Stem Cell-Based Tissue Replacement After Stroke: Factual Necessity or Notorious Fiction?
Stem Cell-Based Tissue Replacement After Stroke: Factual Necessity or Notorious Fiction?
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DOI：
10.1161/strokeaha.114.007803
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发表时间：
2015-08
期刊：
影响因子：
8.3
通讯作者：
Boltze J
中科院分区：
文献类型：
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作者：
Janowski M;Wagner DC;Boltze J
Janowski等，基于干细胞的卒中治疗，来自该试验的2355例患者显示移植部位存在神经毒性免疫反应性神经元，且不存在肿瘤。没有研究移植细胞在宿主神经元回路中的功能整合。[12]随后的II期临床试验在一些患者中得到了改善，但在统计学上也没有证实总体益处。13然而，在评估这些研究的结果时，必须考虑到早期临床试验的统计功效有限。鉴于主要关注安全性方面，且入组的患者数量相对较少，因此任何治疗效果必须具有显著的规模，才能在统计学显著性水平上检测到。虽然在IIa/B期研究中无法预期具有实际疗效的统计学证据，但疗效终点通常包括在研究设计中，并且在决定继续使用相应治疗时被认为是至关重要的，特别是在工业环境中。虽然从经济角度来看可以理解，但这种做法显然存在假阴性结果和过早放弃原本有希望的实验性疗法的风险。由于使用有丝分裂后肿瘤源性神经元的临床研究结果并不完全令人信服，因此使用原代胎儿源性神经干细胞（NSC）的策略已经恢复。此外，现在推测，真正的组织恢复策略将不得不考虑脑组织的所有主要组成部分，即神经元，星形胶质细胞和少突胶质细胞，这可能会带来不同的挑战（图1A）。一项研究令人信服地显示了神经元分化，但没有研究移植物的整合。另一项研究不仅揭示了移植的胚胎内侧神经节隆起前体细胞的神经分化，
Janowski et al Stem Cell–Based Stroke Therapies 2355 patient from this trial revealed neurofilament-immunoreactive neurons at the graft location and the absence of neoplasms. Functional integration of transplanted cells within host neuronal circuitries was not investigated. 12 The subsequent phase II clinical trial resulted in improvements in some patients, but again no overall benefit was confirmed statistically. 13 However, the limited statistical power of early stage clinical trials must be considered when assessing results from such studies. Given the primary focus on safety aspects and the relatively small number of patients enrolled, any therapeutic effect must be of notable size to be detected at statistical significance. Although statistical prove of a therapeutic effect of realistic size cannot be expected in phase IIa/b studies, efficacy end points are often included in the study design and are considered crucial when deciding on the continuation with a respective therapy, particularly in the industrial environment. Although understandable from an economic perspective, this practice clearly bears the risk for false-negative results and premature abandonment of otherwise promising experimental therapies. Because the outcome of clinical studies using postmitotic, tumor-derived neurons has not been completely convincing, the strategy of using primary fetal-derived neural stem cells (NSCs) has been revived. Moreover, it is now speculated that true tissue restoration strategies will have to consider all major components of cerebral tissue, that is, neurons, astro-and oligodendroglia, which may come with different challenges (Figure 1A). One study convincingly showed neuronal differentiation, but integration of the graft was not studied. 15 Another study revealed not only neural differentiation of grafted embryonic medial ganglionic eminence precursor cells but also robust