Hypothermia combined with extracellular vesicles from clonally expanded immortalized mesenchymal stromal cells improves neurodevelopmental impairment in neonatal hypoxic-ischemic brain injury.
Extracellular vesicles
Hypothermia
Long-term neurodevelopmental deficits
Mesenchymal stem/stromal cells
Neonatal encephalopathy
Neonatal hypoxia–ischemia
Neuroinflammation
Neuroregeneration
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
27 Nov 2023
27 Nov 2023
Historique:
received:
08
09
2023
accepted:
16
11
2023
medline:
29
11
2023
pubmed:
28
11
2023
entrez:
28
11
2023
Statut:
epublish
Résumé
Neonatal encephalopathy following hypoxia-ischemia (HI) is a leading cause of childhood death and morbidity. Hypothermia (HT), the only available but obligatory therapy is limited due to a short therapeutic window and limited efficacy. An adjuvant therapy overcoming limitations of HT is still missing. Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) have shown promising therapeutic effects in various brain injury models. Challenges associated with MSCs' heterogeneity and senescence can be mitigated by the use of EVs from clonally expanded immortalized MSCs (ciMSCs). In the present study, we hypothesized that intranasal ciMSC-EV delivery overcomes limitations of HT. Nine-day-old C57BL/6 mice were exposed to HI by occlusion of the right common carotid artery followed by 1 h hypoxia (10% oxygen). HT was initiated immediately after insult for 4 h. Control animals were kept at physiological body core temperatures. ciMSC-EVs or vehicle were administered intranasally 1, 3 and 5 days post HI/HT. Neuronal cell loss, inflammatory and regenerative responses were assessed via immunohistochemistry, western blot and real-time PCR 7 days after insult. Long-term neurodevelopmental outcome was evaluated by analyses of cognitive function, activity and anxiety-related behavior 5 weeks after HI/HT. In contrast to HT monotherapy, the additional intranasal therapy with ciMSC-EVs prevented HI-induced cognitive deficits, hyperactivity and alterations of anxiety-related behavior at adolescence. This was preceded by reduction of striatal neuronal loss, decreased endothelial, microglia and astrocyte activation; reduced expression of pro-inflammatory and increased expression of anti-inflammatory cytokines. Furthermore, the combination of HT with intranasal ciMSC-EV delivery promoted regenerative and neurodevelopmental processes, including endothelial proliferation, neurotrophic growth factor expression and oligodendrocyte maturation, which were not altered by HT monotherapy. Intranasal delivery of ciMSC-EVs represents a novel adjunct therapy, overcoming limitations of acute HT thereby offering new possibilities for improving long-term outcomes in neonates with HI-induced brain injury.
Sections du résumé
BACKGROUND
BACKGROUND
Neonatal encephalopathy following hypoxia-ischemia (HI) is a leading cause of childhood death and morbidity. Hypothermia (HT), the only available but obligatory therapy is limited due to a short therapeutic window and limited efficacy. An adjuvant therapy overcoming limitations of HT is still missing. Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) have shown promising therapeutic effects in various brain injury models. Challenges associated with MSCs' heterogeneity and senescence can be mitigated by the use of EVs from clonally expanded immortalized MSCs (ciMSCs). In the present study, we hypothesized that intranasal ciMSC-EV delivery overcomes limitations of HT.
METHODS
METHODS
Nine-day-old C57BL/6 mice were exposed to HI by occlusion of the right common carotid artery followed by 1 h hypoxia (10% oxygen). HT was initiated immediately after insult for 4 h. Control animals were kept at physiological body core temperatures. ciMSC-EVs or vehicle were administered intranasally 1, 3 and 5 days post HI/HT. Neuronal cell loss, inflammatory and regenerative responses were assessed via immunohistochemistry, western blot and real-time PCR 7 days after insult. Long-term neurodevelopmental outcome was evaluated by analyses of cognitive function, activity and anxiety-related behavior 5 weeks after HI/HT.
RESULTS
RESULTS
In contrast to HT monotherapy, the additional intranasal therapy with ciMSC-EVs prevented HI-induced cognitive deficits, hyperactivity and alterations of anxiety-related behavior at adolescence. This was preceded by reduction of striatal neuronal loss, decreased endothelial, microglia and astrocyte activation; reduced expression of pro-inflammatory and increased expression of anti-inflammatory cytokines. Furthermore, the combination of HT with intranasal ciMSC-EV delivery promoted regenerative and neurodevelopmental processes, including endothelial proliferation, neurotrophic growth factor expression and oligodendrocyte maturation, which were not altered by HT monotherapy.
