Engineered 3D brown-like adipocytes derived from human iPSCs for in vitro preclinical drug discovery and for cell-based therapy to treat obesity – hiPSC-Adipospheres

We have generated organoids derived from human iPSc and from the stromal fraction of adipose tissue using collagen-derived hydrogels to better mimick the native extracellular matrix using advanced microfabrication technologies.
The secondary objective is to demonstrate that adipospheres improve metabolic parameters when transplanted into a preclinical mouse model of obesity.

The novel 3D human beige adipose tissue models we have generated are very similar to native tissue. They can be used i) for screening molecules capable of activating the browning of human white adipose tissue, ii) as a model to better understand its development, physiology and the mechanisms underlying its dysfunction and iii) as an advanced therapy drug ( which after transplantation into the body can be used to treat metabolic dysfunctions related to aging, obesity and metabolic diseases.

From a technological point of view, the project validated an experimental approach for the construction of multisphere architectures by gel placement and photopolymerization. This approach, carried out manually as part of this project, will be to develop a fully automated 3D bioprinting platform of spheroids and photosensitive biomaterials. Then to demonstrate that adipospheres improve metabolic parameters when transplanted into a preclinical mouse model of obesity.

The results have been valorized by the filing of 2 patents, two scientific publications submitted for publication, and 2 already published.

Alternative strategies are urgently required to fight obesity and associated metabolic disorders including diabetes and cardiovascular diseases. Brown and brown-like adipocytes (BAs) store fat, but in contrast to white adipocytes, activated BAs are equipped to dissipate energy stored. Therefore, BAs represent promising cell targets to counteract obesity. However, the scarcity of BAs in adults is a major limitation for a BA-based therapy of obesity, The idea of producing ex vivo BA for transplantation to increase the BA mass in obese patients recently emerged. The proof-of-concept has been validated in murine models as it has been reported that implants of mouse BAs or of human BAs developed from capillary networks were able to restore normoglycemia in diabetic mice and to reduce obesity in Ob/Ob mice.
The lack of a relevant human cell model engineered for mimicking an adipose tissue-like structure is a second major limitation for preclinical discovery of efficient and safe drugs.

The ambition of the hiPSC-Adipospheres project is to further develop this idea and to transform this hypothesis into a reliable technological solution for drug screening and therapeutical use. For this objective, we have operated innvovative choices in terms of cell progenitors and cell culture conditions by bringing together biologists, physiologists and engineers.

Human induced pluripotent stem cells (hiPSCs) appear as an abundant source of multiple cell types of therapeutic interest for drug screening and for autologous transplantation. The main idea of this project is to use of hiPSC-BAs in the obesity field and to potentialize them through optimized cell culture conditions and microenvironment engineering.
Our aim is to generate engineered 3D microenvironments fabricated using advanced light assisted bioprinting methods and capable to host BAs adipospheres. Moreover, since interactions of adipocytes with endothelial cells in crucial of their functionalities, we plan to vascularize hiPSC-BAs. This vascularization will further help their engraftment for the in vivo functional investigations. The vascularization will also be taken into account when designing the host bioprinting by including a microfluidic network allowing their perfusion and thus the distribution of any signalling molecules (batokines, cytokines, growth factors,…), oxygenation and nutrients. These vascularized adipospheres will be used both for a better in vitro prediction of drug candidate efficacy and for cell-based therapy of obesity..

The consortium is composed of three partners with complementary and international recognized expertises in i) adipose progenitors derived from stem cells including hiPSCs, ii) the biology of BAs including their use in cell-based therapy, and in the functional structure of adipose tissue, iii) advanced microfabrication technologies to generate 3D models with fully controlled microenvironments.

Our project targets to provide functional and relevant 3D models to test in vitro drug efficiency and safety and to improve BA therapeutic potential after transplantation. It is new in the field of metabolism disease. Social and economic repercussions of our project may be hugged. The failure rates of drug candidate represents a high cost to the pharmaceutical industry and novel drug screening methods are required. We anticipate that the model we are going to characterize in this project will be integrated in high-throughput screening for drug discovery and in clinical grade manufacturing.
The basic scientists of the consortium are holders of patents and co-founders in start ups, showing their interest in valorising their fundamental research at the clinical and industrial levels.