期刊
STEM CELL RESEARCH & THERAPY
卷 12, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13287-021-02148-5
关键词
Exosomes; Umbilical cord mesenchymal stem cells; Spinal cord injury; microRNAs; TrkA ubiquitination; PC12 cells
资金
- National Key Research and Development Program of China [2017YFA0105403]
- Key Research and Development Program of Guangdong Province [2019B020236002]
- Clinical innovation Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory [2018GZR0201006]
- National Natural Science Foundation of China [31470949, 81772349]
- Guangzhou Health Care Cooperative Innovation Major Project [201704020221]
- Guangzhou Science and Technology Project [201707010115]
- Guangdong Natural Science Foundation [2017A030313594]
- Medical Scientific Research Foundation of Guangdong Province [A2018547]
The study demonstrates that exosomes transferring miR-199a-3p/145-5p into neurons in SCI rats affect TrkA ubiquitination and promote the NGF/TrkA signaling pathway, showing the potential of hUC-MSC-derived exosomes as a promising treatment strategy for SCI.
BackgroundAlthough exosomes, as byproducts of human umbilical cord mesenchymal stem cells (hUC-MSCs), have been demonstrated to be an effective therapy for traumatic spinal cord injury (SCI), their mechanism of action remains unclear.MethodsWe designed and performed this study to determine whether exosomes attenuate the lesion size of SCI by ameliorating neuronal injury induced by a secondary inflammatory storm and promoting neurite outgrowth. We determined the absolute levels of all exosomal miRNAs and investigated the potential mechanisms of action of miR-199a-3p/145-5p in inducing neurite outgrowth in vivo and in vitro.ResultsmiR-199a-3p/145-5p, which are relatively highly expressed miRNAs in exosomes, promoted PC12 cell differentiation suppressed by lipopolysaccharide (LPS) in vitro through modulation of the NGF/TrkA pathway. We also demonstrated that Cblb was a direct target of miR-199a-3p and that Cbl was a direct target of miR-145-5p. Cblb and Cbl gene knockdown resulted in significantly decreased TrkA ubiquitination levels, subsequently activating the NGF/TrkA downstream pathways Akt and Erk. Conversely, overexpression of Cblb and Cbl was associated with significantly increased TrkA ubiquitination level, subsequently inactivating the NGF/TrkA downstream pathways Akt and Erk. Western blot and coimmunoprecipitation assays confirmed the direct interaction between TrkA and Cblb and TrkA and Cbl. In an in vivo experiment, exosomal miR-199a-3p/145-5p was found to upregulate TrkA expression at the lesion site and also promote locomotor function in SCI rats.ConclusionsIn summary, our study showed that exosomes transferring miR-199a-3p/145-5p into neurons in SCI rats affected TrkA ubiquitination and promoted the NGF/TrkA signaling pathway, indicating that hUC-MSC-derived exosomes may be a promising treatment strategy for SCI.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据