Over 5 million people in the UK live with neuropathic pain, yet most drugs that work in animal models fail in humans. This project builds a human cell-based model to test pain treatments directly on human tissue. The problem is that damaged sensory neurons fire excessively, but scientists don’t fully understand what drives that hyperexcitability. Emerging evidence points to macrophages—immune cells that normally clean up damage—as key players. When these macrophages interact with damaged neurons, they release inflammatory signals that make neurons fire more. Previous animal models have identified drug targets, but those targets rarely translate to people. The researchers have already created the first co-culture of human stem-cell-derived sensory neurons and macrophages. They showed that damaged neurons cause macrophages to release pro-inflammatory molecules, and that these macrophages make normally quiet neurons fire spontaneously—mimicking neuropathic pain. Now they want to identify which specific macrophage-derived signals cause the hyperexcitability, and then optimise the model as a drug screening platform. If successful, this human-tissue-based system could replace some animal experiments and provide a more reliable way to test new pain drugs before clinical trials, potentially accelerating treatments for millions of people.
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Neuropathic pain (NeuP) affects over 5 million people in the UK. Excessive electrical activity of damaged sensory neurons is key to NeuP, however, the cellular cues which drive hyperexcitability are not fully understood. Emerging evidence suggests that macrophages directly interacting with sensory neurons make an important contribution. Experimental animal models have greatly advanced our understanding of pain processing, however, most drug targets identified in these models have failed to translate. There is therefore a compelling argument to advance human tissue-based experimental models to study neuroimmune signalling in NeuP. In pilot work, we have established the first co-culture model of human iPSC-derived sensory neurons (iSNs) and macrophages (iMACs). Neuronal damage causes iMACs to undergo putatively proinflammatory morphological, secretory and gene expression changes, consistent with features seen in vivo. For example, we have observed marked increases in the secretion of known pro-algesic cytokines from iMACs when co-cultured with damaged iSNs. Moreover, iMACS induce an increased frequency of firing in normally quiescent iSNs, mirroring the spontaneous activity found in NeuP states in vivo Following on from this work, we now wish to identify which of our candidate pro-algesic mediators upregulated in iMACS are responsible for the hyperexcitability observed in damaged iSNs. In vitro models have a crucial role to play in drug discovery and we believe that our system has significant translational potential as a drug screening platform. Therefore, a secondary aim will be to optimise the model and make it an attractive analgesic testing platform, ready to be deployed widely. NC3Rs training and legacy
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