肠外营养改善患者结局的治疗策略：细胞信号转导网络线索

　　肠绒毛由脉管核心和上皮层组成，其形成过程主要发生在胚胎期。长期PN会导致肠绒毛萎缩、低平，肠吸收和肠屏障功能损害，导致不良临床结局，而暂无证据表明肠绒毛可再生。

　　为了探讨肠绒毛形成过程的细胞和分子机制，美国密歇根大学医学院对小鼠进行研究，发现Notch信号通路能调控胚胎期肠绒毛的血管芽生成，抑制上皮细胞中Notch信号通路可使血管芽过度生长，导致绒毛异常。这为研究肠绒毛的生长过程、修复再生提供了新的方向。

JPEN J Parenter Enteral Nutr. 2016;40:141-143.

Toward Therapeutic Strategies to Improve Patient Outcome With Parenteral Nutrition: Clues From Cell Signaling Networks.

Katherine D. Walton; Deepa Chandhrasekhar; Daniel Teitelbaum; Deborah L. Gumucio.

University of Michigan Medical School, Ann Arbor, MI, USA.

Purpose: Villi increase the intestinal absorptive area by 10-fold. They are composed of an epithelial layer and a mesodermal core that includes vascular and lymphatic networks. Loss of intestinal length (surgical or congenital) or loss of villi due to inflammation can result in malabsorption. Parenteral nutrition provides lifesaving support; however, the villi of patients receiving PN undergo atrophy, shortening/flattening of villi, and decreased barrier function, resulting in compromised protection against intestinal flora. Atrophy is accompanied by remodeling of the vascular core and activation of cell signaling networks used to communicate between the vasculature and epithelial cells of the intestine during development and homeostasis. These cell signaling networks also drive adaptive changes following bowel resection (eg, lengthening and widening); however, there is no evidence that new villi form in adult tissues, and the growth of villi in cultured explants is currently limited. Villus formation may be primarily a fetal event; therefore, understanding how these signaling networks drive villus morphogenesis will aid in identifying therapeutic strategies toward generating villus growth in patients and engineered intestinal tissues. In the fetal mouse, villi emerge from a flat epithelium following the formation of mesodermal cell clusters that grow with the emerging villus and become part of the villus core. Nascent clusters contain vascular elements, without which villi fail to form, providing a direct link between the vasculature and villus growth. Little is known about the timing or molecular signals controlling intestinal vascular development, though in other systems, Notch signaling is a critical regulator. Here, examination in mouse models with altered Notch signaling reveals some of the underlying cellular and molecular mechanisms involved in villus development.

Methods: Vasculature, epithelium, and clusters were stained with tissue-specific antibodies to examine their relationships at key stages of development. Then, to investigate the role of Notch in linking mesenchymal clusters and vasculature, Notch signaling was perturbed by deleting Rbpj, a required cofactor, specifically in the vasculature or in the mesenchymal cluster cells prior to cluster formation. Changes in villus vasculature and cluster pattern were examined to determine the contribution of Notch signaling in each cell type to villus patterning.

Results: Vasculature first appears as individual cells at E10.5. By E12.5, sprouts from the vascular plexus reach toward the epithelium and interact with subepithelial mesenchymal cells. Clusters are first detected at E14 as small aggregations of 5-8 cells that are intimately associated with 2 vascular sprouts. At E14.5 clusters have grown to about 25 cells and continue to be tightly associated with the 2 vascular sprouts. By E15, the clusters contain about 50 cells, and each cluster has a large stellate-like cell that is positive for VEGFRa and Ecadherin and is Notch responsive. Further characterization of the role of this stellate cell in cluster formation, vascular patterning, and villus outgrowth is a future goal. Intestines with loss of Notch signaling in the cluster cells appear to have normal villi with clusters and vasculature similar to control littermates. However, loss of Notch signaling in endothelial cells results in abnormal villi with multiple large clusters and vascular overgrowth.

Conclusions: Notch signaling regulates vascular pattern and development in the embryonic intestine. Loss of endothelial Notch signaling increases vascular sprouting and results in larger villi with multiple clusters. Vascular sprouts may provide a cue for the initiation of mesenchymal clusters.

Financial support: A.S.P.E.N. Rhoads Research Foundation.