Mastracci Teresa L, Sussel Lori
Department of Genetics and Development, Columbia University, New York, NY, USA.
Wiley Interdiscip Rev Dev Biol. 2012 Sep-Oct;1(5):609-28. doi: 10.1002/wdev.44. Epub 2012 Mar 14.
In the developing embryo, appropriate patterning of the endoderm fated to become pancreas requires the spatial and temporal coordination of soluble factors secreted by the surrounding tissues. Once pancreatic progenitor cells are specified in the developing gut tube epithelium, epithelial-mesenchymal interactions, as well as a cascade of transcription factors, subsequently delineate three distinct lineages, including endocrine, exocrine, and ductal cells. Simultaneous morphological changes, including branching, vascularization, and proximal organ development, also influence the process of specification and differentiation. Decades of research using mouse genetics have uncovered many of the key factors involved in pancreatic cell fate decisions. When pancreas development or islet cell functions go awry, due to mutations in genes important for proper organogenesis and development, the result can lead to a common pancreatic affliction, diabetes mellitus. Current treatments for diabetes are adequate but not curative. Therefore, researchers are utilizing the current understanding of normal embryonic pancreas development in vivo, to direct embryonic stem cells toward a pancreatic fate with the goal of transplanting these in vitro generated 'islets' into patients. Mimicking development in vitro has proven difficult; however, significant progress has been made and the current differentiation protocols are becoming more efficient. The continued partnership between developmental biologists and stem cell researchers will guarantee that the in vitro generation of insulin-producing β cells is a possible therapeutic option for the treatment of diabetes.
在发育中的胚胎中，注定要形成胰腺的内胚层的适当模式形成需要周围组织分泌的可溶性因子在空间和时间上的协调。一旦胰腺祖细胞在发育中的肠管上皮中被确定，上皮-间充质相互作用以及一系列转录因子随后会界定出三个不同的谱系，包括内分泌细胞、外分泌细胞和导管细胞。同时发生的形态变化，包括分支、血管形成和近端器官发育，也会影响细胞命运的确定和分化过程。数十年来利用小鼠遗传学进行的研究已经揭示了许多参与胰腺细胞命运决定的关键因素。当胰腺发育或胰岛细胞功能出现异常时，由于对正常器官发生和发育至关重要的基因突变，结果可能导致一种常见的胰腺疾病——糖尿病。目前糖尿病的治疗方法是有效的，但不能治愈。因此，研究人员正在利用目前对体内正常胚胎胰腺发育的了解，引导胚胎干细胞走向胰腺细胞命运，目标是将这些体外生成的“胰岛”移植到患者体内。事实证明，在体外模拟发育过程很困难；然而，已经取得了重大进展，目前的分化方案也变得更加有效。发育生物学家和干细胞研究人员之间持续的合作将确保体外生成产生胰岛素的β细胞成为治疗糖尿病的一种可能的治疗选择。
