Extracellular vesicles derived from Wharton’s jelly mesenchymal stem cells prevent and resolve programmed cell death mediated by perinatal hypoxia-ischemia in neuronal cells

Jörger Messerli, Marianne; Oppliger, Byron; Spinelli, Marialuigia; Thomi, Gierin Florence; Di Salvo, Ivana; Schneider, Philipp; Schoeberlein, Andreina (2018). Extracellular vesicles derived from Wharton’s jelly mesenchymal stem cells prevent and resolve programmed cell death mediated by perinatal hypoxia-ischemia in neuronal cells. Cell transplantation, 27(1), pp. 168-180. Cognizant Communication Corporation 10.1177/0963689717738256

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Hypoxic-ischemic (HI) insult in the perinatal phase harbours a high risk of encephalopathy in the neonate. Brain cells undergo apoptosis, initiating neurodegeneration. So far therapeutic approaches such as cooling remain limited. Transplantation of mesenchymal stem cells (MSC) exhibits therapeutic success despite the short-time survival in the host brain, providing strong evidence that their beneficial effects are largely based on secreted factors, including extracellular vesicles (EV). The aim of this study was to investigate the effects of human Wharton’s jelly MSC (hWJ-MSC)-derived EV on neuroprotection and – regeneration, using an in vitro model of oxygen-glucose-deprivation/reoxygenation (OGD/R) mimicking HI injury in the mouse neuroblastoma cell line neuro2a (N2a). hWJ-MSC-derived EV were isolated from cell culture supernatants by multistep centrifugation and identified by endosomal marker expression and electron microscopy. OGD/R significantly increased DNA fragmentation and Caspase 3 (Casp3) transcription in N2a cells relative to undamaged cells. OGD/R-mediated DNA fragmentation and Casp3 expression could be prevented as well as resolved by the addition of hWJ-MSC-derived EV before and after OGD, respectively. hWJMSC-derived EV also tended to increase the phosphorylation of the B cell lymphoma 2 (Bcl2) family member Bcl-2-Antagonist of Cell Death (BAD) in N2a cells, when added prior or post OGD, thereby inactivating the pro-apoptotic function of BAD. Fluorescence confocal microscopy revealed the close localization of hWJ-MSC-derived EV to the nuclei of N2a cells. Furthermore, EV released their RNA content into the cells. The expression levels of the microRNAs (miR) let-7a and let-7e, known regulators of Casp3, were inversely correlated to Casp3. Our data suggests that hWJ-MSC-derived EV have the potential to prevent and resolve HI-induced apoptosis in neuronal cells in immature neonatal brain. Their antiapoptotic effect seems to be mediated by the transfer of EV-derived let-7-5p miR.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Gynaecology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Pränatale Medizin

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Jörger Messerli, Marianne; Oppliger, Byron; Spinelli, Marialuigia; Thomi, Gierin Florence; Schneider, Philipp and Schoeberlein, Andreina

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

1555-3892

Publisher:

Cognizant Communication Corporation

Funders:

Organisations 316030 not found.
[UNSPECIFIED] CryoSave Switzerland
[UNSPECIFIED] Gottfried and Julia Bangerter-Rhyner Foundation

Language:

English

Submitter:

Andreina Schoeberlein

Date Deposited:

19 Apr 2018 14:40

Last Modified:

24 Oct 2019 09:28

Publisher DOI:

10.1177/0963689717738256

PubMed ID:

29562785

BORIS DOI:

10.7892/boris.112479

URI:

https://boris.unibe.ch/id/eprint/112479

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