CONCLUSION
CONCLUSIONS
Intranasal delivery of ciMSC-EVs represents a novel adjunct therapy, overcoming limitations of acute HT thereby offering new possibilities for improving long-term outcomes in neonates with HI-induced brain injury.
Identifiants
pubmed: 38012640
doi: 10.1186/s12974-023-02961-0
pii: 10.1186/s12974-023-02961-0
pmc: PMC10680187
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
280Subventions
Organisme : European Society for Paediatric Research
ID : RGP2022-YISUG-02/04
Organisme : Horizon 2020
ID : 874721, PREMSTEM
Organisme : European Regional Development Fund
ID : 2014-2020
Organisme : ERA-NET EuroTransBio 11 EVTrust
ID : 031B0332B
Organisme : Else Kröner-Fresenius-Stiftung
ID : 2018_A113
Informations de copyright
© 2023. The Author(s).
Références
Cell Transplant. 2018 Sep;27(9):1328-1339
pubmed: 29692197
Front Physiol. 2019 Mar 19;10:282
pubmed: 30941062
PLoS One. 2015 Mar 16;10(3):e0118889
pubmed: 25774892
J Perinatol. 2009 Jun;29(6):438-43
pubmed: 19242485
Stem Cell Res Ther. 2019 Mar 21;10(1):105
pubmed: 30898154
Transl Stroke Res. 2013 Apr;4(2):189-200
pubmed: 23926451
Lancet. 2010 Jun 5;375(9730):1969-87
pubmed: 20466419
J Child Neurol. 2019 Sep;34(10):556-566
pubmed: 31070085
Brain Inj. 2019;33(7):894-898
pubmed: 30924691
Clin Exp Pediatr. 2021 Dec;64(12):608-618
pubmed: 34044480
Sci Rep. 2020 Jul 23;10(1):12367
pubmed: 32704153
Cold Spring Harb Perspect Biol. 2015 Aug 03;7(8):a021691
pubmed: 26238359
Children (Basel). 2021 Nov 22;8(11):
pubmed: 34828791
Sci Rep. 2016 Apr 28;6:25178
pubmed: 27121655
Brain Sci. 2020 Dec 16;10(12):
pubmed: 33339156
JAMA Netw Open. 2023 May 1;6(5):e2312152
pubmed: 37155168
N Engl J Med. 2022 Jul 14;387(2):148-159
pubmed: 35830641
Stem Cells Transl Med. 2016 Jun;5(6):754-63
pubmed: 27160705
J Extracell Vesicles. 2018 Oct 17;7(1):1528109
pubmed: 30357008
Pharmacol Rev. 2023 Sep;75(5):1043-1061
pubmed: 37280097
Neurosci Biobehav Rev. 2023 Oct;153:105374
pubmed: 37634555
Front Cell Neurosci. 2020 Dec 10;14:601176
pubmed: 33362471
Stroke. 2020 Jun;51(6):1825-1834
pubmed: 32312217
Nat Protoc. 2007;2(2):322-8
pubmed: 17406592
Pediatr Res. 2012 Jul;72(1):63-9
pubmed: 22447318
Pediatr Res. 1998 Jun;43(6):738-45
pubmed: 9621982
Stem Cell Reports. 2014 Mar 27;2(4):440-8
pubmed: 24749069
Leukemia. 2014 Apr;28(4):970-3
pubmed: 24445866
Dev Med Child Neurol. 2015 May;57(5):441-8
pubmed: 25492527
Int J Mol Sci. 2022 Dec 23;24(1):
pubmed: 36613698
Dev Neurosci. 2003 Mar-Aug;25(2-4):116-26
pubmed: 12966210
J Neuropathol Exp Neurol. 2021 Jan 20;80(2):182-198
pubmed: 33212486
Pediatr Res. 2023 Jun;93(7):1819-1827
pubmed: 36195634
Lancet Glob Health. 2021 Sep;9(9):e1273-e1285
pubmed: 34358491
Atherosclerosis. 2023 Nov;384:117278
pubmed: 37770334
