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.
Highlights
Stroke is an acute cerebrovascular disorder caused by insufficient blood supply to the brain due to ischemia or hemorrhage, resulting in extensive loss of neurons and their connections in the damaged brain [1]
These findings demonstrated that adipose-derived mesenchymal stem cells (AdMSCs) engineered to produce Neuregulin 1 (NRG1) could have a greater capacity to release NRG1, AdMSCs themselves could secrete low levels of NRG1
Since we introduced short epidermal growth factor (EGF)-like domain of NRG1 to adenovirus, adenoviral NRG1 could be identified by 7 kD of molecular weight, which was only expressed in NRG1-infected AdMSCs (Fig 3C)
Summary
Stroke is an acute cerebrovascular disorder caused by insufficient blood supply to the brain due to ischemia or hemorrhage, resulting in extensive loss of neurons and their connections in the damaged brain [1]. New approaches including cell-based therapy with multipotent stem cells have demonstrated great promises for functional recovery in patients with stroke [3, 4]. Mesenchymal stem cells (MSCs) have shown substantial benefits due to their immunosuppressive properties and low immunogenicity [5]. Among various MSCs, adipose-derived mesenchymal stem cells (AdMSCs) show several advantages in clinical applications for stroke [6]. Even stem cell therapy is proven to be feasible for stroke [9] and vigorous research efforts have elucidated details of MSCs behaviors after brain injury, MSCs transplantation has achieved only modest success for the treatment of stroke. It is no doubt that innovative approaches or functional improvements of MSCs are required to enhance therapeutic efficacy of current MSCs transplantation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
