Extracellular vesicles from neural progenitor cells promote functional recovery after stroke in mice with pharmacological inhibition of neurogenesis

Abstract

Neural progenitor cells (NPCs) of the subventricular zone proliferate in response to ischemic stroke in the adult mouse brain. Newly generated cells have been considered to influence recovery following a stroke. However, the mechanism underlying such protection is a matter of active study since it has been thought that proliferating NPCs mediate their protective effects by secreting soluble factors that promote recovery rather than neuronal replacement in the ischemic penumbra. We tested the hypothesis that this mechanism is mediated by the secretion of multimolecular complexes in extracellular vesicles (EVs). We found that the molecular influence of oxygen and glucose-deprived (OGD) NPCs-derived EVs is very limited in improving overt neurological alterations caused by stroke compared to our recently reported astrocyte-derived EVs. However, when we inhibited the ischemia-triggered proliferation of NPCs with the chronic administration of the DNA synthesis inhibitor Ara-C, the effect of NPC-derived EVs became evident, suggesting that the endogenous protection exerted by the proliferation of NPC is mainly carried out through a mechanism that involves the intercellular communication mediated by EVs. We analyzed the proteomic content of NPC-derived EVs cargo with label-free relative abundance mass spectrometry and identified several molecular mediators of neuronal recovery within these vesicles. Our findings indicate that NPC-derived EVs are protective against the ischemic cascade activated by stroke and, thus, hold significant therapeutic potential.

A Perspective on the Characterization of Early Neural Progenitor Cell-Derived Extracellular Vesicles for Targeted Delivery to Neuroblastoma Cells

“…In our results, it was found that eND-EVs had neural proteins like Doublecortin, Neuropilin-1, Semaphorin-7a and also eND-EVs were preferentially taken up by neuron-like cells. Therefore, these findings closely align with and expand upon the work of Campero-Romero et al, who showed that NPC-derived EVs carried neural proteins and they are involved in many neural functions [47]. Moreover, the detection of neural proteins in eND-EVs in our results correlates with Gao et al's findings that NPC-derived EVs carried neural proteins such as growth factors [51].…”

“…Adult neural progenitor cells are associated with maintaining and repairing the central nervous system, explaining the presence of such protein markers [45,46]. Besides, there are studies in the literature on proteomic analysis of neural progenitor cellsderived EVs (NPC-EVs) [47]. In the studies, it was stated that NPC-EVs take part in not only some neural functions but also neural progenitor-related proteins such as Teneurin-4 and Semaphorin-6 A, which are present in the NPC-EVs.…”

Inhibition of Apoptosis in a Model of Ischemic Stroke Leads to Enhanced Cell Survival, Endogenous Neural Precursor Cell Activation and Improved Functional Outcomes

“…Therapeutics targeting NPC survival, such as cyclosporin A, have been shown to improve stroke outcomes [13][14][15]. Studies suggest that surviving NPCs can differentiate to replace dying neurons or provide trophic support after injury [11,16,17]. Hence, therapies that target downstream effector caspase-3 and caspase-7 have the potential to improve NPC survival in the brain, both in their periventricular niche as well as in the cortical stroke injury site.…”

Exploring mitochondrial targeting: an innovative fluorescent probe reveals Nernstian potential and partitioning combination

“…We then conducted a study using primary cortical neurons subjected to oxygen–glucose deprivation (OGD), which was induced by exposing the cells to a glucose-free DMEM medium (Gibco) in a hypoxia chamber with a 100% N 2 atmosphere for 2 h as previously reported. 25 The lack of oxygen and energetic resources triggers an alteration at a morphological and functional level. This results in the failure of multiple neuronal actions, such as cell communication, and the progressive disruption of neuronal projections including axons and dendrites, compromising cell surveillance.…”