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首页> 外文期刊>British Biotechnology Journal >Constraining the Pluripotent Fate of HumanEmbryonic Stem Cells for Tissue Engineeringand Cell Therapy a€“ The Turning Point of Cell-Based Regenerative Medicine
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Constraining the Pluripotent Fate of HumanEmbryonic Stem Cells for Tissue Engineeringand Cell Therapy a€“ The Turning Point of Cell-Based Regenerative Medicine

机译：限制人类胚胎干细胞的多能命运用于组织工程和细胞治疗-基于细胞的再生医学的转折点

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To date, the lack of a clinically-suitable source of engraftable human stem/progenitor cells with adequate neurogenic potential has been the major setback in developing safe and effective cell-based therapies for regenerating the damaged or lost CNS structure and circuitry in a wide range of neurological disorders. Similarly, the lack of a clinically-suitable human cardiomyocyte source with adequate myocardium regenerative potential has been the major setback in regenerating the damaged human heart. Given the limited capacity of the CNS and heart for self-repair, there is a large unmet healthcare need to develop stem cell therapies to provide optimal regeneration and reconstruction treatment options to restore normal tissues and function. Derivation of human embryonic stem cells (hESCs) provides a powerful in vitro model system to investigate molecular controls in human embryogenesis as well as an unlimited source to generate the diversity of human somatic cell types for regenerative medicine. However, realizing the developmental and therapeutic potential of hESC derivatives has been hindered by the inefficiency and instability of generating clinically-relevant functional cells from pluripotent cells through conventional uncontrollable and incomplete multi-lineage differentiation. Recent advances and breakthroughs in hESC research have overcome some major obstacles in bringing hESC therapy derivatives towards clinical applications, including establishing defined culture systems for de novo derivation and maintenance of clinical-grade pluripotent hESCs and lineage-specific differentiation of pluripotent hESCs by small molecule induction. Retinoic acid was identified as sufficient to induce the specification of neuroectoderm direct from the pluripotent state of hESCs and trigger a cascade of neuronal lineage-specific progression to human neuronal progenitors and neurons of the developing CNS in high efficiency, purity, and neuronal lineage specificity by promoting nuclear translocation of the neuronal specific transcription factor Nurr-1. Similarly, nicotinamide was rendered sufficient to induce the specification of cardiomesoderm direct from the pluripotent state of hESCs by promoting the expression of the earliest cardiac-specific transcription factor Csx/Nkx2.5 and triggering progression to cardiac precursors and beating cardiomyocytes with high efficiency. This technology breakthrough enables direct conversion of pluripotent hESCs into a large supply of high purity neuronal cells or heart muscle cells with adequate capacity to regenerate CNS neurons and contractile heart muscles for developing safe and effective stem cell therapies. Transforming pluripotent hESCs into fate-restricted therapy derivatives dramatically increases the clinical efficacy of graft-dependent repair and safety of hESC-derived cellular products. Such milestone advances and medical innovations in hESC research allow generation of a large supply of clinical-grade hESC therapy derivatives targeting for major health problems, bringing cell-based regenerative medicine to a turning point.
机译：迄今为止，在临床上缺乏可移植的具有适当神经源性潜力的人干/祖细胞的来源已成为开发安全有效的基于细胞的疗法以广泛再生受损或丢失的中枢神经系统结构和电路的主要障碍。神经系统疾病。类似地，缺乏具有足够的心肌再生潜力的临床上合适的人心肌细胞来源已成为使受损的人心脏再生的主要障碍。鉴于中枢神经系统和心脏自我修复的能力有限，迫切需要开发干细胞疗法以提供最佳的再生和重建治疗方案以恢复正常组织和功能的医疗保健需求。人类胚胎干细胞（hESCs）的衍生提供了强大的体外模型系统，以研究人类胚胎发生中的分子控制，并提供了无限的来源来产生人类体细胞类型的多样性，以进行再生医学。然而，通过常规的不可控制的和不完全的多谱系分化从多能细胞产生临床相关的功能性细胞的效率低下和不稳定，阻碍了hESC衍生物的开发和治疗潜力的实现。 hESC研究的最新进展和突破克服了将hESC治疗衍生物推向临床应用的一些主要障碍，包括建立用于从头衍生和维持临床级多能hESC的明确培养系统以及通过小分子诱导进行多能hESC的谱系特异性分化。维甲酸被认为足以从hESC的多能状态直接诱导神经外胚层的规格，并通过高效，高纯度和神经元谱系特异性触发一系列神经元谱系特异性进展到人类神经元祖细胞和发育中的CNS神经元。促进神经元特异性转录因子Nurr-1的核易位。同样，通过促进最早的心脏特异性转录因子Csx / Nkx2.5的表达并触发向心脏前体的进展并高效跳动心肌细胞，烟酰胺已足以从hESC的多能状态直接诱导心脏中胚层的规格。这项技术突破使多能性hESC直接转化为大量高纯度神经元细胞或心肌细胞，并具有足够的能力再生CNS神经元和收缩性心肌，从而开发出安全有效的干细胞疗法。将多能hESC转化为受命运限制的治疗衍生物，可显着提高移植物依赖性修复的临床疗效以及hESC衍生的细胞产品的安全性。 hESC研究中的如此里程碑式进展和医学创新，使得能够产生大量针对主要健康问题的临床级hESC治疗衍生物，从而使基于细胞的再生医学成为一个转折点。

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