03

REPOSITORIES: GEO

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Project description:Among the vertebrates, teleost and urodele amphibians are capable of regenerating their central nervous system. We have used crush injury method on zebrafish spinal cord, which is a common mammalian mode of injury in spinal cord. To identify the molecular mechanisms of the underlying cellular events during regeneration of zebrafish spinal cord, we have employed high density oligonucleotide microarrays and profiled the temporal transcriptome dynamics during the entire phenomenon. A total of 3842 genes expressed differentially with significant fold changes during spinal cord regeneration. Cluster analysis revealed event specific dynamic expression of genes related to inflammation, cell death, cell migration, cell proliferation, neurogenesis, neural patterning and axonal regrowth. We have also validated the expression pattern of 14 genes (which include inflammatory regulators, cell cycle regulators, pattern forming genes and signaling molecules) by different methodologies. Spatio-temporal analysis of STAT3 expression suggested its possible function in controlling inflammation and cell proliferation. Genes involved in the proliferating neural progenitors and their dorso-ventral patterning (sox2 and dbx2) are differentially expressed. Injury induced cell proliferation is controlled by many cell cycle regulators and some of them also show their common expression in other regenerating systems like fin, heart and retina. We also reported unusual expression pattern of certain pathway genes like one carbon folate metabolism and N-glycan biosynthesis which have not been reported during regeneration of spinal cord. Genes like stat3, socs3, atf3, mmp9 and sox11, which are known to control peripheral nervous system (PNS) regeneration in mammals, are also upregulated in zebrafish spinal cord injury (SCI) thus creating PNS like environment after injury. Our study provides a comprehensive genetic blue print of diverse cellular response(s) during regeneration of zebrafish spinal cord that could be used to induce successful regeneration in mammals. The spinal cord has been injured by crushing dorso-ventrally for 1 sec with a number 5 Dumont forceps at the level of 15th/16th vertebrae. Later the wound were sealed by placing a suture. Both spinal cord injured and sham operated fish were allowed to regenerate and the progress of regeneration was observed after 1, 3, 7, 10 and 15 days of injury. Zebrafishes were anesthetized deeply for 5 minutes in 0.1% tricaine (MS222; Sigma, USA) and approximately 1mm length of spinal cord both rostrally and caudally from injury epicenter were dissected out from 50-60 fishes in each batch and pooled for RNA extraction.

Project description:The inflammatory response after spinal cord injury (SCI) is an important contributor to secondary damage. Infiltrating macrophages can acquire a spectrum of activation states, however, the microenvironment at the SCI site favors macrophage polarization into a pro-inflammatory phenotype, which is one of the reasons why macrophage transplantation has failed. In this study, we investigated the therapeutic potential of the macrophage secretome for SCI recovery. We investigated the effect of the secretome in vitro using peripheral and CNS-derived neurons and human neural stem cells. Moreover, we perform a pre-clinical trial using a SCI compression mice model and analyzed the recovery of motor, sensory and autonomic functions. Instead of transplanting the cells, we injected the paracrine factors and extracellular vesicles that they secrete, avoiding the loss of the phenotype of the transplanted cells due to local environmental cues. We demonstrated that different macrophage phenotypes have a distinct effect on neuronal growth and survival, namely, the alternative activation with IL-10 and TGF-β1 (M(IL-10+TGF-β1)) promotes significant axonal regeneration. We also observed that systemic injection of soluble factors and extracellular vesicles derived from M(IL-10+TGF-β1) macrophages promotes significant functional recovery after compressive SCI and leads to higher survival of spinal cord neurons. Additionally, the M(IL-10+TGF-β1) secretome supported the recovery of bladder function and decreased microglial activation, astrogliosis and fibrotic scar in the spinal cord. Proteomic analysis of the M(IL-10+TGF-β1)-derived secretome identified clusters of proteins involved in axon extension, dendritic spine maintenance, cell polarity establishment, and regulation of astrocytic activation. Overall, our results demonstrated that macrophages-derived soluble factors and extracellular vesicles might be a promising therapy for SCI with possible clinical applications.

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RNA-Seq analysis after spinal cord injury in lamprey reveals distinct transcriptional responses during functional recovery in spinal cord and brain

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