McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario M5G 1L7, Canada.
Semin Cell Dev Biol. 2012 Aug;23(6):701-10. doi: 10.1016/j.semcdb.2012.06.010. Epub 2012 Jun 26.
The loss of beta cells in Type I diabetes ultimately leads to insulin dependence and major complications that are difficult to manage by insulin injections. Given the complications associated with long-term administration of insulin, cell-replacement therapy is now under consideration as an alternative treatment that may someday provide a cure for this disease. Over the past 10 years, islet transplantation trials have demonstrated that it is possible to replenish beta cell function in Type I diabetes patients and, at least temporarily, eliminate their dependency on insulin. While not yet optimal, the success of these trials has provided proof-of-principle that cell replacement therapy is a viable option for treating diabetes. Limited access to donor islets has launched a search for alternative source of beta cells for cell therapy purposes and focused the efforts of many investigators on the challenge of deriving such cells from human embryonic (hESCs) and induced pluripotent stem cells (hiPSCs). Over the past five years, significant advances have been made in understanding the signaling pathways that control lineage development from human pluripotent stem cells (hPSCs) and as a consequence, it is now possible to routinely generate insulin producing cells from both hESCs and hiPSCs. While these achievements are impressive, significant challenges do still exist, as the majority of insulin producing cells generated under these conditions are polyhormonal and non functional, likely reflecting the emergence of the polyhormonal population that is known to arise in the early embryo during the phase of pancreatic development known as the 'first transition'. Functional beta cells, which arise during the second phase or transition of pancreatic development have been generated from hESCs, however they are detected only following transplantation of progenitor stage cells into immunocompromised mice. With this success, our challenge now is to define the pathways that control the development and maturation of this second transition population from hPSCs, and establish conditions for the generation of functional beta cells in vitro.
1 型糖尿病中β细胞的丧失最终导致胰岛素依赖和难以通过胰岛素注射来控制的主要并发症。鉴于长期使用胰岛素的相关并发症，细胞替代疗法目前正被考虑作为一种替代治疗方法，有朝一日可能为这种疾病提供治愈方法。在过去的 10 年中，胰岛移植试验已经证明，在 1 型糖尿病患者中补充β细胞功能是可能的，并且至少可以暂时消除他们对胰岛素的依赖。尽管还不是最佳方案，但这些试验的成功已经证明了细胞替代疗法是治疗糖尿病的一种可行选择。由于供体胰岛的数量有限，人们开始寻找替代的β细胞来源，用于细胞治疗，并促使许多研究人员致力于从人类胚胎（hESCs）和诱导多能干细胞（hiPSCs）中获得这些细胞的挑战。在过去的五年中，在理解控制人类多能干细胞（hPSCs）谱系发育的信号通路方面取得了重大进展，因此现在可以从 hESCs 和 hiPSCs 中常规地生成产生胰岛素的细胞。尽管这些成就令人印象深刻，但仍然存在重大挑战，因为在这些条件下生成的大多数产生胰岛素的细胞都是多激素的和无功能的，这可能反映了在胰腺发育的“第一过渡”阶段已知的多激素群体的出现。已经从 hESCs 中生成了功能性β细胞，但仅在将祖细胞阶段的细胞移植到免疫功能低下的小鼠中后才能检测到它们。随着这一成功，我们现在的挑战是定义控制从 hPSCs 中发育和成熟的第二过渡群体的途径，并为体外生成功能性β细胞建立条件。
