Leveraging the genetic diversity of human stem cells in therapeutic approaches.
Leveraging the genetic diversity of human stem cells in therapeutic approaches.
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DOI：
10.1016/j.jmb.2021.167221
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发表时间：
2021-08
影响因子：
5.6
通讯作者：
M. Tegtmeyer;R. Nehme
中科院分区：
文献类型：
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作者：
M. Tegtmeyer;R. Nehme
自15年前发现以来，人类多能干细胞( )技术已经开始给科学和医学带来革命性的变化，迅速从调查性研究扩展到药物发现和开发。在过去的十年里，利用hPSC的努力主要集中在通过增强分化方法来增加人类细胞模型的复杂性和活体保真度。虽然这些进展促进了对疾病机制的新见解，并影响了临床药物的发现和开发，但仍有几个因素限制了hPSC模型的实用性。在这次审查中，我们强调了扩大其影响范围的重要但未被探索的途径。我们侧重于(I)现有hPSC收集的多样性的重要性，以及它们在研究不同遗传背景、血统和性别的个体的治疗策略方面的利用；(Ii)选择具有治疗意义的hPSC模型的考虑；(Iii)充分扩大基于细胞的研究规模的策略；以及(Iv)在培养皿中进行临床试验的进展和限制。此外，我们主张利用hPSC模型的翻译能力，并使用创新的、可扩展的方法来了解遗传偏见以及性别和血统对疾病机制、药物疗效和反应的影响。HPSC创新的下一个十年将为人类疾病的遗传基础提供广泛的见解，并使快速进步能够在不同的人类群体中开发、调整用途和确保下一代疾病疗法的安全性。
Since their discovery 15 years ago, human pluripotent stem cell (hPSC) technologies have begun to revolutionize science and medicine, rapidly expanding beyond investigative research to drug discovery and development. Efforts to leverage hPSCs over the last decade have focused on increasing both the complexity andin vivofidelity of human cellular models through enhanced differentiation methods. While these evolutions have fostered novel insights into disease mechanisms and influenced clinical drug discovery and development, there are still several considerations that limit the utility of hPSC models. In this review, we highlight important, yet underexplored avenues to broaden their reach. We focus on (i) the importance of diversifying existing hPSC collections, and their utilization to investigate therapeutic strategies in individuals from different genetic backgrounds, ancestry and sex; (ii) considerations for the selection of therapeutically relevant hPSC-based models; (iii) strategies to adequately increase the scale of cell-based studies; and (iv) the advances and constraints of clinical trials in a dish. Moreover, we advocate for harnessing the translational capabilities of hPSC models along with the use of innovative, scalable approaches for understanding genetic biases and the impact of sex and ancestry on disease mechanisms and drug efficacy and response. The next decade of hPSC innovation is poised to provide vast insights into the genetic basis of human disease and enable rapid advances to develop, repurpose, and ensure the safety of the next generation of disease therapies across diverse human populations.