Exosome Derived from Human Neural Stem Cells Improves Motor Activity and Neurogenesis in a Traumatic Brain Injury Model

Abstract

Traumatic brain injury (TBI) is a leading cause of mortality and long-lasting disability globally. Although novel treatment options have been investigated, no effective therapeutic opportunities for TBI exist. Accumulating studies demonstrated that the paracrine mechanisms of stem cells may allow them to orchestrate regenerative processes after TBI. So far, very little attention has been paid to the beneficial effects of human neural stem cells (hNSCs) in comparison to their exosomes as a paracrine mechanism. This study is aimed at comparing the effect of hNSCs with their exosomes in a TBI model. For in vitro assessments, we cultured hNSCs using the neurosphere method and isolated hNSC-derived exosomes from culture supernatants. For in vivo experiments, male rats were divided into three groups ( n = 8 /group): TBI group: rats were subjected to a unilateral mild cortical impact; hNSC group: rats received a single intralesional injection of 2 × 10 6 hNSCs after TBI; and exosome group: rats received a single intralesional injection of 63 μg protein of hNSC-derived exosomes after TBI. Neurological assessments, neuroinflammation, and neurogenesis were performed at the predetermined time points after TBI. Our results indicated that the administration of exosomes improved the neurobehavioral performance measured by the modified neurological severity score (mNSS) on day 28 after TBI. Furthermore, exosomes inhibited the expression of reactive astrocytes as a key regulator of neuroinflammation marked by GFAP at the protein level, while enhancing the expression of Doublecortin (DCX) as a neurogenesis marker at the mRNA level. On the other hand, we observed that the expression of stemness markers (SOX2 and Nestin) was elevated in the hNSC group compared to the exosome and TBI groups. To sum up, our results demonstrated that the superior effects of exosomes versus parent hNSCs could be mediated by improving mNSS score and increasing DCX in TBI. Considerably, more work will need to be done to determine the beneficial effects of exosomes versus parent cells in the context of TBI.

Efficacy of extracellular vesicles of different cell origins in traumatic brain injury: A systematic review and network meta-analysis

“…The mNSS neurological function assessment at day 7 after TBI, a total of 15 studies were eligible ( Zhang et al, 2015 , 2017 , 2020 ; Li et al, 2019 ; Ni et al, 2019 ; Yang et al, 2019 ; Chen et al, 2020 ; Long et al, 2020 ; Xu et al, 2020 ; He et al, 2021 ; Zhang W. et al, 2021 ; Zhang Y. et al, 2021 ; Abedi et al, 2022 ; Cui et al, 2022 ; Zhang et al, 2022 ). The network diagram ( Figure 4A ) showed four interventions and control comparisons, including AEVs, MEVs, neural stem cell-derived extracellular vesicles (NSCEVs) and MSCEVs.…”

“…The mNSS neurological function assessment at day 14 after TBI, a total of 14 studies were eligible (Zhang et al, 2015(Zhang et al, , 2017(Zhang et al, , 2020Li et al, 2019;Ni et al, 2019;Yang et al, 2019;Chen et al, 2020;Long et al, 2020;Xu et al, 2020;He et al, 2021;Zhang Y. et al, 2021;Abedi et al, 2022;Cui et al, 2022;. The network diagram (Figure 5A (87.12%).…”

“…The mNSS neurological function assessment at day 21 after TBI, a total of 10 studies were eligible (Zhang et al, 2015(Zhang et al, , 2017(Zhang et al, , 2020Li et al, 2019;Yang et al, 2019;Chen et al, 2020;Zhang Y. et al, 2021;Abedi et al, 2022;Cui et al, 2022;. The network diagram (Figure 6A 6C) showed that NSCEVs (6.76%) had the best curative effect, followed by MSCEVs (28.82%), MEVs (80.07%), and Control (84.35%).…”

Traumatic brain injury: Mechanisms, manifestations, and visual sequelae

“…In the context of TBI, the secretome of MSC has the capacity to enhance endogenous neurogenesis (Liu et al, 2020;Badner and Cummings, 2022). Porcine and rodent models show that extracellular vesicles released by MSC can promote endogenous angiogenesis and neurogenesis, reduce inflammation, and facilitate cognitive and sensorimotor recovery after TBI (Abedi et al, 2022;Bambakidis et al, 2022). This highlights the significance of the trophic support these cells provide during exogenous application (Spees et al, 2016;Liu et al, 2020).…”

Neural stem/progenitor cell‐derived extracellular vesicles: A novel therapy for neurological diseases and beyond

“…In recent years, EV‐based stem cell‐free therapies have been investigated in the course of TBI treatment. Abedi et al 165 . reported that administration of NSC‐EVs improved recent‐period neurological behaviors and promoted neurogenesis after TBI.…”