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.