Chronic demyelination of rabbit lesions is attributable to failed oligodendrocyte progenitor cell repopulation

Abstract

The failure of remyelination in the human CNS contributes to axonal injury and disease progression in multiple sclerosis (MS). In contrast to regions of chronic demyelination in the human brain, remyelination in murine models is preceded by abundant oligodendrocyte progenitor cell (OPC) repopulation, such that OPC density within regions of demyelination far exceeds that of normal white matter (NWM). As such, we hypothesized that efficient OPC repopulation was a prerequisite of successful remyelination, and that increased lesion volume may contribute to the failure of OPC repopulation in human brain. In this study, we characterized the pattern of OPC activation and proliferation following induction of lysolecithin-induced chronic demyelination in adult rabbits. The density of OPCs never exceeded that of NWM and oligodendrocyte density did not recover even at 6 months post-injection. Rabbit OPC recruitment in large lesions was further characterized by chronic Sox2 expression in OPCs located in the lesion core and upregulation of quiescence-associated Prrx1 mRNA at the lesion border. Surprisingly, when small rabbit lesions of equivalent size to mouse were induced, they too exhibited reduced OPC repopulation. However, small lesions were distinct from large lesions as they displayed an almost complete lack of OPC proliferation following demyelination. These differences in the response to demyelination suggest that both volume dependent and species-specific mechanisms are critical in the regulation of OPC proliferation and lesion repopulation and suggest that alternate models will be necessary to fully understand the mechanisms that contribute to failed remyelination in MS.

Multimodally trackable and clinically translatable platform for modelling human demyelinating brain diseases by temporally dispersed chemically induced lesions in the pig brain

“…Interestingly, we found a certain degree of putatively secondary axonal pathology (around 15% of axons) inherent to the subacute treatment group, which deviates from the paradigm of a pure demyelinating noninflammatory LPC-induced lesion in rodent studies and more closely resembles results from rabbit and macaque studies (15,16). This is to our knowledge the first description of subacute LPC-induced and altogether demyelinating lesion dynamics in the pig brain, since a previous study has focused solely on the acute stage (14).…”

“…The de-/remyelination dynamics observed in MiniSWINE differed to a certain extent from those described in rodent models (17,55). The latency to remyelination took intermediate values between the 2-3 weeks described in rodent studies(17, 49) and the incomplete remyelination even 6 weeks post-induction in other large animal models (15,16). This is in line with recent reports describing not only the lesion volume, but also speciesinherent differences in OPC infiltration of the lesion, proliferation and differentiation as the main factors determining the remyelination status (16).…”

“…Neurological diseases that have already been modelled in the minipig subspecies include Parkinson's disease, Huntington's disease and experimental autoimmune encephalomyelitis (EAE) (11,12) , (13). Also, LPC and ethidium bromide-induced demyelination have been proven to lead to signs compatible with demyelination in the cerebral WM of larger, domestic landrace pigs (14) and to reliable demyelination of the rabbit cerebral WM (15) and of the non-human primate (macaque) optic nerve (16). However, there is considerable heterogeneity in the reported timelines of myelin-related events across species, ranging from initial reports of relatively quick demyelination (i.e., ensuing within 30 min and reaching full extent within 4 days(17)) and complete remyelination without evidence of substantial axonal damage within 5-6 weeks in the case of rodent models (18)(19)(20), to persistent demyelination conducive of axonal degeneration even 8 weeks after LPC injection in the macaque optic nerve.…”

Control of OPC proliferation and repopulation by the intellectual disability gene PAK1 under homeostatic and demyelinating conditions

“…OPCs become progressively depleted in chronic lesions where limited remyelination occurs in preclinical rodent models of demyelination (Mason et al, 2004). The "OPC depletion" concept is further supported by recent data demonstrating that impaired OPC repopulation is the major reason preventing successful myelin repair in larger animal models of demyelination (Cooper et al, 2023). Although extensive effort has been dedicated to defining how OPC terminal differentiation is regulated (Emery, 2010), it is equally important and necessary to study mechanisms underlying OPC proliferation and repopulation given OPC inadequacy or depletion in demyelinating lesions.…”

Validating a minipig model of reversible cerebral demyelination using human diagnostic modalities and electron microscopy

“… 5 , 14 Such control can minimise neurological deficits and ethical constraints for CNS demyelinating disease modelling—including in pigs. Also, LPC and ethidium bromide-induced demyelination have been proven to lead to signs compatible with demyelination in the cerebral WM of large, domestic landrace pigs 15 and demonstrated demyelination in the rabbit cerebral WM 16 and the non-human primate (macaque) optic nerve. 17 However, there is considerable heterogeneity in the reported timelines of myelin-related events across species, ranging from reports of relatively quick demyelination (i.e., ensuing within 30 min and reaching full extent within four days 18 and complete remyelination without evidence of substantial axonal damage within 5–6 weeks in the case of rodent models), 19 , 20 , 21 to persistent demyelination conducive of axonal degeneration even eight weeks after LPC injection in the macaque optic nerve.…”