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 and in vivo fidelity 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 clinal 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.

自 15 年前发现以来，人类多能干细胞 (hPSC) 技术已经开始彻底改变科学和医学，迅速从调查研究扩展到药物发现和开发。过去十年利用 hPSC 的努力集中在增加复杂性和体内通过增强的分化方法提高人类细胞模型的保真度。虽然这些演变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，但仍有一些考虑因素限制了 hPSC 模型的效用。在本次审查中，我们强调了重要但尚未充分探索的途径来扩大其影响范围。我们专注于 (i) 使现有 hPSC 集合多样化的重要性，以及它们用于研究来自不同遗传背景、血统和性别的个体的治疗策略；(ii) 选择治疗相关的基于 hPSC 的模型的考虑因素；iii) 充分扩大细胞研究规模的战略；iv) 培养皿中临床试验的进展和限制。而且，我们提倡利用 hPSC 模型的转化能力以及使用创新的、可扩展的方法来理解遗传偏差以及性别和血统对疾病机制和药物疗效和反应的影响。下一个十年的 hPSC 创新有望为人类疾病的遗传基础提供广泛的见解，并推动快速进展以开发、重新利用和确保下一代疾病疗法在不同人群中的安全性。