Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana, USA.
Pathology and Laboratory Medicine, Weill Cornell Medical College, New York City, New York, USA.
FASEB J. 2018 May;32(5):2381-2394. doi: 10.1096/fj.201700746R. Epub 2017 Dec 21.
Stroke continues to be a leading cause of death and disability worldwide, yet effective treatments are lacking. Previous studies have indicated that stem-cell transplantation could be an effective treatment. However, little is known about the direct impact of transplanted cells on injured brain tissue. We wanted to help fill this knowledge gap and investigated effects of hematopoietic stem/progenitor cells (HSPCs) on the cerebral microcirculation after ischemia-reperfusion injury (I/RI). Treatment of HSPCs in I/RI for up to 2 wk after cerebral I/RI led to decreased mortality rate, decreased infarct volume, improved functional outcome, reduced microglial activation, and reduced cerebral leukocyte adhesion. Confocal microscopy and fluorescence-activated cell sorting analyses showed transplanted HSPCs emigrate preferentially into ischemic cortex brain parenchyma. We isolated migrated HSPCs from the brain; using RNA sequencing to investigate the transcriptome, we found metallothionein (MT, particularly MT-I) transcripts were dramatically up-regulated. Finally, to confirm the significance of MT, we exogenously administered MT-I after cerebral I/RI and found that it produced neuroprotection in a manner similar to HSPC treatment. These findings provide novel evidence that the mechanism through which HSPCs promote repair after stroke maybe via direct action of HSPC-derived MT-I and could therefore be exploited as a useful therapeutic strategy for stroke.-Smith, H. K., Omura, S., Vital, S. A., Becker, F., Senchenkova, E. Y., Kaur, G., Tsunoda, I., Peirce, S. M., Gavins, F. N. E. Metallothionein I as a direct link between therapeutic hematopoietic stem/progenitor cells and cerebral protection in stroke.
中风仍然是全球范围内导致死亡和残疾的主要原因，但缺乏有效的治疗方法。先前的研究表明，干细胞移植可能是一种有效的治疗方法。然而，对于移植细胞对受损脑组织的直接影响知之甚少。我们希望帮助填补这一知识空白，并研究造血干细胞/祖细胞（HSPC）对缺血再灌注损伤（I/RI）后大脑微循环的直接影响。在大脑 I/RI 后 2 周内对 HSPC 进行治疗，可降低死亡率、减少梗死体积、改善功能预后、减少小胶质细胞激活和减少脑白细胞黏附。共聚焦显微镜和荧光激活细胞分选分析表明，移植的 HSPC 优先迁移到缺血性皮质脑实质。我们从大脑中分离出迁移的 HSPC；使用 RNA 测序来研究转录组，我们发现金属硫蛋白（MT，特别是 MT-I）转录物显著上调。最后，为了证实 MT 的重要性，我们在大脑 I/RI 后外源性给予 MT-I，发现它以类似于 HSPC 治疗的方式产生神经保护作用。这些发现为 HSPC 促进中风后修复的机制可能是通过 HSPC 衍生的 MT-I 的直接作用提供了新的证据，因此可以作为中风的一种有用的治疗策略。-Smith，H.K.，Omura，S.，Vital，S.A.，Becker，F.，Senchenkova，E.Y.，Kaur，G.，Tsunoda，I.，Peirce，S.M.，Gavins，F.N.E. 金属硫蛋白 I 作为治疗性造血干细胞/祖细胞与中风中大脑保护之间的直接联系。