J Neuroinflammation. 2021 Nov 13;18(1):266
pubmed: 34772426
Behav Brain Res. 1997 Jun;86(1):105-12
pubmed: 9105588
Acta Neuropathol. 2013 Mar;125(3):395-412
pubmed: 23269317
Genes Brain Behav. 2008 Jun;7(4):496-505
pubmed: 18182070
Physiol Rev. 2014 Oct;94(4):1077-98
pubmed: 25287860
Mech Ageing Dev. 2021 Jun;196:111473
pubmed: 33766745
Psychopharmacology (Berl). 1994 Mar;114(2):288-96
pubmed: 7838922
Neuroscience. 2003;118(4):1023-32
pubmed: 12732247
Front Neurol. 2020 May 27;11:449
pubmed: 32536903
Stroke. 2022 Feb;53(2):381-390
pubmed: 34983246
Cytotherapy. 2023 Aug;25(8):821-836
pubmed: 37055321
Cytotherapy. 2023 Feb;25(2):138-147
pubmed: 36244910
N Engl J Med. 2014 Jul 10;371(2):140-9
pubmed: 25006720
Semin Fetal Neonatal Med. 2021 Oct;26(5):101274
pubmed: 34330680
J Comp Physiol Psychol. 1979 Feb;93(1):74-104
pubmed: 221551
Brain Behav Immun. 2018 May;70:118-130
pubmed: 29454023
Cochrane Database Syst Rev. 2003;(4):CD003311
pubmed: 14583966
Psicothema. 2006 Feb;18(1):100-4
pubmed: 17296016
Neurosci Biobehav Rev. 2005 Jan;28(8):811-25
pubmed: 15642623
CNS Neurosci Ther. 2018 Dec;24(12):1100-1114
pubmed: 30350341
Sci Rep. 2020 Jul 2;10(1):10833
pubmed: 32616806
Acta Paediatr. 2021 Oct;110(10):2756-2765
pubmed: 34160861
Cytotherapy. 2023 Aug;25(8):847-857
pubmed: 37097266
J Neuroinflammation. 2015 Feb 20;12:32
pubmed: 25889641
Arch Dis Child Fetal Neonatal Ed. 2020 Jan;105(1):8-13
pubmed: 31036702
J Pediatr. 2015 Nov;167(5):987-93.e3
pubmed: 26387012
Semin Fetal Neonatal Med. 2021 Oct;26(5):101256
pubmed: 34154945
Stroke. 2019 Jun;50(6):1548-1557
pubmed: 31084324
J Neuroinflammation. 2022 Jun 11;19(1):139
pubmed: 35690757
J Extracell Vesicles. 2018 Nov 23;7(1):1535750
pubmed: 30637094
Neurosci Res. 2016 Jul;108:24-33
pubmed: 26851769
Front Mol Neurosci. 2017 Apr 11;10:106
pubmed: 28442994
J Clin Med. 2019 Jan 24;8(2):
pubmed: 30682787
Pharmaceutics. 2023 Feb 27;15(3):
pubmed: 36986649
Brain Res Mol Brain Res. 1998 Jun 1;57(1):1-9
pubmed: 9630473
N Engl J Med. 2012 May 31;366(22):2085-92
pubmed: 22646631
Pediatr Res. 2007 Dec;62(6):646-51
pubmed: 17957163
Brain Behav Immun. 2017 Feb;60:220-232
pubmed: 27847282
Stem Cell Res. 2020 Jul;46:101866
pubmed: 32563975
Cells. 2019 Aug 08;8(8):
pubmed: 31398924
Exp Neurol. 2016 Sep;283(Pt A):264-75
pubmed: 27349408
Curr Protoc Stem Cell Biol. 2020 Dec;55(1):e128
pubmed: 32956560
Brain Behav Immun. 2021 Feb;92:234-244
pubmed: 33333168
Pharmaceutics. 2022 Mar 12;14(3):
pubmed: 35336004
Pharmacol Biochem Behav. 1994 Sep;49(1):171-6
pubmed: 7816869
Brain Dev. 1997 Jul;19(5):326-38
pubmed: 9253485
Inflamm Regen. 2023 Apr 17;43(1):24
pubmed: 37069694
Int J Mol Sci. 2017 Dec 26;19(1):
pubmed: 29278365
J Cereb Blood Flow Metab. 2007 Feb;27(2):282-92
pubmed: 16736041