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

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.

SUBMITTER: Ryu S

PROVIDER: S-EPMC6764745 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Ryu Sun S Lee Jae-Min JM Bae Cheong A CA Moon Chae-Eun CE Cho Kyung-Ok KO

PloS one 20190927 9

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 a ...[more]

PMID: 31560696

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Project description:Background/Objective: Stroke is a leading global cause of adult disability. As the population ages as well as suffers co-morbidities, it is expected that the stroke burden will increase further. There are no established safe and effective restorative treatments to facilitate a good functional outcome in stroke patients. Cell-based therapies, which have a wide therapeutic window, might benefit a large percentage of patients, especially if combined with different restorative strategies. In this study, we tested whether the therapeutic effect of human adipose tissue-derived mesenchymal stem cells (ADMSCs) could be further enhanced by rehabilitation in an experimental model of stroke. Methods: Focal cerebral ischemia was induced in adult male Sprague Dawley rats by permanently occluding the distal middle cerebral artery (MCAO). After the intravenous infusion of vehicle (n = 46) or ADMSCs (2 × 106) either at 2 (n = 37) or 7 (n = 7) days after the operation, half of the animals were housed in an enriched environment mimicking rehabilitation. Subsequently, their behavioral recovery was assessed by a neurological score, and performance in the cylinder and sticky label tests during a 42-day behavioral follow-up. At the end of the follow-up, rats were perfused for histology to assess the extent of angiogenesis (RECA-1), gliosis (GFAP), and glial scar formation. Results: No adverse effects were observed during the follow-up. Combined ADMSC therapy and rehabilitation improved forelimb use in the cylinder test in comparison to MCAO controls on post-operative days 21 and 42 (P < 0.01). In the sticky label test, ADMSCs and rehabilitation alone or together, significantly decreased the removal time as compared to MCAO controls on post-operative days 21 and 42. An early initiation of combined therapy seemed to be more effective. Infarct size, measured by MRI on post-operative days 1 and 43, did not differ between the experimental groups. Stereological counting revealed an ischemia-induced increase both in the density of blood vessels and the numbers of glial cells in the perilesional cortex, but there were no differences among MCAO groups. Glial scar volume was also similar in MCAO groups. Conclusion: Early delivery of ADMSCs and combined rehabilitation enhanced behavioral recovery in an experimental stroke model. The mechanisms underlying these treatment effects remain unknown.

Dataset Information

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

Publications

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

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