Single-nucleus transcriptomic analysis reveals divergence of glial cells in peripheral somatosensory system between human and mouse

Abstract

Glial cells play a crucial role in regulating physiological and pathological functions, such as sensation, infections, acute injuries, and chronic neurodegenerative disorders. Glial cells include astrocytes, microglia, and oligodendrocytes in the central nervous system (CNS) and satellite glial cells (SGCs) in the peripheral nervous system (PNS). Despite the understanding of glial subtypes and functional heterogeneity in animal models achieved by single-cell or single-nucleus RNA sequencing, no research has investigated the transcriptomic profiles of glial cells in the human PNS and spinal cord. Here, we used high-throughput single-nucleus RNA sequencing to map the cellular and molecular heterogeneity of SGCs in the human dorsal root ganglion (DRG) and astrocytes, microglia, and oligodendrocytes in the human spinal cord. To explore the conservation and divergence across species, we compared these human findings with those from mice. Additionally, the expression profiles of risk genes of common DRG and spinal cord diseases in glial cells were compared between humans and mice. As a result, little SGCs heterogeneity was found in both human and mouse DRG. In the human spinal cord, astrocytes, microglia, and oligodendrocytes were respectively divided into six distinct transcriptomic subclusters. In the mouse spinal cord, astrocytes, microglia, and oligodendrocytes were divided into six, five, and six distinct transcriptomic subclusters, respectively. The comparative results revealed substantial heterogeneity in all glial cells between humans and mice. Notably, we also identified transcriptomic heterogeneity in several classical genes and risk genes for neurological disorders across humans and mice. Together, the present data comprehensively profiled glial cell heterogeneity and provides a powerful resource for investigating the cellular basis of glial-related physiological and pathological conditions in peripheral somatosensory system.

Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling

“…To evaluate the potential relevance of our results from mouse models to human conditions, we performed snRNA-seq analysis of human lumbar spinal cords and compared their neuron and astrocyte subtypes with that of mouse spinal cords. We found that, the human neurons 31 and astrocytes 32 and the mouse counterparts showed similar clusters based on the transcriptomic characteristics, suggesting the similar heterogeneity in neurons and astrocytes of human and mouse spinal cords. In addition, we compared the expression profiles of Wnt5a in neurons and ROR2 in astrocytes, and observed that Wnt5a was expressed in homologous neuronal clusters (Suppl.…”

“…The snRNA-seq results for Wnt5a in neurons and ROR2 in astrocytes came from the deposited large datasets that published in bioRxiv 31, 32 . snRNA-seq was performed as described 31 .…”

Role of sodium leak channel (NALCN) in sensation and pain: an overview

“…Therefore, it will be interesting to determine the role of UNC80 and UNC79 in pain and sensation, which might also be novel targets for controlling pain. More importantly, although NALCN is also widely expressed in the human DRG and spinal cord Zhang et al, 2022), evidence that NALCN regulates pain in humans has not yet been found. Future studies are needed to explore whether NALCN is a key target for controlling human pain, which will spur drug development and facilitate successful clinical translation from rodent findings.…”

“…Notably, whether reduced NALCN activity in the DRG and/or spinal cord leads to abnormal biological functions, such as motor behaviors, needs to be validated in future studies. A recent study revealed that NALCN is also expressed in the glial cells of the DRG and spinal cord in both humans and rodents (Zhang et al, 2022). The role of NALCN in glial cells should also be determined, as the activities of glial cells are involved in pain sensation.…”