Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Education City, Doha, Qatar.
Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, U.S.A.
Biol Rev Camb Philos Soc. 2018 Feb;93(1):364-389. doi: 10.1111/brv.12349. Epub 2017 Jun 22.
The loss of functional β cells leads to development of diabetes. Several studies have shown that β cells are specified through several stages of progenitors during pancreas development, each stage defined by the expression of specific transcription factors (TFs). Understanding signalling pathways that control the differentiation and specification processes during embryogenesis will facilitate efforts to obtain functional β cells in vitro. Our current knowledge of the mechanisms involved in pancreatic β cell development and survival under normal or diabetic conditions has come largely from animal studies. However, there are marked differences in islet structure and physiological properties between humans and animals, and not all phenotypes of human diabetes can be recapitulated in animal models. Therefore, human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced PSCs (hiPSCs) offer a great opportunity for increasing our understanding of the pathways regulating human pancreatic β-cell development and survival. Furthermore, hPSCs provide a renewable source of functional pancreatic β cells for cell replacement therapy as well as disease modelling. Herein, we discuss the signalling pathways involved in the development of pancreatic β cells during embryogenesis. Additionally, we describe how these pathways are manipulated in vitro to differentiate hPSCs into functional β cells. Finally, we highlight the progress that has been made for the applications of those cells in treating and modelling diabetes.
功能性β细胞的丧失会导致糖尿病的发生。有几项研究表明，β细胞是在胰腺发育过程中通过几个祖细胞阶段特化而来的，每个阶段都由特定转录因子（TF）的表达来定义。了解控制胚胎发生过程中分化和特化的信号通路将有助于在体外获得功能性β细胞。我们目前对正常或糖尿病条件下胰腺β细胞发育和存活所涉及的机制的了解主要来自于动物研究。然而，人类和动物之间在胰岛结构和生理特性上存在明显差异，并非所有人类糖尿病的表型都可以在动物模型中重现。因此，人类多能干细胞（hPSCs），包括人类胚胎干细胞（hESCs）和人类诱导多能干细胞（hiPSCs），为我们增加对调节人类胰腺β细胞发育和存活的通路的理解提供了很好的机会。此外，hPSCs 为细胞替代治疗和疾病建模提供了可再生的功能性胰腺β细胞来源。本文讨论了胚胎发生过程中胰腺β细胞发育所涉及的信号通路。此外，我们还描述了如何在体外操纵这些通路将 hPSCs 分化为功能性β细胞。最后，我们强调了在治疗和模拟糖尿病方面应用这些细胞所取得的进展。
