Biology subjects

Chrysostomidou, P.

Publications and source records attributed to Chrysostomidou, P..

3 recordsLinked to original sources

bioRxiv2026

Precision cell-state silencing of injured afferents alleviates spontaneous neuropathic pain

Excessive primary afferent activity sustains neuropathic pain, but safe and effective therapeutic inhibition has proved elusive. Realising the promise of gene therapies to meet this challenge requires strategies to identify and selectively target the neuronal populations responsible. Here, we use chemo- and optogenetic approaches to demonstrate that activity in injured afferents drives spontaneous pain but is dispensable for normal sensory function, thereby creating a therapeutic opportunity. Guided by chromatin accessibility profiling, we create an injury-responsive viral vector that confers >95% specificity for injured sensory neurons. Combined with the translationally relevant chemogenetic PSAM4-GlyR, this targeting module effectively silences hyperexcitable human sensory neurons and alleviates spontaneous neuropathic pain in mice. These findings establish precision cell-state targeting of sensory neurons as a promising therapeutic strategy for chronic pain.

neuroscience↗

bioRxiv2025

Macrophages amplify the spontaneous activity of damaged sensory neurons in a human co-culture model of neuropathic pain

Neuropathic pain is a highly prevalent condition for which treatments are hampered by low efficacy and dose-limiting side-effects. Injury to the somatosensory nervous system causes maladaptive plasticity that initiates and maintains chronic pain. Emerging evidence suggests that inflammatory cells of the innate immune system shape the response of the injured nervous system and thereby contribute to the pathogenesis of pain. Data from preclinical models and human patient biopsies have specifically implicated peripheral macrophage populations for a pro-algesic role, yet how these cell types influence damaged sensory neurons and whether they directly contribute to neuronal hyperexcitability is unclear. Here, we have developed an iPSC co-culture system to study the interactions of macrophages and sensory neurons in a fully humanised experimental model. We found that analogous to endogenous counterparts, iPSC-derived macrophages (iMacs) display a dynamic molecular and functional profile that is highly dependent on neuronal state. Co-culture with injured iPSC-derived sensory neurons (iSNs) induces morphological, gene expression, and secretory profile changes in iMacs that are consistent with the response of macrophages to nerve injury in vivo. iMacs in turn amplify spontaneous firing in damaged sensory neurons, implicating macrophages in this cardinal feature of neuropathic pain. These results illustrate the utility of an iPSC-based model to study signalling between these two cell types; they support a role for macrophages in directly amplifying damaged sensory neuron activity and highlight disrupting pathological signalling between these cell types as a promising strategy for future analgesic drug development.

neuroscience↗

bioRxiv2023

Peripheral nerve injury results in a biased loss of sensory neuron sub-populations

There is a rich literature describing loss of dorsal root ganglion (DRG) neurons following peripheral axotomy, but the vulnerability of discrete subpopulations has not yet been characterised. Furthermore, the extent and even presence of neuron loss following injury has recently been challenged. In this study, we have used a range of transgenic recombinase driver mouse lines to genetically label molecularly defined subpopulations of DRG neurons and track their survival following traumatic nerve injury. We find that spared nerve injury (SNI) leads to a marked loss of cell containing DRG-volume and a concomitant loss of small diameter DRG neurons. Neuron loss occurs unequally across subpopulations and is particularly prevalent in non-peptidergic nociceptors, marked by expression of Mrgprd. We show that this subpopulation is almost entirely lost following SNI and severely depleted (by roughly 50%) following sciatic nerve crush. Finally, we used an in vitro model of DRG neuron survival to demonstrate that non-peptidergic nociceptor loss is likely dependent on the absence of neurotrophic support. Together, these results profile the extent to which DRG neuron subpopulations can survive axotomy, with implications for our understanding of nerve injury-induced plasticity and pain.

neuroscience↗