| Background and Objective Stroke and glioma are two important types of central nervous system(CNS)diseases with high morbidity,high disability,and high mortality worldwide.There is an urgent demand to develop new potential therapies against stroke and glioma.Stem cell-based therapeutic strategies provide new perspectives for stroke and glioma therapy.Increasing evidences indicate that the positive effect of such stem cell-based therapy are mediated by exosomes(Exos)released from the administered stem cells.The use of stem cell derived-exosomes represents a promising therapeutic strategy for the treatment of stroke and glioma.However,the most commonly investigated adult stem cells,such as mesenchymal stem cells(MSCs)harvested from bone marrow and adipose tissue,have limited source,invasive procedures for cell extraction,and finite amplification capacity,severely hampering their clinical application.Therefore,it is of great clinical significance to explore the promising seed cells to extract exosomes for clinical translation.In this study,we investigated the therapeutic effect and potential mechanism of exosomes derived from urine stem cells(USC-Exos)and exosomes derived from induced pluripotent stem cell-derived MSCs(iMSC-Exos)on ischemic stroke,and the therapeutic effect of multipotential stem cells-derived exosomes and functionalized exosomes from multipotential stem cells on glioma.Methods 1.The therapeutic effect and potential mechanism of exosomes derived from stem cells on ischemic stroke.1)The therapeutic effect and potential mechanism of USC-Exos on ischemic stroke: the effect of USC-Exos on neuroprotection and neurogenesis were evaluated in the middle cerebral artery occlusion(MCAO)model in rats.Neural stem cells(NSCs)subjected to oxygen-glucose deprivation/reoxygenation(OGD/R)were used to mimic ischemic stroke in vitro.The effect and the protenial mechanism of USC-Exos on the proliferation and neuronal differentiation of OGD/R stimulated NSCs were examined,respectively.2)The therapeutic effect and potential mechanism of iMSC-Exos on ischemic stroke: the effect of iMSC-Exos on neuroprotection and angiogenesis were evaluated in the MCAO rats.The effect of iMSC-Exos on the migration and tubular formation of OGD/R stimulated HUVECs was assessed in vitro.The possible mechanism of iMSC-Exos mediated pro-angiogenesis effect was explored in vivo and in vitro.2.The application of functionalized exosomes from multipotential stem cells in the treatment of glioma。 1)The effect of multipotential stem cells-derived exosomes on glioma:the anti-glioma effect of embryonic stem cells-derived exosomes(ESC-Exos)was evaluated in vitro and in vivo.2)Anti-glioma effect of functionalized exosomes from multipotential stem cells:ESC-exos were conjugated with tumor-targeted peptide c(RGDy K)and loaded with PTX synchronously,named c RGD-Exo-PTX.We then investigated whether the engineered exosomes delivered more efficiently to glioma cells versus free drug alone and drug-loaded ESC-Exos using an in vitro glioma model and in vivo subcutaneous and orthotopic xenografts.Results 1.The therapeutic effect and potential mechanism of exosomes derived from stem cells on ischemic stroke.1)The therapeutic effect and potential mechanism of USC-Exos on ischemic stroke.a)USC-Exos confered neuroprotective effect by promoting the proliferation and neuronal differentiation of NSCs in MCAO rats.b)USC-Exos noticeably increased the proliferation and neuronal differentiation of NSCs subjected to OGD/R.c)The pro-neurogenesis effect of USC-Exos may be partially attributed to HDAC6 inhibition via the transfer of exosomal mi R-26 a.2)The therapeutic effect and potential mechanism of iMSC-Exos on ischemic stroke.a)iMSC-Exos confered neuroprotective effect by promoting angiogenesis in MCAO rats.b)iMSC-Exos noticeably increased the migration and tube formation of HUVECs subjected to OGD/R.c)iMSC-Exos promoted angiogenesis via a decrease in autophagy,a process that was dependent on STAT3 activation.2.The application of functionalized exosomes from multipotential stem cells in the treatment of glioma.1)The effect of multipotential stem cells-derived exosomes on glioma.a)ESC-Exos exerted anti-glioma effect by inhibiting cell proliferation and promoting cell apoptosis in vitro,and restrained glioma growth in vivo.2)Anti-glioma effect of functionalized exosomes from multipotential stem cells.b)The engineered exosomes,named c RGD-Exo-PTX,were demonstrated to possess excellent glioma-targeting ability in vitro and in vivo..c)c RGD-Exo-PTX improve the curative efficacy of PTX in vitro and in vivo.Conclusions 1.Stem cell-derived exosomes have significant therapeutic effect on ischemic stroke.1)USC-Exos promote neurogenesis and functional recovery in post-stroke treatment,which is potentially mediated by regulating mi R-26a/HDAC6 axis.2)iMSC-Exos promote angiogenesis and functional recovery in post-stroke treatment,which is potentially mediated by inhibiting autophagy via the STAT3 pathway activation.2.Functionalized exosomes from multipotential stem cells have significant therapeutic effect in the treatment of glioma.1)Multipotential stem cells-derived exosomes have significant anti-glioma effect in vitro and in vivo.2)Functionalized exosomes from multipotential stem cells have strong targeting ability and therapeutic effect in glioma,which provide a powerful tool for brain tumors and other CNS diseases therapy.3.USC-Exos,iMSC-Exos,and ESC-Exos have many advantages,such as stable performance,convenient for industrialization,and the feasibility to be tailored to maximize clinical benefit.This study provides new choices in translation of suitable stem cell-derived exosomes-based therapy to clinical applications against CNS diseases. |
