In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes.
In vivo reprogramming of pancreatic acinar cells to three islet endocrine subtypes.
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作者：
Li W;Nakanishi M;Zumsteg A;Shear M;Wright C;Melton DA;Zhou Q
成体细胞的直接谱系转化是再生医学的一种有前途的方法。谱系转换的一个主要挑战是产生特定的细胞亚型。胰岛含有三种主要的胰岛分泌内分泌亚型：胰岛素+ β细胞、胰高血糖素+ α细胞和生长抑素+ δ细胞。我们先前报道了三种转录因子Ngn 3、Mafa和Pdx 1的组合直接将胰腺腺泡细胞重编程为β细胞。我们现在表明，腺泡细胞可以分别被Ngn 3和Ngn 3 +Mafa转化为δ样和α样细胞。因此，三种主要的胰岛内分泌亚型可以通过腺泡重编程来衍生。Ngn 3促进腺泡细胞中一般内分泌状态的建立，并且还在不存在其他因子的情况下促进δ-特化。在α-和β-细胞诱导期间，δ-特化反过来被Mafa和Pdx 1抑制。这些研究确定了一组定义的因素，其组合行动重新编程腺泡细胞在体内不同的胰岛内分泌亚型。DOI：http://dx.doi.org/10.7554/eLife.01846.001在哺乳动物中，胰腺负责通过从专门的β细胞分泌胰岛素来控制血糖。胰腺中的其他细胞，称为δ细胞和α细胞，分泌其他激素来帮助β细胞。糖尿病是当这个系统崩溃时引起的：要么身体攻击自己的β细胞（I型糖尿病），要么身体停止对胰岛素的适当反应（II型）。I型糖尿病通常用胰岛素注射治疗，但人们对替代有缺陷的β细胞的可能性越来越感兴趣。在先前的工作中，第四种类型的胰腺细胞，称为腺泡细胞，被重新编程为β细胞，Li等人现在已经表明，同样的技术也可以用于产生α和δ细胞。正如重编程的β细胞分泌胰岛素，就像真实的β细胞一样，重编程的α细胞和δ细胞也表现得像真实的α细胞和δ细胞。重编程技术依赖于使用三种转录因子的组合，它们被称为Ngn 3，Pdx 1和Mafa，以处理小鼠的腺泡细胞。以前，研究表明，使用所有三种转录因子的组合将腺泡细胞重编程为β细胞。现在，Li等人表明Ngn 3转录因子本身似乎抑制了通常在腺泡细胞中表达的某些基因，并继续导致腺泡细胞成为δ细胞。然而，Ngn 3和Mafa的组合产生α-和δ-细胞的混合物。下一个挑战是调整这种重编程技术，从人体组织来源产生不同类型的激素分泌细胞，以探索其治疗潜力。DOI：http://dx.doi.org/10.7554/eLife.01846.002网站
Direct lineage conversion of adult cells is a promising approach for regenerative medicine. A major challenge of lineage conversion is to generate specific cell subtypes. The pancreatic islets contain three major hormone-secreting endocrine subtypes: insulin+ β-cells, glucagon+ α-cells, and somatostatin+ δ-cells. We previously reported that a combination of three transcription factors, Ngn3, Mafa, and Pdx1, directly reprograms pancreatic acinar cells to β-cells. We now show that acinar cells can be converted to δ-like and α-like cells by Ngn3 and Ngn3+Mafa respectively. Thus, three major islet endocrine subtypes can be derived by acinar reprogramming. Ngn3 promotes establishment of a generic endocrine state in acinar cells, and also promotes δ-specification in the absence of other factors. δ-specification is in turn suppressed by Mafa and Pdx1 during α- and β-cell induction. These studies identify a set of defined factors whose combinatorial actions reprogram acinar cells to distinct islet endocrine subtypes in vivo. DOI: http://dx.doi.org/10.7554/eLife.01846.001 In mammals, the pancreas is responsible for controlling blood sugar by secreting insulin from specialized β-cells. Other cells in the pancreas, called δ-cells and α-cells, secrete other hormones to assist the β-cells. Diabetes is caused when this system breaks down: either the body attacks its own β-cells (type I diabetes), or the body stops responding properly to insulin (type II). Type I diabetes is usually treated with insulin injections, but there is increasing interest in the possibility of replacing the defective β-cells instead. Building on previous work in which a fourth type of pancreatic cell, called an acinar cell, was reprogrammed to become a β-cell, Li et al. have now shown that the same technique can be used to produce α- and δ-cells as well. Just as the reprogrammed β-cells secreted insulin, like real β-cells, the reprogrammed α- and δ-cells also behaved like real α- and δ-cells. The reprogramming technique relies on using a combination of three transcription factors—which are called Ngn3, Pdx1 and Mafa—to treat the acinar cells from mice. Previously, it was shown that using a combination of all three transcription factors reprogrammed the acinar cells to become β-cells. Now, Li et al. show that the Ngn3 transcription factor on its own appears to suppress certain genes that are usually expressed in acinar cells, and goes on to cause the acinar cells to become δ-cells. However, a combination of Ngn3 and Mafa produces a mixture of α- and δ-cells. The next challenge is to adapt this reprogramming technique to generate different types of hormone secreting cells from human tissue sources in order to explore its therapeutic potential. DOI: http://dx.doi.org/10.7554/eLife.01846.002