视网膜变性疾病可引起视网膜神经细胞死亡,最终可致盲.对于罹患视网膜神经细胞损伤相关疾病的患者,我们必须找到一种安全、有效地替换这些细胞的方法进行治疗.神经干细胞( NSCs)是一类能向神经细胞和胶质细胞分化的特殊干细胞,作为视网膜主要的内源性NSCs,Müller细胞具有在视网膜损伤后进入细胞周期增生并分化为神经细胞的能力.在脊椎动物中,视网膜Müller细胞自发的再生效率很高,而哺乳动物中这一能力几乎消失.随着研究的深入,发现一些转录因子,如Ascl1、sox2、lin28和atoh7等具有促进Müller细胞增生并分化为神经细胞的功能,其中Ascl1联合组蛋白脱乙酰酶抑制剂能使小鼠Müller细胞分化的神经细胞整合进入视网膜并能对光做出反应.此外,外源性干细胞的移植也可以诱导Müller细胞重编程.虽然这些研究结果极有应用前景,但与斑马鱼相比,哺乳动物Müller细胞增生再生的能力仍十分有限,可能有某种尚不明确的反向机制抑制了Müller细胞的重编程能力.寻找更多能增强Müller细胞重编程能力的新因子将成为亟待解决的重要问题.%Retinal degeneration is an incurable and irreversible blinding disease caused by the retinal neural cell death. An effective and safe strategy to substitute these injured cells is necessary for retinal recovery. Neural stem cells (NSCs) can differentiate into neural and glial cells. While Müller cells,the main endogenous NSCs in retina, have the features to reentry into the cell cycle and differentiate into neural cells after retinal damage. Although it is highly effective for retinal Müller cell differentiation spontaneously after retinal injury in vertebrates,this feature is rigorously restricted in mammals. Recently,some transcription factors,such as Ascl1,sox2,lin28 and atoh7,can drive quiescent Müller cells back into proliferation to generate new retinal neurons. Moreover,combining Ascl1 expression with a histone deacetylase inhibitor can bypass the limitation and increase the generation of new neurons in adult retina. These regenerated neurons integrate the existing neuronal network and are able to respond to light,indicating that they can likely be used to restore vision. In addition,transplantation of exogenous stem cells can induce Müller cell reprogramming. While these results are extremely promising, the regenerative response is still limited, likely because the proliferative capacity of mammalian Müller cells is low in comparison to their zebrafish counterparts. There may be some kinds of unclear reverse mechanism that suppresses the reprogramming of Müller cells. It is indeed necessary to identify new factors increasing the efficiency of regenerative response.
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