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诱导多能干细胞技术作为一种潜在的脊髓损伤临床治疗方法的系统评价。

Systematic review of induced pluripotent stem cell technology as a potential clinical therapy for spinal cord injury.

机构信息

Spinal Cord Repair Laboratory, School of Anatomy, Physiology and Human Biology, The University of Western Australia, Perth, Western Australia.

出版信息

Cell Transplant. 2013;22(4):571-617. doi: 10.3727/096368912X655208. Epub 2012 Aug 27.


DOI:10.3727/096368912X655208
PMID:22944020
Abstract

Transplantation therapies aimed at repairing neurodegenerative and neuropathological conditions of the central nervous system (CNS) have utilized and tested a variety of cell candidates, each with its own unique set of advantages and disadvantages. The use and popularity of each cell type is guided by a number of factors including the nature of the experimental model, neuroprotection capacity, the ability to promote plasticity and guided axonal growth, and the cells' myelination capability. The promise of stem cells, with their reported ability to give rise to neuronal lineages to replace lost endogenous cells and myelin, integrate into host tissue, restore functional connectivity, and provide trophic support to enhance and direct intrinsic regenerative ability, has been seen as a most encouraging step forward. The advent of the induced pluripotent stem cell (iPSC), which represents the ability to "reprogram" somatic cells into a pluripotent state, hails the arrival of a new cell transplantation candidate for potential clinical application in therapies designed to promote repair and/or regeneration of the CNS. Since the initial development of iPSC technology, these cells have been extensively characterized in vitro and in a number of pathological conditions and were originally reported to be equivalent to embryonic stem cells (ESCs). This review highlights emerging evidence that suggests iPSCs are not necessarily indistinguishable from ESCs and may occupy a different "state" of pluripotency with differences in gene expression, methylation patterns, and genomic aberrations, which may reflect incomplete reprogramming and may therefore impact on the regenerative potential of these donor cells in therapies. It also highlights the limitations of current technologies used to generate these cells. Moreover, we provide a systematic review of the state of play with regard to the use of iPSCs in the treatment of neurodegenerative and neuropathological conditions. The importance of balancing the promise of this transplantation candidate in the light of these emerging properties is crucial as the potential application in the clinical setting approaches. The first of three sections in this review discusses (A) the pathophysiology of spinal cord injury (SCI) and how stem cell therapies can positively alter the pathology in experimental SCI. Part B summarizes (i) the available technologies to deliver transgenes to generate iPSCs and (ii) recent data comparing iPSCs to ESCs in terms of characteristics and molecular composition. Lastly, in (C) we evaluate iPSC-based therapies as a candidate to treat SCI on the basis of their neurite induction capability compared to embryonic stem cells and provide a summary of available in vivo data of iPSCs used in SCI and other disease models.

摘要

移植疗法旨在修复中枢神经系统(CNS)的神经退行性和神经病理学状况,已经利用和测试了多种细胞候选物,每种细胞都有其独特的优点和缺点。每种细胞类型的使用和流行程度受到多种因素的指导,包括实验模型的性质、神经保护能力、促进可塑性和引导轴突生长的能力以及细胞的髓鞘形成能力。干细胞的前景,据报道,它们能够产生神经元谱系来替代丢失的内源性细胞和髓鞘,整合到宿主组织中,恢复功能连接,并提供营养支持以增强和指导内在的再生能力,被视为最令人鼓舞的一步。诱导多能干细胞(iPSC)的出现代表了将体细胞“重编程”为多能状态的能力,为潜在的临床应用带来了新的细胞移植候选物,旨在促进 CNS 的修复和/或再生。自 iPSC 技术的最初发展以来,这些细胞已经在体外和许多病理条件下得到了广泛的表征,并且最初被报道与胚胎干细胞(ESCs)相当。本综述强调了新出现的证据,表明 iPSC 不一定与 ESCs 不可区分,并且可能具有不同的“状态”多能性,在基因表达、甲基化模式和基因组异常方面存在差异,这可能反映了不完全重编程,并因此影响这些供体细胞在治疗中的再生潜力。它还强调了当前用于生成这些细胞的技术的局限性。此外,我们系统地回顾了 iPSC 在治疗神经退行性和神经病理学疾病中的应用现状。在这些新兴特性的背景下平衡这种移植候选物的前景的重要性至关重要,因为潜在的临床应用正在逼近。本综述的三个部分中的第一部分讨论了(A)脊髓损伤(SCI)的病理生理学以及干细胞疗法如何积极改变实验性 SCI 的病理学。B 部分总结了(i)将转基因递送到生成 iPSC 的可用技术和(ii)最近比较 iPSC 与 ESCs 在特性和分子组成方面的比较数据。最后,在(C)中,我们根据它们与胚胎干细胞相比的诱导神经元突起的能力来评估基于 iPSC 的疗法作为治疗 SCI 的候选物,并提供了 iPSC 在 SCI 和其他疾病模型中使用的可用体内数据的摘要。

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