Offre de thèse : Development of fat-on-chip model to study liver/fat tissue interactions during NAFLD progression
Sujet : Development of fat-on-chip model to study liver/fat tissue interactions during NAFLD progression
Laboratoire/équipe : UMR CNRS 7338 Biomécanique et Bioingénierie
Mots clés : Adipocytes, 3D cell culture, microfluidics, organoid, organ-on-chip, NAFLD
Among metabolic diseases, non-alcoholic fatty liver disorder (NAFLD) is becoming the most frequent liver disease. Nowadays, it is estimated that around 24% of European adults develop NAFLD, 10–30% of them will evolve to NASH, among which 10–15% will develop fibrosis/cirrhosis and liver hepatocarcinoma. NAFLD prevalence increases to 57% in obese subjects, 70% in diabetic subjects and 90% in morbidly obese people. Although the food was identified as one source, the origin and the sequence of the development of the NAFLD is still controversial. Because NAFLD is systemic disease, the challenges are to consider the interactions between the different organs involved in the disease progression. In fact, the fat accumulation (adipocytes expansion) associated to NAFLD constitutes a serious threat in the disease development. Adipose tissue secretes free fatty acids (FFAs) and hormones, known as adipokines, and thus seems to play a major role in the development of NAFLD. To our knowledge, there is no relevant in vitro human “classical” 2D culture recapitulating the liver/adipose tissue interactions. Furthermore, animal studies fail to produce data that can be extrapolated to human.
To address these issues, we propose an organ-on-chip strategy allowing to reproduce the fat and liver crosstalks. BMBI has developed a large panel of liver-on-chip models using cell line and primary hepatocytes. BMBI collaborates also with LIMMS (U Tokyo), which developing healthy and NAFLD multicellular liver-on-chip using hiPSCs.
The present PhD project will focus on the development of fat-on-chip model. The first part of the PhD will request to optimize the fat cell culture conditions as well as the microfluidic system, to ensure the biological functionality of the model. For that purpose, adipocyte cell line will be cultured in spheroids in microfluidic biochip. To optimize the model, we will study the influence of several parameters: spheroids size, spheroids inoculation density, biochip design and flow rate. Then, human primary adipocyte will be used to propose relevant human fat-on-chip model.
In the framework of the “Joint PHD Programme call University of Tokyo and CNRS”, a second PhD student will develop healthy and NAFLD liver-on-chip model in Tokyo (LIMMS). The connection/crosstalks between the two developed organ-on-chip will be performed/studied during exchange visits between BMBI and LIMMS.