Therapeutic efficacy of neuregulin 1-expressing human adipose-derived mesenchymal stem cells for ischemic stroke


Autoři: Sun Ryu aff001;  Jae-Min Lee aff001;  Cheong A. Bae aff001;  Chae-Eun Moon aff001;  Kyung-Ok Cho aff001
Působiště autorů: Department of Pharmacology, College of Medicine, The Catholic University of Korea, Seoul, South Korea aff001;  Catholic Neuroscience Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea aff002;  Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea, Seoul, South Korea aff003;  Institute of Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, South Korea aff004
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222587

Souhrn

Adipose-derived mesenchymal stem cells (AdMSCs) have been reported to ameliorate neurological deficits after acute ischemic stroke. As neuregulin 1 (NRG1, or heregulin 1), a growth factor with versatile functions in the central nervous system, has demonstrated protective effects against ischemic brain injuries, we have generated NRG1-overexpressing AdMSCs in order to investigate whether NRG1-AdMSCs could enhance therapeutic benefits of AdMSCs in ischemic stroke. After AdMSCs were infected with adenoviral NRG1, increased NRG1 secretion in NRG1-AdMSCs was confirmed with ELISA. At 1 d after ischemic stroke that was induced by the occlusion of middle cerebral artery (MCAo) for 60 min in Sprague Dawley (SD) rats, adenoviral NRG1, AdMSCs, NRG1-AdMSCs, or PBS were injected into the striatum and serial neurologic examinations were performed. Administration of NRG1-AdMSCs resulted in significant improvement of functional outcome following stroke compared to AdMSCs- or adenoviral NRG1-treated group, in addition to the reduction in the infarct size evaluated by hematoxylin and eosin staining. When NRG1 expression in the brain was examined by double immunofluorescence to human nuclei (HuNu)/NRG1 and ELISA, NRG1-AdMSCs demonstrated marked increase in NRG1 expression. Moreover, western blot analysis further showed that transplantation of NRG1-AdMSCs significantly increased both endogenous and adenoviral NRG1 expression compared to AdMSCs-treated group. To elucidate molecular mechanisms, NRG1-associated downstream molecules were evaluated by western blot analysis. Expression of ErbB4, a receptor for NRG1, was markedly increased by NRG1-AdMSCs administration, in addition to pMAPK and pAkt, crucial molecules of NRG1-ErbB4 signaling. Taken together, our data suggest that NRG1-AdMSCs can provide excellent therapeutic potential in ischemic stroke by activating NRG1-ErbB4 signaling network.

Klíčová slova:

Brain damage – Cerebral ischemia – Enzyme-linked immunoassays – Ischemic stroke – MAPK signaling cascades – Mesenchymal stem cells – Stem cell therapy – Adenoviruses


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