Validating a minipig model of reversible cerebral demyelination using human diagnostic modalities and electron microscopy
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Validating a minipig model of reversible cerebral demyelination using human diagnostic modalities and electron microscopy. / Ancău, Mihai; Tanti, Goutam Kumar; Butenschoen, Vicki Marie; Gempt, Jens; Yakushev, Igor; Nekolla, Stephan; Mühlau, Mark; Scheunemann, Christian; Heininger, Sebastian; Löwe, Benjamin; Löwe, Erik; Baer, Silke; Fischer, Johannes; Reiser, Judith; Ayachit, Sai S; Liesche-Starnecker, Friederike; Schlegel, Jürgen; Matiasek, Kaspar; Schifferer, Martina; Kirschke, Jan S; Misgeld, Thomas; Lueth, Tim; Hemmer, Bernhard.
In: EBIOMEDICINE, Vol. 100, 02.2024, p. 104982.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Validating a minipig model of reversible cerebral demyelination using human diagnostic modalities and electron microscopy
AU - Ancău, Mihai
AU - Tanti, Goutam Kumar
AU - Butenschoen, Vicki Marie
AU - Gempt, Jens
AU - Yakushev, Igor
AU - Nekolla, Stephan
AU - Mühlau, Mark
AU - Scheunemann, Christian
AU - Heininger, Sebastian
AU - Löwe, Benjamin
AU - Löwe, Erik
AU - Baer, Silke
AU - Fischer, Johannes
AU - Reiser, Judith
AU - Ayachit, Sai S
AU - Liesche-Starnecker, Friederike
AU - Schlegel, Jürgen
AU - Matiasek, Kaspar
AU - Schifferer, Martina
AU - Kirschke, Jan S
AU - Misgeld, Thomas
AU - Lueth, Tim
AU - Hemmer, Bernhard
N1 - Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.
PY - 2024/2
Y1 - 2024/2
N2 - BACKGROUND: Inflammatory demyelinating diseases of the central nervous system, such as multiple sclerosis, are significant sources of morbidity in young adults despite therapeutic advances. Current murine models of remyelination have limited applicability due to the low white matter content of their brains, which restricts the spatial resolution of diagnostic imaging. Large animal models might be more suitable but pose significant technological, ethical and logistical challenges.METHODS: We induced targeted cerebral demyelinating lesions by serially repeated injections of lysophosphatidylcholine in the minipig brain. Lesions were amenable to follow-up using the same clinical imaging modalities (3T magnetic resonance imaging, 11C-PIB positron emission tomography) and standard histopathology protocols as for human diagnostics (myelin, glia and neuronal cell markers), as well as electron microscopy (EM), to compare against biopsy data from two patients.FINDINGS: We demonstrate controlled, clinically unapparent, reversible and multimodally trackable brain white matter demyelination in a large animal model. De-/remyelination dynamics were slower than reported for rodent models and paralleled by a degree of secondary axonal pathology. Regression modelling of ultrastructural parameters (g-ratio, axon thickness) predicted EM features of cerebral de- and remyelination in human data.INTERPRETATION: We validated our minipig model of demyelinating brain diseases by employing human diagnostic tools and comparing it with biopsy data from patients with cerebral demyelination.FUNDING: This work was supported by the DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198) and TRR 274/1 2020, 408885537 (projects B03 and Z01).
AB - BACKGROUND: Inflammatory demyelinating diseases of the central nervous system, such as multiple sclerosis, are significant sources of morbidity in young adults despite therapeutic advances. Current murine models of remyelination have limited applicability due to the low white matter content of their brains, which restricts the spatial resolution of diagnostic imaging. Large animal models might be more suitable but pose significant technological, ethical and logistical challenges.METHODS: We induced targeted cerebral demyelinating lesions by serially repeated injections of lysophosphatidylcholine in the minipig brain. Lesions were amenable to follow-up using the same clinical imaging modalities (3T magnetic resonance imaging, 11C-PIB positron emission tomography) and standard histopathology protocols as for human diagnostics (myelin, glia and neuronal cell markers), as well as electron microscopy (EM), to compare against biopsy data from two patients.FINDINGS: We demonstrate controlled, clinically unapparent, reversible and multimodally trackable brain white matter demyelination in a large animal model. De-/remyelination dynamics were slower than reported for rodent models and paralleled by a degree of secondary axonal pathology. Regression modelling of ultrastructural parameters (g-ratio, axon thickness) predicted EM features of cerebral de- and remyelination in human data.INTERPRETATION: We validated our minipig model of demyelinating brain diseases by employing human diagnostic tools and comparing it with biopsy data from patients with cerebral demyelination.FUNDING: This work was supported by the DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198) and TRR 274/1 2020, 408885537 (projects B03 and Z01).
KW - Swine
KW - Humans
KW - Animals
KW - Mice
KW - Demyelinating Diseases/diagnostic imaging
KW - Cuprizone
KW - Swine, Miniature
KW - Multiple Sclerosis/diagnostic imaging
KW - Myelin Sheath/pathology
KW - White Matter/pathology
KW - Microscopy, Electron
KW - Disease Models, Animal
U2 - 10.1016/j.ebiom.2024.104982
DO - 10.1016/j.ebiom.2024.104982
M3 - SCORING: Journal article
C2 - 38306899
VL - 100
SP - 104982
JO - EBIOMEDICINE
JF - EBIOMEDICINE
SN - 2352-3964
ER -
