Intranasally delivered mesenchymal stromal cells decrease glial inflammation early in prion disease

Intranasally delivered mesenchymal stromal cells decrease glial inflammation early in prion disease

Mesenchymal stromal cells (MSCs) are an intriguing avenue for the treatment of neurological disorders due to their ability to migrate to sites of neuroinflammation and respond to paracrine signaling in those sites by secreting cytokines, growth factors, and other neuromodulators. We potentiated this...

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Published in:Frontiers in neuroscience Vol. 17; p. 1158408
Main Authors: Hay, Arielle J D, Latham, Amanda S, Mumford, Genova, Hines, Amelia D, Risen, Sydney, Gordon, Elizabeth, Siebenaler, Connor, Gilberto, Vincenzo S, Zabel, Mark D, Moreno, Julie A
Format: Journal Article
Language:English
Published: Switzerland Frontiers Research Foundation 12-05-2023
Frontiers Media S.A
Subjects:
Astrocytes
Body fat
Chemokines
Creutzfeldt-Jakob disease
Cytokines
Gliosis
Growth factors
Hippocampus
Infections
Inflammasomes
Inflammation
Laboratories
Mesenchymal stem cells
mesenchymal stromal cells
Microglia
Neurodegeneration
Neurodegenerative diseases
Neurological diseases
Neuromodulation
Neuroscience
NF-κB protein
Paracrine signalling
prion
Prion protein
Protein folding
Proteins
Pyrin protein
Stromal cells
Vacuoles
United States > US
Colorado
prion
cytokines
astrocytes
inflammation
microglia
mesenchymal stromal cells
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Summary:Mesenchymal stromal cells (MSCs) are an intriguing avenue for the treatment of neurological disorders due to their ability to migrate to sites of neuroinflammation and respond to paracrine signaling in those sites by secreting cytokines, growth factors, and other neuromodulators. We potentiated this ability by stimulating MSCs with inflammatory molecules, improving their migratory and secretory properties. We investigated the use of intranasally delivered adipose-derived MSCs (AdMSCs) in combating prion disease in a mouse model. Prion disease is a rare, lethal neurodegenerative disease that results from the misfolding and aggregation of the prion protein. Early signs of this disease include neuroinflammation, activation of microglia, and development of reactive astrocytes. Later stages of disease include development of vacuoles, neuronal loss, abundant aggregated prions, and astrogliosis. We demonstrate the ability of AdMSCs to upregulate anti-inflammatory genes and growth factors when stimulated with tumor necrosis factor alpha (TNFα) or prion-infected brain homogenates. We stimulated AdMSCs with TNFα and performed biweekly intranasal deliveries of AdMSCs on mice that had been intracranially inoculated with mouse-adapted prions. At early stages in disease, animals treated with AdMSCs showed decreased vacuolization throughout the brain. Expression of genes associated with Nuclear Factor-kappa B (NF-κB) and Nod-Like Receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling were decreased in the hippocampus. AdMSC treatment promoted a quiescent state in hippocampal microglia by inducing changes in both number and morphology. Animals that received AdMSCs showed a decrease in both overall and reactive astrocyte number, and morphological changes indicative of homeostatic astrocytes. Although this treatment did not prolong survival or rescue neurons, it demonstrates the benefits of MSCs in combatting neuroinflammation and astrogliosis.
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Edited by: Virawudh Soontornniyomkij, Mahidol University, Thailand
Reviewed by: Jack Harry Brelstaff, University of Cambridge, United Kingdom; Motohiro Horiuchi, Hokkaido University, Japan
ISSN:1662-4548
1662-453X
1662-453X
DOI:10.3389/fnins.2023.1158408