Abstract
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.
| Original language | English |
|---|---|
| Article number | e0222587 |
| Journal | PLoS ONE |
| Volume | 14 |
| Issue number | 9 |
| DOIs | |
| State | Published - 1 Sep 2019 |
Bibliographical note
Funding Information:This work was supported by a grant (14172MFDS974) from Ministry of Food and Drug Safety in 2016, the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) funded by the Ministry of Health & Welfare (HI15C2854), National Research Foundation of Korea (NRF) grants funded by the Korean government (NRF-2019R1A2C1003958), and the Catholic Medical Center Research Foundation made in the program year of 2019 (awarded to KOC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2019 Ryu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.