The digestive tract is a vital organ characterized by its exceptional length and its morphological and functional regionalization. It is present in all species where it ensures food intake, its transit and the elimination of feces (de Santa Barbara et al., 2002).
The embryonic digestive tract is a tubular structure, consisting of endoderm and splanchnic mesoderm. Its final morphology requires a regionalization of this organ along the anteroposterior (AP) axis into different organs such as the esophagus, stomach, duodenum, intestine and colon. During digestive organogenesis, the endoderm differentiates into the epithelium; the splanchnic mesoderm, evolves into mesenchyme, and differentiates along the radial axis (RAD) into four distinct concentric layers, depending on their distance from the epithelium. The most peripheral region differentiates into longitudinal and circular layers of smooth muscle cells (SMC) which provide contractions of the digestive tract. These processes of differentiation according to the different axes that occur during development are essential for the digestive tract to be able to carry out its basic function (de Santa Barbara et al., 2002; Faure and de Santa Barbara, 2011). In addition, mature SMCs have the unique ability to be able to dedifferentiate into proliferative progenitors to ensure the growth of digestive tissue during the pediatric period (Le Guen et al. 2015).
Our basic research focuses on the identification of the mechanisms that control the differentiation of digestive mesenchymal progenitors in SMC cells and their plasticity.
Our studies on the development of digestive smooth muscle have shown that regulation of the BMP, FGF, NOTCH, and YAP/TAZ signaling pathways is essential in controlling the differentiation of SMCs and their plasticity (Notarnicola et al., 2012; Sagnol et al., 2014; Faure et al. 2015; Sagnol et al. 2016; McKey et al. 2016; Guérin et al. 2020; Guerin et al. 2022). Since the YAP/TAZ pathway controls the expression of regulators of the dynamics of the fusion/fission process of mitochondria (Nagaraj et al. 2012; Deng et al. 2016), we are interested in mitochondrial metabolism. It is now well argued that embryonic pluripotent stem cells, during their differentiating, switch from the glycolysis pathway to the oxidative phosphorylation. This notion of metabolic plasticity according to cellular needs is not restricted to cancer cells or pluripotent stem cells and could regulate digestive mesenchymal progenitor differentiation.
Moreover, we recently focused on the mechanisms that characterize the maturation of digestive smooth muscle. We have established a transcriptomic profile of the late stages of the differentiation process (Unpublished data). We assessed the mechanisms that regulate digestive motility during development and showed that the enteric nervous system and interstitial cells of Cajal are essential for the differentiation and functionality of digestive smooth muscle (Faure et al. 2015; Bourret et al 2017; Chevalier et al. 2020; Sicard et al. 2022).
The main objectives of the Fundamental Research Axis are to better characterize the mechanisms that regulate the process of differentiation of mesenchymal progenitors, with particular emphasis on mitochondrial metabolic regulation (objective 1) and to determine the mechanisms that govern SMC maturation and the establishment of digestive motility (objective 2). The strength of this project resides on the multitude of complementary approaches developed, combining animal models and new innovative approaches (chicken embryo ultrasound, 3-dimensional imaging), in vitro use of avian and human primary digestive cell models, evaluation of the mitochondrial metabolism and the development of novel functional approaches (Deshayes et al. 2020).