ESC‐sEVs Rejuvenate Senescent Hippocampal NSCs by Activating Lysosomes to Improve Cognitive Dysfunction in Vascular Dementia

Abstract

Vascular dementia (VD) is one of the most common types of dementia, however, the intrinsic mechanism is unclear and there is still lack of effective medications. In this study, the VD rats exhibit a progressive cognitive impairment, as well as a time‐related increasing in hippocampal neural stem cells (H‐NSCs) senescence, lost and neurogenesis decline. Then, embryonic stem cell‐derived small extracellular vesicles (ESC‐sEVs) are intravenously injected into VD rats. ESC‐sEVs treatment significantly alleviates H‐NSCs senescence, recovers compromised proliferation and neuron differentiation capacity, and reverses cognitive impairment. By microarray analysis and RT‐qPCR it is identified that several miRNAs including miR‐17‐5p, miR‐18a‐5p, miR‐21‐5p, miR‐29a‐3p, and let‐7a‐5p, that can inhibit mTORC1 activation, exist in ESC‐sEVs. ESC‐sEVs rejuvenate H‐NSCs senescence partly by transferring these miRNAs to inhibit mTORC1 activation, promote transcription factor EB (TFEB) nuclear translocation and lysosome resumption. Taken together, these data indicate that H‐NSCs senescence cause cell depletion, neurogenesis reduction, and cognitive impairment in VD. ESC‐sEVs treatment ameliorates H‐NSCs senescence by inhibiting mTORC1 activation, and promoting TFEB nuclear translocation and lysosome resumption, thereby reversing senescence‐related neurogenesis dysfunction and cognitive impairment in VD. The application of ESC‐sEVs may be a novel cell‐free therapeutic tool for patients with VD, as well as other aging‐related diseases.

Extracellular Vesicles: “Stealth Transport Aircrafts” for Drugs

“…A number of studies have shown that EVs derived from mesenchymal stem cells (MSCs) can be used for stem cell replacement therapy [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21]. In most cases, it is not clear which component of the unmodified EVs exerts curative effects.…”

“…ESC-sEVs can restore the damaged proliferation and neuronal differentiation ability, and reverse cognitive impairment. The application of ESC-sEVs may be a new cell-free treatment tool for VD and other diseases related to aging [8].…”

“…Because they have anti-inflammatory, anti-apoptotic and anti-microbial capability, and promote angiogenesis and the repair and regeneration of damaged tissues. As mentioned above, EVs derived from MSCs have been widely used in the treatment of central nervous system diseases, cardiovascular diseases, bone and cartilage damage repair and regeneration, wound repair, and other organ damage repair and regeneration [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21].…”

Ligustilide enhances hippocampal neural stem cells activation to restore cognitive function in the context of postoperative cognitive dysfunction

“…Transient or repeated global cerebral ischaemia during surgery is regarded as a key cause of POCD because it can induce cerebral ischaemia reperfusion injury, cause neuronal‐damagement and neuroinflammation, and result in irreversible impairment of brain cells (Hovens et al, 2016; van Harten et al, 2012). The hippocampus is the key structure involved in cognition (Hu et al, 2020), and hippocampal pyramidal neurons are particularly vulnerable to ischaemia reperfusion insult (Li et al, 2019). For example, studies have demonstrated that cerebral ischaemia can result in delayed hippocampal pyramidal neurons death and impaired cognition in both humans and animals (Kirino, 1982; Neumann et al, 2013; Pulsinelli et al, 1982).…”

“…For example, studies have demonstrated that cerebral ischaemia can result in delayed hippocampal pyramidal neurons death and impaired cognition in both humans and animals (Kirino, 1982; Neumann et al, 2013; Pulsinelli et al, 1982). Hippocampal neural stem cells (H‐NSCs) and their neurogenesis play crucial roles in maintaining and restoring of hippocampal structure and hippocampus‐dependent brain functions, because loss of H‐NSCs and decreased neurogenesis can lead to reduced neuroplasticity and neurological disorders, while restoring H‐NSCs and promoting their neurogenesis benefit hippocampal structure and functional repair by increasing the production of functional granule neurons and their integration into the existing hippocampal circuits (Hu et al, 2020; Toda & Gage, 2018; van Praag et al, 2002). Therefore, we hypothesized that the improvement of H‐NSCs proliferation and neurogenesis would benefit cognitive recovery in the context of POCD.…”