Biology subjects

Jager, S. E.

Publications and source records attributed to Jager, S. E..

6 recordsLinked to original sources

bioRxiv2024

Satellite glial cells from adult DRG dedifferentiate in vitro and can be reprogrammed into nociceptor-like neurons

In dorsal root ganglia (DRG), neuronal loss has been reported in patients with neuropathic pain, raising the question of whether the DRG, as part of the peripheral nervous system (PNS), harbor an endogenous cell source for neural repair. We found that adult mouse DRG harbor glial cells that dedifferentiate in vitro into Sox2/Sox10-positive glial progenitor-like cells. Coexpression of the developmental transcription factors Neurog1 and Neurog2 was sufficient to induce both neuronal and glial phenotypes. Nerve growth factor supported the maturation of a subset of neurons into nociceptor-like cells expressing functional TrpA1, TrpV1, and TTX-resistant NaV channels. We report the limitation that we miss factors allowing consistent maturation to the sensory neuron profile. In summary, in the PNS, adult DRG-derived glial cells can acquire neural progenitor-like properties, show bipotent reprogramming competence, and may serve as an intrinsic cell source for sensory circuit regeneration.

neuroscience↗

bioRxiv2023

mPD5, an efficacious PICK1 inhibitor for treating chronic pain

Chronic pain is a complex, debilitating, and escalating health problem worldwide, impacting one in five adults. Current treatment is compromised by dose-limiting side effects including high abuse liability, loss of ability to function socially and professionally, fatigue, drowsiness, and apathy. PICK1 has emerged as a promising target for the treatment of chronic pain conditions. Here, we develop and characterize a cell-permeable fatty acid conjugated bivalent peptide inhibitor of PICK1 and assess its effects on acute and chronic pain. The myristoylated myr-NPEG4-(HWLKV)2, (mPD5), self-assembles into core-shell micelles that provide favourable pharmacodynamic properties and relieves ongoing and evoked mechanical hypersensitivity, thermal hypersensitivity as well as anxio-depressive symptoms in mouse models of neuropathic and inflammatory pain following subcutaneous administration. No overt no side effects were associated with mPD5 administration, and it has no effect on acute nociception. Finally, neuropathic pain is relieved far into the chronic phase (18 weeks post SNI surgery) and while the effect of a single injection ceases after a few hours, repeated administration provides pain relief lasting up to 20 hours after the last injection.

pharmacology and toxicology↗

bioRxiv2023

Recombinant dimeric PDZ protein inhibitors for long-term relief of chronic pain by AAV therapeutics

The inadequate state of current pain treatments, the chronic nature of particularly neuropathic pain, and the high impact on quality of life render chronic pain conditions relevant for gene therapy. Here, we describe the development and application of self-assembling dimeric peptide inhibitors of the pain-associated scaffolding protein PICK1 (protein interacting with C-kinase 1) delivered by adeno-associated viral (AAV) vectors. In mice, these peptides prevented mechanical allodynia in inflammatory and neuropathic pain models and reversed neuropathic pain in advanced stages up to one year. Pain relief was obtained by targeting several relays along the somatosensory pain pathways unaccompanied by overt adverse side effects, while selective transduction of peripheral neurons was sufficient for providing full pain relief. We further confirmed PICK1 expression and peptide target engagement in mice and human donor tissue, and we conclude that AAV therapeutics, based on recombinant PICK1 inhibitors, represent a potential clinically meaningful strategy for persistent neuropathic pain conditions. One Sentence SummaryAlleviating neuropathic pain by PICK1-directed gene therapy.

neuroscience↗

bioRxiv2022

In vivo calcium imaging shows that satellite glial cells have increased activity in painful states

Satellite glial cells (SGCs) are important for proper neuronal function of primary sensory neurons to whom they provide homeostatic support. Most research of SGC function has been performed with in vitro studies, but recent advances in calcium imaging and transgenic mouse models have enabled this first in vivo study of single cell SGC function in mouse models of inflammation and neuropathic pain. We found that in naive condition SGCs do not respond in a time-locked fashion to neuronal firing. In painful inflammatory and neuropathic states we detected time-locked signals in a subset of SGCs, but only with suprathreshold stimulation of the sciatic nerve. Surprisingly therefore, we conclude that most calcium signals in SGCs seem to develop at arbitrary intervals not directly linked to neuronal activity patterns. More in line with expectations, our experiments also revealed that the number of active SGCs was increased under conditions of inflammation or nerve injury. This could reflect the increased requirement for homeostatic support across dorsal root ganglion neuron populations, which are more active during such painful states.

neuroscience↗

bioRxiv2021

Comparative transcriptional analysis of the satellite glial cell injury response

Satellite glial cells (SGCs) tightly surround and support primary sensory neurons in the peripheral nervous system and are increasingly recognized for their involvement in the development of neuropathic pain following nerve injury. The SGCs are difficult to investigate due to their flattened shape and tight physical connection to neurons in vivo and their rapid changes in phenotype and protein expression when cultured in vitro. Consequently, several aspects of SGC function under normal conditions as well as after a nerve injury remain to be explored. The recent advance in single cell RNAseq technologies has enabled a new approach to investigate SGCs. Here we publish a dataset from mice subjected to sciatic nerve injury as well as a dataset from dorsal root ganglia cells after 3 days in culture. We use a meta-analysis approach to compare the injury response with that in other published datasets and conclude that SGCs share a common signature following sciatic nerve crush and sciatic ligation, involving transcriptional regulation of cholesterol biosynthesis. We also observed a considerable transcriptional change when culturing SGCs, suggesting that some differentiate into a specialised in vitro state, while others start resembling Schwann cell-like precursors. The datasets are available via the Broad Institute Single Cell Portal.

neuroscience↗

bioRxiv2019

A transcriptional toolbox for exploring peripheral neuro-immune interactions.

Correct communication between immune cells and peripheral neurons is crucial for the protection of our bodies. Its breakdown is observed in many common, often painful conditions, including arthritis, neuropathies and inflammatory bowel or bladder disease. Here, we have characterised the immune response in a mouse model of neuropathic pain using flow cytometry and cell-type specific RNA sequencing (RNA-seq). We found few striking sex differences, but a very persistent inflammatory response, with increased numbers of monocytes and macrophages up to 3[1/2] months after the initial injury. This raises the question of whether the commonly used categorisation of pain into \"inflammatory\" and \"neuropathic\" is one that is mechanistically appropriate. Finally, we collated our data with other published RNA-seq datasets on neurons, macrophages and Schwann cells in naive and nerve injury states. The result is a practical web-based tool for the transcriptional data-mining of peripheral neuroimmune interactions.\n\nhttp://rna-seq-browser.herokuapp.com/

neuroscience↗