Acute Systemic White Blood Cell Changes following Degenerative Cervical Myelopathy (DCM) in a Mouse Model

Abstract

Degenerative cervical myelopathy (DCM) is caused by age-related degeneration of the cervical spine, causing chronic spinal cord compression and inflammation. The aim of this study was to assess whether the natural progression of DCM is accompanied by hematological changes in the white blood cell composition. If so, these changes can be used for diagnosis complementing established imaging approaches and for the development of treatment strategies, since peripheral immunity affects the progression of DCM. Gradual compression of the spinal cord was induced in C57B/L mice at the C5-6 level. The composition of circulating white blood cells was analyzed longitudinally at four time points after induction of DCM using flow cytometry. At 12 weeks, serum cytokine levels were measured using a Luminex x-MAP assay. Neurological impairment in the mouse model was also assessed using the ladder walk test and CatWalk. Stepping function (* p < 0.05) and overground locomotion (*** p < 0.001) were impaired in the DCM group. Importantly, circulating monocytes and T cells were affected primarily at 3 weeks following DCM. T cells were two-fold lower in the DCM group (*** p < 0.0006), whereas monocytes were four-fold increased (*** p < 0.0006) in the DCM compared with the sham group. Our data suggest that changes in white blood cell populations are modest, which is unique to other spinal cord pathologies, and precede the development of neurobehavioral symptoms.

Impaired communication at the neuromotor axis during Degenerative Cervical Myelopathy

“…Polymer implantation in C5-6 segments causes progressive stenosis at the central canal, triggering changes in the vasculature and the immune response, among other phenotypes ( Karadimas et al, 2013 ; Vidal et al, 2017 ; Ulndreaj et al, 2022 ). We examined in detail the SC histology focusing on motoneurons as a read-out of motor disorders ( Wilson et al, 2023 ; Figure 2A ).…”

“…In contrast, the biopolymer polyurethane elastomer Aquaprene C works like an expandable material made of water-absorbing polyurethane elastomer that increases its volume more than 200% in 24 h inducing acute damage, different from the progression of the human pathology ( Kim et al, 2004 ; Ijima et al, 2017 ). Here, we used a synthetic aromatic polyether polymer that offers clinical advantages to model DCM in mice, such as the ability to nucleate the precipitation of phosphate anions emulating the progressive osteoid formation in accessible vertebral segments of implantation, resembling histopathological and behavioral features of clinical presentation ( Klironomos et al, 2011 ; Karadimas et al, 2013 ; Desimone et al, 2021 ; Laliberte et al, 2021 ; Ulndreaj et al, 2022 ). Using this model, we presented a systematic analysis of the pathobiology observed, including loss of motoneurons, motor impairment, and neuromuscular degeneration, as well as muscle loss and wasting ( Otsu, 1979 ; Karadimas et al, 2013 ; Badhiwala et al, 2020 ).…”

“…We have focused our study on this sex because the incidence of DCM is greater in men versus women and because the male DCM mouse model has shown the highest dysbiosis compared with the female DCM mouse model ( Nouri et al, 2022 ; Farkas et al, 2023 ). The DCM mouse model was generated using an aromatic polyether polymer as previously described ( Karadimas et al, 2013 ; Ulndreaj et al, 2022 ). In brief, the aromatic polyether acts as a scaffold for inorganic salts that progressively precipitate, increasing the stenosis of the central canal on the cervical spinal cord segment.…”

“…Animals were divided into two groups: DCM ( n = 4) and sham ( n = 3). A sham was included for comparison, in which the polyether polymer was inserted for 30 s and then removed to simulate and control for any potential minor trauma associated with material insertion ( Karadimas et al, 2013 ; Vidal et al, 2017 ; Ulndreaj et al, 2022 ). All mice were examined 24 h after surgery for signs of neurological deficits ( Vidal et al, 2017 ), which resulted in the exclusion of the animal from the study if positive signs were observed (i.e., reduced ankle movement and plantar stepping and upper and/or lower limb stiffness and/or weakness).…”

“…Early narrowing of the spinal canal leads to the sensory and motor hallmark symptoms that include gait and balance abnormalities, leg weakness or stiffness, arm pain, loss of manual dexterity, and abnormal sensations in the hands, as well as gastrointestinal dysfunction ( McCormack and Weinstein, 1996 ; Nouri et al, 2015 , 2020 ). At a different level, chronic compression of the spinal cord triggers microvasculature disruption, reducing the number of endothelial cells, increasing neuronal and oligodendroglial cell apoptosis, and promoting axonal degeneration of the proximal corticospinal segment to the compression site, as well as increasing neuroinflammation ( Yu et al, 2011 ; Karadimas et al, 2015 ; Jiang et al, 2017 ; Vidal et al, 2017 ; Ulndreaj et al, 2022 ).…”