Batista Claudia M C, Kippin Tod E, Willaime-Morawek Sandrine, Shimabukuro Marília Kimie, Akamatsu Wado, van der Kooy Derek
Neurobiology Research Group, Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario, Canada M5S 3E1.
J Neurosci. 2006 Oct 11;26(41):10452-60. doi: 10.1523/JNEUROSCI.2850-06.2006.
Neural stem and progenitor cells are located in the subependyma of the adult forebrain. An increase in adult subependymal cell proliferation is reported after various kinds of brain injury. We demonstrate an expansion of neural precursor cells in the postnatal subependyma in a murine genetic disease model of Huntington's disease (HD), the R6/2 mouse. We used the in vitro neurosphere assay as an index of the number of neural stem cells in vivo and to assess proliferation kinetics in vitro and in vivo bromodeoxyuridine labeling to assess the progenitor cell population and their fates. Disease progression in this model leads to an increase in the numbers of neural stem cells in the adult striatal subependyma. This increase is produced cell non-autonomously by events in the R6/2 brains as the mice become increasingly symptomatic. Once the neural stem cell increase is induced in vivo, it is maintained during in vitro passaging of neural stem cells, but the neural stem cell increase is not reproduced during in vitro passaging of neural stem cells from presymptomatic R6/2 mice. In addition, we show that some of the R6/2 neural progenitor cells show a change from their normal migration destiny toward the olfactory bulb. Instead, some of these cells migrate into the striatum, one of the main affected areas in HD. Our findings demonstrate that HD damage recruits precursor cells in two ways: expansion of neural stem cells and altered migration of progenitor cells.
神经干细胞和祖细胞位于成年前脑的室管膜下区。据报道，在各种脑损伤后，成年室管膜下细胞的增殖会增加。我们在亨廷顿舞蹈病（HD）的小鼠遗传疾病模型R6/2小鼠中，证明了出生后室管膜下神经前体细胞的扩增。我们使用体外神经球测定法作为体内神经干细胞数量的指标，并通过体外和体内溴脱氧尿苷标记来评估增殖动力学，以评估祖细胞群体及其命运。该模型中的疾病进展导致成年纹状体室管膜下神经干细胞数量增加。随着小鼠症状越来越明显，这种增加是由R6/2脑内的事件非自主产生的。一旦在体内诱导神经干细胞增加，在神经干细胞的体外传代过程中这种增加会持续存在，但从症状前的R6/2小鼠分离的神经干细胞在体外传代过程中不会再现神经干细胞的增加。此外，我们表明一些R6/2神经祖细胞显示出从其正常向嗅球迁移的命运发生改变。相反，其中一些细胞迁移到纹状体，这是HD中主要受影响的区域之一。我们的研究结果表明，HD损伤以两种方式募集前体细胞：神经干细胞的扩增和祖细胞迁移的改变。
