Lees Justin G, Tuch Bernard E
Diabetes Transplant Unit, Prince of Wales Hospital/University of New South Wales, Randwick, New South Wales, Australia.
Regen Med. 2006 May;1(3):327-36. doi: 10.2217/17460751.1.3.327.
Cellular therapies to treat Type 1 diabetes are being devised and the use of human embryonic stem cells (hESCs) offers a solution to the issue of supply, because hESCs can be maintained in a pluripotent state indefinitely. Furthermore, hESCs have advantages in terms of their plasticity and reduced immunogenicity. Several strategies that have so far been investigated indicate that hESCs are capable of differentiating into insulin producing beta-cell surrogates. However the efficiency of the differentiation procedures used is generally quite low and the cell populations derived are often highly heterogenous. A strategy that appears to have long term potential is to design differentiation procedures based on the ontogeny of the beta-cell. The focus of this strategy is to replicate signaling processes that are known to be involved in the maturation of a beta-cell. The earliest pancreatic progenitors found in the developing vertebrate fetus are produced via a process known as gastrulation and form part of the definitive endoderm germ layer. hESCs have recently been differentiated into definitive endoderm with high efficiency using a differentiation procedure that mimics the signaling that occurs during gastrulation and the formation of the definitive endoderm. Subsequent events during pancreas development involve a section of the definitive endoderm forming into pancreatic epithelium, which then branches into the pancreatic mesenchyme to form islet clusters of endocrine cells. A proportion of the endocrine precursor cells within islets develop into insulin producing beta-cells. The challenge currently is to design hESC differentiation procedures that mimic the combined events of these stages of beta-cell development.
治疗1型糖尿病的细胞疗法正在被研发，而人类胚胎干细胞（hESCs）的使用为供应问题提供了解决方案，因为hESCs可以无限期地维持在多能状态。此外，hESCs在可塑性和降低免疫原性方面具有优势。迄今为止研究的几种策略表明，hESCs能够分化为产生胰岛素的β细胞替代物。然而，所使用的分化程序的效率通常相当低，并且衍生的细胞群体往往高度异质。一种似乎具有长期潜力的策略是基于β细胞的个体发生来设计分化程序。该策略的重点是复制已知参与β细胞成熟的信号传导过程。在发育中的脊椎动物胎儿中发现的最早的胰腺祖细胞是通过一种称为原肠胚形成的过程产生的，并且是确定的内胚层胚层的一部分。最近，利用一种模仿原肠胚形成和确定内胚层形成过程中发生的信号传导的分化程序，hESCs已被高效分化为确定的内胚层。胰腺发育过程中的后续事件包括确定的内胚层的一部分形成胰腺上皮，然后分支进入胰腺间充质以形成内分泌细胞的胰岛簇。胰岛内的一部分内分泌前体细胞发育成产生胰岛素的β细胞。目前的挑战是设计模仿β细胞发育这些阶段的联合事件的hESC分化程序。
