Neural Stem Cell-Derived Exosomes Regulate Neural Stem Cell Differentiation Through miR-9-Hes1 Axis

Abstract

Exosomes, a key element of the central nervous system microenvironment, mediate intercellular communication via horizontally transferring bioactive molecules. Emerging evidence has implicated exosomes in the regulation of neurogenesis. Recently, we compared the neurogenic potential of exosomes released from primary mouse embryonic neural stem cells (NSCs) and astrocyte-reprogrammed NSCs, and observed diverse neurogenic potential of those two exosome populations in vitro. However, the roles of NSC-derived exosomes on NSC differentiation and the underlying mechanisms remain largely unknown. In this study, we firstly demonstrated that NSC-derived exosomes facilitate the differentiation of NSCs and the maturation of both neuronal and glial cells in defined conditions. We then identified miR-9, a pro-neural miRNA, as the most abundantly expressed miRNA in NSC-derived exosomes. The silencing of miR-9 in exosomes abrogates the positive effects of NSC-derived exosomes on the differentiation of NSCs. We further identified Hes1 as miR-9 downstream target, as the transfection of Hes1 siRNA restored the differentiation promoting potential of NSC-derived exosomes after knocking down exosomal miR-9. Thus, our data indicate that NSC-derived exosomes facilitate the differentiation of NSCs via transferring miR-9, which sheds light on the development of cell-free therapeutic strategies for treating neurodegeneration.

Induced neural progenitor cell‐derived extracellular vesicles promote neural progenitor cell survival via extracellular signal‐regulated kinase pathway

“…14,15 These miRNAs in EVs significantly promote neurogenesis in vitro. 14,15 These findings implied the importance to examine the involvement of iNPC-EVcontaining miRNAs in the regulation of cell survival, which is under investigation. In summary, our study identified EVs as an essential element of iNPC-mediated modification of microenvironment and provided new evidence for the inextricable crosstalk between cell extrinsic and intrinsic factors in regulating NPC survival.…”

Human neural stem cell-derived extracellular vesicles protect against Parkinson’s disease pathologies

“…As an alternative therapy, extracellular vesicles (EVs), which play a key role in intercellular communication through the transmission of unique molecular signatures, have been proposed [ 16 ]. Stem cell-derived EVs are from cells of origin that can regulate tissue regeneration [ 17 , 18 ]. In particular, hypothalamic NSC-derived exosomes significantly slow senescence-mediated NSC loss through exosomal miRNA delivery [ 19 ].…”

Challenges in the Development of Drug Delivery Systems Based on Small Extracellular Vesicles for Therapy of Brain Diseases

“…Some recent studies report the relevance of neural cell-derived sEVs to be used in neurodegenerative conditions ( Huo et al, 2021 ). The direct conversion of somatic cells into induced neural precursor cells (iNPCs) provides abundant production of sEVs ( Ma et al, 2019 ; Yuan P. et al, 2021 ), mainly if using bioreactors ( Baghbaderani et al, 2011 ; Miranda et al, 2016 ). These sEVs after transplantation revealed to have therapeutic properties in ischemic stroke ( Zhang et al, 2020 ).…”