Dorsal Root Injury—A Model for Exploring Pathophysiology and Therapeutic Strategies in Spinal Cord Injury

Aldskogius, Håkan; Kozlova, Elena N.

doi:10.3390/cells10092185

Cited by 7 publications

(5 citation statements)

References 167 publications

(199 reference statements)

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“…In preclinical models, the 'neuronal loss' phenotype has, to our knowledge, never been observed. SGC are activated in response to peripheral postganglionic and preganglionic injury, as well as dorsal or ventral root avulsion (17,42,43). In human tissue, we did not detect any signs of gliosis using typical SGC markers like GS, and FABP7.…”

Section: Discussionmentioning

confidence: 55%

Molecular and cellular processes of deafferentation after plexus injury in human dorsal root ganglia

Rittner,

Sodmann,

Degenbeck

et al. 2024

Preprint

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Plexus injury results in lifelong suffering from flaccid paralysis, sensory loss, and intractable pain. For this clinical problem, regenerative medicine concepts set high expectations. However, it is completely unknown how dorsal root ganglia (DRG) are affected by accidental deafferentation. Here, we investigated human DRG in a clinically characterized cohort of patients with plexus injury. Avulsed DRG from 13 patients were collected during reconstructive nerve surgery. DRG were analyzed using large-scale microscopy, deep learning-based bioimage analysis, and RNA fragment sequencing of histopathological slices. In about half of the patients, we found a complete loss of DRG units consisting of neurons, satellite glial cells (SGC), and macrophages. The DRG cells were replaced by mesodermal/connective tissue. In the other half of the patients, the cellular units were well preserved and we found no gliosis and no significant neuronal loss. Furthermore, the expression of subtype-specific sensory neuron marker genes was preserved. However, downregulation of neuronal attributes associated with ion transport, synapses, and neuronal projection indicated a dormant neuronal phenotype. Injured DRG showed signs of ongoing inflammation and connective tissue remodeling. Patients with ‘neuronal preservation’ had less pain than patients with ‘neuronal loss’. Arm function improved after the nerve reconstruction, but the pain phenotype did not. With this study, we call for early intervention after injury to protect the DRG from complete cell loss. Pain patients may benefit from anti-inflammatory therapy. Future regenerative medicine concepts will need at least two translational directions: reafferentation of existing DRG units or replacement of the entire DRG.

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Section: Discussionmentioning

confidence: 55%

Molecular and cellular processes of deafferentation after plexus injury in human dorsal root ganglia

Rittner,

Sodmann,

Degenbeck

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…SGC are activated in response to peripheral postganglionic and preganglionic injury as well as dorsal or ventral root avulsion. 16,42,43 In human tissue, we did not detect any signs of gliosis using typical SGC markers like GS, and FABP7. GS/GLUL is found in 50 % of rodent and 10 % of human SGCboth on mRNA and protein.…”

Section: Discussionmentioning

confidence: 64%

Human dorsal root ganglia after plexus injury: either preservation or loss of the multicellular unit

Schulte

Degenbeck

Aue

et al. 2023

Preprint

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Objective: Plexus injury results in lifelong suffering of flaccid paralysis, sensory loss, and intractable pain. For this clinical problem, regenerative medicine concepts, such as cell replacement for restoring dorsal root ganglion (DRG) function, set high expectations. However, it is completely unclear which DRG cell types are affected by plexus injury. Methods: We investigated the cellular composition of human DRG in a clinically characterized cohort of patients with plexus injury. Avulsed DRG of 13 patients were collected during reconstructive nerve surgery. Then, we analyzed the cellular composition of the DRG with a human-adapted objective deep learning-based analysis of large-scale microscopy images. Results: Surprisingly, in about half of the patients, the injury-affected DRG no longer contained DRG cells. The complete entity of neurons, satellite glial cells, and microglia was lost and replaced by mesodermal/connective tissue. In the other half of patients, the cellular entity of the DRG was well preserved. We found no loss of neurons, no gliosis, and macrophages close to single sensory neuron/satellite glial cell entities. Patients with "neuronal preservation" had less pain than patients with "neuronal loss". Interpretation: The findings classify plexus injury patients in two categories: type I (neuronal preservation) and type II (neuronal loss). We call for early, post-accidental interventions to protect the entire DRG and improved MRI diagnostics to detect "neuronal loss". Regenerative medicine to restore DRG function will need at least two translational directions: reafferentation of existing DRG units for type I injuries; or replacement of the entire DRG structure for type II patients.

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“…When considering a holistic approach to the bSCI, it is likely that the propagation of the blast wave also leaves other critical units of the nervous system, such as the spinal nerves, susceptible to damage. When spinal root avulsions occur, they can lead to loss of sensory and autonomic function or paralysis, but most commonly leads to neuropathic pain ( Aldskogius and Kozlova, 2021 ). One study investigated the relationship between the severity of nerve root deformation and the extent of microglial and astrocyte response.…”

Section: Discussionmentioning

confidence: 99%

A closed-body preclinical model to investigate blast-induced spinal cord injury

Norris,

Weatherbee,

Murphy

et al. 2023

Front. Mol. Neurosci.

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Blast-induced spinal cord injuries (bSCI) are common and account for 75% of all combat-related spinal trauma. It remains unclear how the rapid change in pressure contributes to pathological outcomes resulting from these complex injuries. Further research is necessary to aid in specialized treatments for those affected. The purpose of this study was to develop a preclinical injury model to investigate the behavior and pathophysiology of blast exposure to the spine, which will bring further insight into outcomes and treatment decisions for complex spinal cord injuries (SCI). An Advanced Blast Simulator was used to study how blast exposure affects the spinal cord in a non-invasive manner. A custom fixture was designed to support the animal in a position that protects the vital organs while exposing the thoracolumbar region of the spine to the blast wave. The Tarlov Scale and Open Field Test (OFT) were used to detect changes in locomotion or anxiety, respectively, 72 h following bSCI. Spinal cords were then harvested and histological staining was performed to investigate markers of traumatic axonal injury (β-APP, NF-L) and neuroinflammation (GFAP, Iba1, S100β). Analysis of the blast dynamics demonstrated that this closed-body model for bSCI was found to be highly repeatable, administering consistent pressure pulses following a Friedlander waveform. There were no significant changes in acute behavior; however, expression of β-APP, Iba1, and GFAP significantly increased in the spinal cord following blast exposure (p < 0.05). Additional measures of cell count and area of positive signal provided evidence of increased inflammation and gliosis in the spinal cord at 72 h after blast injury. These findings indicated that pathophysiological responses from the blast alone are detectable, likely contributing to the combined effects. This novel injury model also demonstrated applications as a closed-body SCI model for neuroinflammation enhancing relevance of the preclinical model. Further investigation is necessary to assess the longitudinal pathological outcomes, combined effects from complex injuries, and minimally invasive treatment approaches.

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Dorsal Root Injury—A Model for Exploring Pathophysiology and Therapeutic Strategies in Spinal Cord Injury

Cited by 7 publications

References 167 publications

Molecular and cellular processes of deafferentation after plexus injury in human dorsal root ganglia

Molecular and cellular processes of deafferentation after plexus injury in human dorsal root ganglia

Human dorsal root ganglia after plexus injury: either preservation or loss of the multicellular unit

A closed-body preclinical model to investigate blast-induced spinal cord injury

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