Abstract
Widespread death of transplanted mesenchymal stem cells (MSCs) hampers the development of stem cell therapy for Alzheimer disease (AD). Cell pre-conditioning might help cope with this challenge. We tested whether let-7f-5p-modified MSCs could prolong the survival of MSCs after transplantation. When exposed to Aβ25−35 in vitro, MSCs showed significant early apoptosis with decrease in the let-7f-5p levels and increased caspase-3 expression. Upregulating microRNA let-7f-5p in MSCs alleviated Aβ25−35-induced apoptosis by decreasing the caspase-3 levels. After computerized analysis and the luciferase reporter assay, we identified that caspases-3 was the target gene of let-7f-5p. In vivo, hematoxylin and eosin staining confirmed the success of MSCs transplantation into the lateral ventricles, and the let-7f-5p upregulation group showed the lowest apoptotic rate of MSCs detected by TUNEL immunohistochemistry analysis and immunofluorescence. Similarly, bioluminescent imaging showed that let-7f-5p upregulation moderately prolonged the retention of MSCs in brain. In summary, we identified the anti-apoptotic role of let-7f-5p in Aβ25−35-induced cytotoxicity, as well as the protective effect of let-7f-5p on survival of grafted MSCs by targeting caspase-3 in AD models. These findings show a promising approach of microRNA-modified MSCs transplantation as a therapy for neurodegenerative diseases.
Highlights
Bone marrow-derived mesenchymal stem cells (BM-MSCs) are a class of stem cells with low immunogenicity and are available in large amounts (Lo Furno et al, 2017)
All experiments were approved by the Laboratory Animal Care Center of Zhengzhou University and were performed according to the guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of Zhengzhou University, China
We first identified that Aβ25−35 could induce cell apoptosis of MSCs, mainly early apoptosis, with caspase-3 activation and let-7f-5p suppression
Summary
Bone marrow-derived mesenchymal stem cells (BM-MSCs) are a class of stem cells with low immunogenicity and are available in large amounts (Lo Furno et al, 2017). They are capable of homing to lesion tissues (De Becker and Riet, 2016), and secreting different neurotrophic growth factors (NTFs) to promote regeneration and neuroprotection (Koniusz et al, 2016; Petrou et al, 2016). The use of MSCs in clinical treatments does not raise significant religious or ethical issues (Tanna and Sachan, 2014). MSCs hold great potential in stem cell-based therapies for neurodegenerative diseases (Volkman and Offen, 2017). Extensive investigations have shown that MSCs can cross the blood-brain
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