Exosomes as a potential messenger unit during heterochronic parabiosis for amelioration of Huntington's disease
Exosomes as a potential messenger unit during heterochronic parabiosis for amelioration of Huntington's disease
复制标题
DOI：
10.1016/j.nbd.2021.105374
复制
发表时间：
2021-05-06
影响因子：
6.1
通讯作者：
Kim，Manho
中科院分区：
文献类型：
--
作者：
Lee，Mijung;Im，Wooseok;Kim，Manho
亨廷顿舞蹈病（HD）早在临床表现之前就开始出现病理，然而，目前还没有完全治愈的治疗方法，只有少数研究报道延缓了亨廷顿舞蹈病的进展。近年来研究表明异慢性异种共生对神经退行性疾病具有调节作用。尽管异慢性异种共生过程中正因子的运输过程很重要，但由于运输过程是纳米尺度的，因此很难确定信使单位，因此对其的理解有限。我们在R6/2小鼠模型中证实了异慢性异种共生可以调节HD，并确定了青年血清中传递阳性因子的信使单位。方法sr6 /2小鼠分别与幼龄野生型小鼠（n= 13）、老年野生型小鼠（n= 8）、R6/2小鼠（n= 6）手术连接，观察异慢性异种共生的影响。5 ~ 6周龄转基因小鼠与野生型小鼠组成的配对在单笼中观察6周。用年轻或年老小鼠的血清及其分离的外泌体处理其HD细胞的玻璃细胞模型。用脑SVZ培养的神经干细胞进行分化，建立HD的玻璃体细胞模型。结果异慢性异种共生后，HD小鼠体重减轻，存活率提高。此外，突变型亨廷顿蛋白聚集（EM48p< 0.005）、线粒体功能障碍的改善（pgp -1ap< 0.05, p-CREB/CREB p< 0.005）、细胞死亡（p53 p< 0.05, Baxp< 0.05, Cleaved-caspase3 p< 0.05）和认知（DCXp< 0.5）几乎完全恢复。此外，用年轻血清外泌体处理HD玻璃细胞模型可改善突变型亨廷顿蛋白聚集（EM48p< 0.05）、线粒体生物发生（p- creb /CREBp< 0.005）、细胞死亡（p53 p< 0.05、Bax p< 0.005、Cleaved-caspase3 p< 0.05、Bcl-2 p< 0.05）和细胞增殖（WST-1 p< 0.005）。结论我们发现，通过异慢性异种共生共享血液循环可以改善HD的整体病理，此外，我们还证明了外泌体可能是传递阳性因子的信使，显示了来自年轻血液的外泌体改善HD的潜力。
BackgroundHuntington's disease (HD) starts its pathology long before clinical manifestation, however, there is no therapy to cure it completely and only a few studies have been reported for delaying the progression of HD. Recently, it has been shown that heterochronic parabiosis can modulate the neurodegenerative diseases. Despite the importance of the transportation process of positive factors during heterochronic parabiosis, there were limited understandings because the transportation process is nanoscale, which makes it difficult to identify the messenger unit. We demonstrated that heterochronic parabiosis could modulate HD in R6/2 mice model, and identified the messenger unit for transferring positive factors in the young blood serum.MethodsR6/2 mice were surgically connected with young wild-type mice (n= 13), old wild-type mice (n= 8), or R6/2 mice (n= 6) to examine the effect of heterochronic parabiosis. Parabionts composed of 5- to 6-week-old transgenic and wild-type mice were observed for 6 weeks in a single cage. Thein vitrocellular model of HD cells were treated by the blood serum of the young or old mice, and by the exosomes isolated from thereof. Thein vitrocellular model of HD were developed by differentiating neural stem cells cultured from SVZ of the brain.ResultsAfter the heterochronic parabiosis, the weight loss and survival of HD mice was improved. Also, mutant Huntingtin aggregation (EM48p< 0.005), improvement of mitochondria dysfunction (PGC-1ap< 0.05, p-CREB/CREB p < 0.005), cell death (p53 p < 0.05, Baxp< 0.05, Cleaved-caspase3 p < 0.05), and cognition (DCXp< 0.5) showed a near complete restoration. In addition, treatingin vitrocellular model of HD by the exosomes from young blood serum improved mutant Huntingtin aggregation (EM48p< 0.05), mitochondria biogenesis (p-CREB/CREBp< 0.005), cell death (p53 p < 0.05, Bax p < 0.005, Cleaved-caspase3 p < 0.05, Bcl-2 p < 0.05), and cell proliferation (WST-1 p < 0.005).ConclusionsWe found that the overall pathology of HD could be improved by the shared blood circulation through heterochronic parabiosis, furthermore, we demonstrated that the exosomes could be messengers for transferring positive factors, showing the potential of exosomes from young blood for the amelioration of HD.