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Human birth tissue products as a regenerative medicine for post-surgical pain through multi-modal action

ABSTRACT: Post-surgical pain causes significant suffering. Extracts of the human amniotic membrane (AM) may be novel regenerative matrices, but little is known about their use in pain treatment. Locally applying FLO (particulates of AM) in mice acutely attenuated post-surgical pain hypersensitivity and inhibited its transition to a prolonged state after plantar-incision. Mechanistically, this was achieved through direct nociceptive neuronal inhibition via CD44-dependent mechanisms and indirect anti-pain effect by attenuating immune cell recruitment and promoting wound healing. We purified heavy chain-hyaluronic acid/pentraxin 3 (HC-HA/PTX3) from human AM as a major bioactive matrix component for pain relief, as it mirrored FLO-induced analgesia and nociceptive neuronal inhibition. Strikingly, HC-HA/PTX3 triggered acute cytoskeleton rearrangement to inhibit ion channels on nociceptive neurons, presenting a novel cellular mechanism for pain control. Moreover, long-term drug treatment broadly changed neuronal gene expression. Our study demonstrated the potential and mechanisms of a naturally occurring biologic from human birth tissues as non-opioid treatments for post-surgical pain.

ORGANISM(S): Mus musculus

PROVIDER: GSE242389 | GEO | 2024/06/25

REPOSITORIES: GEO

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Project description:Objective – Following destabilization of the medial meniscus (DMM), mice develop experimental osteoarthritis (OA) and associated pain behaviors that are dependent on the stage of disease. We aimed to describe changes in gene expression in knee-innervating dorsal root ganglia (DRG) after surgery, in order to identify molecular pathways associated with three pre-defined pain phenotypes: “post-surgical pain”, “early-stage OA pain”, and “persistent OA pain”. Design – We performed DMM or sham surgery in 10-week old male C57BL/6 mice and harvested L3-L5 DRG 4, 8, and 16 weeks after surgery or from age-matched naïve mice (n=3/group). RNA was extracted and an Affymetrix Mouse Transcriptome Array 1.0 was performed. Three pain phenotypes were defined: “post-surgical pain” (sham and DMM 4-week vs. 14-week old naïve), “early OA pain” (DMM 4-week vs. sham 4-week), and “persistent OA pain” (DMM 8- and 16-week vs. naïve and sham 8- and 16-week). ‘Top hit’ genes were defined as p<0.001. Pathway analysis (Ingenuity Pathway Analysis) was conducted using differentially expressed genes defined as p<0.05. In addition, we performed qPCR for Ngf and immunohistochemistry for F4/80+ macrophages in the DRG. Results – For each phenotype, top hit genes identified a small number of differentially expressed genes, some of which have been previously associated with pain (7/67 for “post-surgical pain”; 2/14 for “early OA pain”; 8/37 for “persistent OA pain”). Overlap between groups was limited, with 8 genes differentially regulated (p<0.05) in all three phenotypes. Pathway analysis showed that in the persistent OA pain phase many of the functions of differentially regulated genes are related to immune cell recruitment and activation. Genes previously linked to OA pain (CX3CL1, CCL2, TLR1, and NGF) were upregulated in this phenotype and contributed to activation of the neuroinflammation canonical pathway. In separate sets of mice, we confirmed that Ngf was elevated in the DRG 8 weeks after DMM (p=0.03), and numbers of F4/80+ macrophages were increased 16 weeks after DMM (p=0.002 vs. Sham). Conclusion- These transcriptomics findings support the idea that distinct molecular pathways discriminate early from persistent OA pain. Pathway analysis suggests neuroimmune interactions in the DRG contribute to initiation and maintenance of pain in OA. We grouped samples based on pain phenotype in the DMM mouse model of osteoarthritis. Group 1: post-surgical pain (DMM and sham +4 week samples); Group 2: post-surgical control (Naïve +4 week samples); Group 3: Early osteoarthritis pain (DMM +4 week samples); Group 4: Early controls (sham+4 and naive+4 week samples); Group 5: Persistent pain (DMM+8 and DMM+16 week samples); Group 6: Persistent controls (sham+8, naive+8, sham+16, and naive +16 samples). We compared Group 1 vs Group 2; Group 3 vs Group 4; and Group 5 vs Group 6 to draw the conclusions presented in our manuscript.

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Human birth tissue products as a regenerative medicine for post-surgical pain through multi-modal action

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