Middendorp Sabine, Schneeberger Kerstin, Wiegerinck Caroline L, Mokry Michal, Akkerman Ronald D L, van Wijngaarden Simone, Clevers Hans, Nieuwenhuis Edward E S
Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
Stem Cells. 2014 May;32(5):1083-91. doi: 10.1002/stem.1655.
Differentiation and specialization of epithelial cells in the small intestine are regulated in two ways. First, there is differentiation along the crypt-villus axis of the intestinal stem cells into absorptive enterocytes, Paneth, goblet, tuft, enteroendocrine, or M cells, which is mainly regulated by WNT. Second, there is specialization along the cephalocaudal axis with different absorptive and digestive functions in duodenum, jejunum, and ileum that is controlled by several transcription factors such as GATA4. However, so far it is unknown whether location-specific functional properties are intrinsically programmed within stem cells or if continuous signaling from mesenchymal cells is necessary to maintain the location-specific identity of the small intestine. Using the pure epithelial organoid technique, we show that region-specific gene expression profiles are conserved throughout long-term cultures of both mouse and human intestinal stem cells and correlated with differential Gata4 expression. Furthermore, the human organoid culture system demonstrates that Gata4-regulated gene expression is only allowed in absence of WNT signaling. These data show that location-specific function is intrinsically programmed in the adult stem cells of the small intestine and that their differentiation fate is independent of location-specific extracellular signals. In light of the potential future clinical application of small intestine-derived organoids, our data imply that it is important to generate GATA4-positive and GATA4-negative cultures to regenerate all essential functions of the small intestine.
小肠上皮细胞的分化和特化通过两种方式进行调控。首先，肠道干细胞沿隐窝-绒毛轴分化为吸收性肠上皮细胞、潘氏细胞、杯状细胞、簇状细胞、肠内分泌细胞或M细胞，这主要由WNT调控。其次，十二指肠、空肠和回肠沿头尾轴具有不同的吸收和消化功能，这种特化由几种转录因子如GATA4控制。然而，到目前为止，尚不清楚位置特异性功能特性是在干细胞内固有编程的，还是间充质细胞的持续信号对于维持小肠的位置特异性特征是必需的。利用纯上皮类器官技术，我们发现区域特异性基因表达谱在小鼠和人类肠道干细胞的长期培养中都得以保留，并且与Gata4的差异表达相关。此外，人类类器官培养系统表明，Gata4调控的基因表达仅在没有WNT信号时才会发生。这些数据表明，位置特异性功能在小肠的成体干细胞中是固有编程的，并且它们的分化命运独立于位置特异性细胞外信号。鉴于小肠来源的类器官未来潜在的临床应用，我们的数据意味着生成GATA4阳性和GATA4阴性培养物对于再生小肠的所有基本功能很重要。
