Human sensory neuron and macrophage co-culture; developing a model to test agents capable of disrupting painful neuroimmune signalling

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.