Exosomes Derived from Nerve Stem Cells Loaded with FTY720 Promote the Recovery after Spinal Cord Injury in Rats by PTEN/AKT Signal Pathway

Abstract

Background. Spinal cord injury (SCI) remains a challenge owing to limited therapies. The exosome of neural stem cells (NSCs-Exos) and FTY720 transplantation could improve SCI effectively. However, the effect and mechanism of NSCs-Exos combined with FTY720 (FTY720-NSCs-Exos) transplantation in the treatment of SCI are not fully understood. Methods. Sprague Dawley rats (8-week-old) were used to establish the SCI model, followed by the treatment of NSCs-Exos, FTY720, and FTY720-NSCs-Exos. The effect of FTY720, NSCs-Exos, and FTY720-NSCs-Exos combination treatment on hindlimb function, pathological changes, apoptosis activity, and the expression of spinal edema-related proteins and apoptosis-related proteins in SCI models were investigated by BBB scoring, HE staining, TUNEL staining and immunohistochemistry, and Western blotting. Meanwhile, the effect of these treatments on spinal cord microvascular endothelial cells (SCMECs) was detected under hypoxic circumstance. Results. Our results found that FTY720-NSCs-Exos could alleviate pathological alterations and ameliorate the hindlimb function and oxygen insufficiency in model mice after SCI. In addition, exosomes could ameliorate the morphology of neurons, reduce inflammatory infiltration and edema, decrease the expression of Bax and AQP-4, upregulate the expression of claudin-5 and Bcl-2, and inhibit cell apoptosis. At the same time, in vitro experiments showed that FTY720-NSCs-Exos could protect the barrier of SCMECs under hypoxic circumstance, and the mechanism is related to PTEN/AKT pathway. Conclusion. FTY720-NSCs-Exos therapy displayed a positive therapeutic effect on SCI by regulating PTEN/AKT pathway and offered a new therapy for SCI.

FTY720 attenuates APAP‑induced liver injury via the JAK2/STAT3 signaling pathway

“…It has been demonstrated that FTY720 could inhibit the proliferation of glomerular mesangial cells by inducing cell cycle arrest and apoptosis, possibly via the regulation of the expression of cell cycle-related genes and BAX/BCL-2 ( 47 ). In addition, exosomes could ameliorate the morphology of neurons, reduce inflammatory infiltration and edema, decrease the expression of BAX and AQP-4, upregulate the expression of claudin-5 and BCL-2 and inhibit cell apoptosis ( 48 ).…”

Therapeutic Effect of Exosomes Derived From Stem Cells in Spinal Cord Injury: A Systematic Review Based on Animal Studies

“…Among the included 32 studies, only two studies were controlled studies ( 29 , 33 ), and the remaining 30 studies were randomized controlled studies. The species of animals included SD rats ( 19 – 21 , 28 – 37 , 39 , 40 , 42 – 44 , 46 , 47 , 49 – 53 , 55 , 56 ), Wistar rats ( 41 , 54 ), and C57BL/6 mice ( 38 , 45 , 48 ); gender included male ( 28 , 30 – 32 , 38 – 45 , 49 , 53 , 54 ) and female ( 19 , 20 , 29 , 33 , 34 , 36 , 37 , 46 – 48 , 50 – 52 , 55 , 56 ), two studies did not report the sex of the animals ( 21 , 35 ); the weights of animals were between 150 ( 41 ) and 300 g ( 20 , 44 ), the weight of the mouse was between 17 and 22 g ( 48 ), and seven of the studies did not report the weight of the animals ( 21 , 29 , 30 , 38 , 42 , 45 , 50 ); age was between 6 ( 38 , 44 , 45 , 50 , 51 ) and 12 weeks ( 47 , 56 ), and nine of the studies did not report the age of the animals ( …”

“…Six studies reported types of exosomes but did not report specific sources ( 31 , 32 , 38 , 40 , 45 , 46 ). The transplantation route of exosomes included tail vein ( 19 – 21 , 29 – 32 , 34 – 50 , 52 – 56 ), intranasally ( 33 ) and subcutaneous ( 51 ), and one study did not report the route of exosome transplantation ( 28 ); the time transplantation of exosome ranged from 0 ( 19 , 20 , 31 , 38 , 41 , 44 – 47 , 49 ) to 24 h ( 42 , 43 ) after modeling, one study did not report the time of exosome transplantation ( 40 ); dose of exosomes ranged from 20 ( 29 ) to 200 μg ( 28 , 30 – 33 , 36 – 38 , 41 , 43 , 45 – 49 , 53 , 56 ); the control group includes PBS ( 19 – 21 , 28 – 32 , 34 , 35 , 38 , 39 , 41 , 43 – 51 , 53 – 56 ), saline ( 33 , 36 , 37 , 40 , 42 ), and blank ( 52 ). Basic information of the study subjects was summarized in Supplementary Table 2 .…”

“…In our study, the protein expression levels of apoptotic proteins (BAX) were significantly lower in the Exo group than in the negative group, while the anti-apoptotic protein (Bcl-2) level was observed to be significantly elevated. This suggests that exosomes have a protective effect on neuronal apoptosis induced by SCI ( 29 ).…”

“…Among the included 32 studies, only two studies were controlled studies (29,33), and the remaining 30 studies were randomized controlled studies. The species of animals included SD rats (19-21, 28-37, 39, 40, 42-44, 46, 47, 49-53, 55, 56), Wistar rats (41,54), and C57BL/6 mice (38,45,48); gender included male (28, 30-32, 38-45, 49, 53, 54) and female (19, 20, 29, 33, 34, 36, 37, 46-48, 50-52, 55, 56), two studies did not report the sex of the animals (21,35); the weights of animals were between 150 (41) and 300 g (20,44), the weight of the mouse was between 17 and 22 g ( 48), and seven of the studies did not report the weight of the animals (21,29,30,38,42,45,50); age was between 6 (38,44,45,50,51) and 12 weeks (47, 56), and nine of the studies did not report the age of the animals (19, 21, 35-37, 42, 46, 51, 52); samples size were between 10 (51) and 100 (41); models of SCI included contusion (20, 21, 28-32, 34-53, 56), hemisection (54), and transection (19,33,55); the types of exosomes included the exosomes of bone marrow mesenchymal stem cells of SD rats (BMSCs-Exo) (20, 21, 28, 30, 34-37, 39, 42-44, 47, 49, 52, 53, 56), BMSCs-Exo of Wistar rats (41,54), BMSCs-Exo of human (19,33,…”