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Coding transcriptome analyses reveal altered functions underlying immunotolerance of PEG-fused rat sciatic nerve allografts

ABSTRACT: Coding transcriptome analyses reveal altered functions underlying immunotolerance of PEG-fused rat sciatic nerve allografts

PROVIDER: PRJNA607330 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11107303_1.fastq.gz	Fastqsanger.gz
	SRR11107303_2.fastq.gz	Fastqsanger.gz
	SRR11107304_1.fastq.gz	Fastqsanger.gz
	SRR11107304_2.fastq.gz	Fastqsanger.gz
	SRR11107305_1.fastq.gz	Fastqsanger.gz

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Project description:Purpose: Current methods to repair ablation-type peripheral nerve injuries (PNIs) using peripheral nerve allografts (PNAs) often result in poor functional recovery due to immunological rejection as well as slow and inaccurate outgrowth of regenerating axon sprouts. In contrast, ablation-type PNIs repaired by PNAs using a multistep protocol, in which one step uses the membrane fusogen polyethylene glycol (PEG), permanently restore sciatic-mediated behaviors within weeks. Axons and cells within the PNA remain viable, even though outbred host and donor tissues are neither immunosuppressed nor tissue matched. PEG-fused PNAs exhibit significantly reduced T cell and macrophage infiltration, apoptosis, and expression of major histocompatibility complex I/II. In this study, we analyzed the coding transcriptome of PEG-fused PNAs to determine possible mechanisms underlying immunosuppression. Methods: Ablation-type sciatic PNIs in adult Sprague Dawley rats were repaired using PNAs and a PEG-fusion protocol combined with neurorrhaphy. Electrophysiological and behavioral recovery tests confirmed successful PEG-fusion of PNAs. RNA sequencing analyzed differential expression profiles of protein-coding genes between PEG-fused PNAs and NC PNAs (not treated with PEG) at 14d PO, along with Unoperated nerves. Sequencing results were validated by Quantitative Reverse Transcription PCR (RT-qPCR). Results: PEG-fused PNAs display significant downregulation of a great many gene transcripts associated with innate and adaptive allorejection responses. Many Schwann cell-associated transcripts are upregulated, and many cellular processes such as extracellular matrix remodeling, cell and tissue development are particularly enriched. Transcripts encoding several potentially immunosuppressive proteins (e.g. Thrombospondins 1 and 2) are upregulated in PEG-fused PNAs. Conclusions: This study is the first to characterize the coding transcriptome of PEG-fused PNAs, and identifies possible links between alterations of the extracellular matrix and suppression of the allorejection response. The results establish a molecular-basis to understand mechanisms underlying PEG-mediated immunosuppression.

Project description:BACKGROUND:Current methods to repair ablation-type peripheral nerve injuries (PNIs) using peripheral nerve allografts (PNAs) often result in poor functional recovery due to immunological rejection as well as to slow and inaccurate outgrowth of regenerating axonal sprouts. In contrast, ablation-type PNIs repaired by PNAs, using a multistep protocol in which one step employs the membrane fusogen polyethylene glycol (PEG), permanently restore sciatic-mediated behaviors within weeks. Axons and cells within PEG-fused PNAs remain viable, even though outbred host and donor tissues are neither immunosuppressed nor tissue matched. PEG-fused PNAs exhibit significantly reduced T cell and macrophage infiltration, expression of major histocompatibility complex I/II and consistently low apoptosis. In this study, we analyzed the coding transcriptome of PEG-fused PNAs to examine possible mechanisms underlying immunosuppression. METHODS:Ablation-type sciatic PNIs in adult Sprague-Dawley rats were repaired using PNAs and a PEG-fusion protocol combined with neurorrhaphy. Electrophysiological and behavioral tests confirmed successful PEG-fusion of PNAs. RNA sequencing analyzed differential expression profiles of protein-coding genes between PEG-fused PNAs and negative control PNAs (not treated with PEG) at 14 days PO, along with unoperated control nerves. Sequencing results were validated by quantitative reverse transcription PCR (RT-qPCR), and in some cases, immunohistochemistry. RESULTS:PEG-fused PNAs display significant downregulation of many gene transcripts associated with innate and adaptive allorejection responses. Schwann cell-associated transcripts are often upregulated, and cellular processes such as extracellular matrix remodeling and cell/tissue development are particularly enriched. Transcripts encoding several potentially immunosuppressive proteins (e.g., thrombospondins 1 and 2) also are upregulated in PEG-fused PNAs. CONCLUSIONS:This study is the first to characterize the coding transcriptome of PEG-fused PNAs and to identify possible links between alterations of the extracellular matrix and suppression of the allorejection response. The results establish an initial molecular basis to understand mechanisms underlying PEG-mediated immunosuppression.

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Coding transcriptome analyses reveal altered functions underlying immunotolerance of PEG-fused rat sciatic nerve allografts

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