Cierpka-Kmiec Katarzyna, Wronska Agata, Kmiec Zbigniew
Department of Hypertension and Diabetology, Medical University of Gdansk, Poland, Gdańsk, Poland.
Department of Histology, Medical University of Gdansk, Poland.
Folia Histochem Cytobiol. 2019;57(1):1-14. doi: 10.5603/FHC.a2019.0001. Epub 2019 Mar 14.
Diabetes mellitus is a chronic disease that affects hundreds of millions of people worldwide. Type 1 diabetes (T1D) is characterized by the lack of pancreatic β-cells that had been destroyed as a result of an autoimmune response. Therefore, in patients with T1D, the replacement therapy with functional β-cells derived from extrinsic sources could be a preferable option as compared to insulin treatment. Unfortunately, successful transplantation of whole pancreata or pancreatic islets into patients with diabetes is available only to a fraction of them due to the scarcity of donors. The rapid development of cell reprogramming methods made it possible to generate large numbers of human β-like cells derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs). This review describes the basis of in vitro differentiaton protocols of β-like cells that mimic changes of the main signaling pathways during the key stages of human and murine pancreas development, which are described first. During the last 15 years it was found that there are no important differences between hESCs and hiPSCs in their differentiation capacities into β-like cells and the expression profiles of the key transcription factors. The in vitro produced β-like cells are immature as demonstrated by functional tests in rodents and single-cell transcriptomic and proteomic analyses. After the transplantation of the β cell progenitors into immunocompromised diabetic mice, a few weeks have to pass before the increased insulin levels in response to glucose load appear. There is a continuous progress in the development of open-type encapsulation devices which allow the vascularization of the transplanted cells and protect them against host's immune cells. The results of the first clinical trial of human partially differentiated endocrine progenitors of β cells transplanted into patients with T1D will be published in the year 2019. It is hoped that further improvements in the techniques of large-scale generation of the β-like cells derived from human pluripotent stem cells will bring us closer to their clinical application as a form of cause-directed therapy for people with diabetes.
糖尿病是一种影响全球数亿人的慢性疾病。1型糖尿病（T1D）的特征是由于自身免疫反应导致胰腺β细胞缺失。因此，与胰岛素治疗相比，用外源性功能β细胞进行替代治疗可能是T1D患者的更优选择。不幸的是，由于供体稀缺，只有一小部分糖尿病患者能够成功接受全胰腺或胰岛移植。细胞重编程方法的快速发展使得从人类胚胎干细胞（hESCs）或人类诱导多能干细胞（hiPSCs）中大量生成人类β样细胞成为可能。本综述首先描述了人类和小鼠胰腺发育关键阶段主要信号通路变化的β样细胞体外分化方案的基础。在过去15年中发现，hESCs和hiPSCs在分化为β样细胞的能力以及关键转录因子的表达谱方面没有重要差异。如在啮齿动物中的功能测试以及单细胞转录组和蛋白质组分析所示，体外产生的β样细胞是不成熟的。将β细胞祖细胞移植到免疫受损的糖尿病小鼠中后，需要几周时间才能出现对葡萄糖负荷的胰岛素水平升高。开放式封装装置的开发不断取得进展，这些装置允许移植细胞血管化并保护它们免受宿主免疫细胞的攻击。将人类部分分化的β细胞内分泌祖细胞移植到T1D患者中的首次临床试验结果将于2019年公布。希望人类多能干细胞来源的β样细胞大规模生成技术的进一步改进能使我们更接近将其作为糖尿病患者病因导向治疗的临床应用。
