TY - JOUR
T1 - Intranasally Administered MSC-Derived Extracellular Vesicles Reverse Cisplatin-Induced Cognitive Impairment
AU - Milutinovic, Bojana
AU - Mahalingam, Rajasekaran
AU - Mendt, Mayela
AU - Arroyo, Luis
AU - Seua, Alexandre
AU - Dharmaraj, Shruti
AU - Shpall, Elizabeth
AU - Heijnen, Cobi J.
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/7
Y1 - 2023/7
N2 - Neurotoxic side effects of chemotherapy include deficits in attention, memory, and executive functioning. Currently, there are no FDA-approved therapies. In mice, cisplatin causes long-term cognitive deficits, white matter damage, mitochondrial dysfunction, and loss of synaptic integrity. We hypothesized that MSC-derived small extracellular vesicles (sEVs) could restore cisplatin-induced cognitive impairments and brain damage. Animals were injected with cisplatin intraperitoneally and treated with MSC-derived sEVs intranasally 48 and 96 h after the last cisplatin injection. The puzzle box test (PBT) and the novel object place recognition test (NOPRT) were used to determine cognitive deficits. Synaptosomal mitochondrial morphology was analyzed by transmission electron microscopy. Immunohistochemistry using antibodies against synaptophysin and PSD95 was applied to assess synaptic loss. Black-Gold II staining was used to quantify white matter integrity. Our data show that sEVs enter the brain in 30 min and reverse the cisplatin-induced deficits in executive functioning and working and spatial memory. Abnormalities in mitochondrial morphology, loss of white matter, and synaptic integrity in the hippocampus were restored as well. Transcriptomic analysis revealed upregulation of regenerative functions after treatment with sEVs, pointing to a possible role of axonal guidance signaling, netrin signaling, and Wnt/Ca2+ signaling in recovery. Our data suggest that intranasal sEV treatment could become a novel therapeutic approach for the treatment of chemobrain.
AB - Neurotoxic side effects of chemotherapy include deficits in attention, memory, and executive functioning. Currently, there are no FDA-approved therapies. In mice, cisplatin causes long-term cognitive deficits, white matter damage, mitochondrial dysfunction, and loss of synaptic integrity. We hypothesized that MSC-derived small extracellular vesicles (sEVs) could restore cisplatin-induced cognitive impairments and brain damage. Animals were injected with cisplatin intraperitoneally and treated with MSC-derived sEVs intranasally 48 and 96 h after the last cisplatin injection. The puzzle box test (PBT) and the novel object place recognition test (NOPRT) were used to determine cognitive deficits. Synaptosomal mitochondrial morphology was analyzed by transmission electron microscopy. Immunohistochemistry using antibodies against synaptophysin and PSD95 was applied to assess synaptic loss. Black-Gold II staining was used to quantify white matter integrity. Our data show that sEVs enter the brain in 30 min and reverse the cisplatin-induced deficits in executive functioning and working and spatial memory. Abnormalities in mitochondrial morphology, loss of white matter, and synaptic integrity in the hippocampus were restored as well. Transcriptomic analysis revealed upregulation of regenerative functions after treatment with sEVs, pointing to a possible role of axonal guidance signaling, netrin signaling, and Wnt/Ca2+ signaling in recovery. Our data suggest that intranasal sEV treatment could become a novel therapeutic approach for the treatment of chemobrain.
KW - chemobrain
KW - cognition
KW - extracellular vesicle
KW - mitochondria
KW - MSC
KW - synaptic integrity
KW - white matter
UR - http://www.scopus.com/inward/record.url?scp=85165981706&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85165981706&partnerID=8YFLogxK
U2 - 10.3390/ijms241411862
DO - 10.3390/ijms241411862
M3 - Article
C2 - 37511623
AN - SCOPUS:85165981706
SN - 1661-6596
VL - 24
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 14
M1 - 11862
ER -