Immunoengineering Body Fat: Modelling microphages in a 3D-bioprinted human adipose tissue model

Obesity is a rising epidemic affecting a large number of the world population and is a risk for many diseases such as diabetes, heart disease and cancers. It is characterised by the deposition of large amounts of fat tissue in the body and around the organs. This fat tissue is mainly composed of specialised cells that store energy as fat known as adipocytes and immune cells known as macrophages. Macrophages act as immune sentinels, identifying foreign bodies and pathogens and eliminating them. In the fat tissue of obese individuals however, macrophages are thought to cause chronic inflammation which is the main mechanism for developing obesity associated complications such as diabetes. There are two types of macrophages in fat tissues. Tissue resident macrophages (TRMs), which are formed in the fetus and migrate to tissues where they create self-renewing cells over an individual's life time. The second type of macrophages are bone marrow derived macrophages (BMMs), they are produced in the bone marrow in adults and are recruited into tissues in response to inflammation. To study the role of these macrophages in obesity and metabolic diseases such as diabetes, this project will develop a tissue-engineered 3D printed model of human fat tissue containing the two types of macrophage sources. To model the BMMs, we will isolate bone marrow derived cells from human blood and differentiate them to macrophages; to model the TRMs we will use human stem cells with embryonic properties that can be differentiated into macrophages following the same process as during the embryo's development; finally to model the fat tissue environment, we will isolate adipocytes from human fat tissues. These three cells will be 3D bioprinted into a biomaterial construct to allow the cells to interact together in 3D. The combination of cells and biomaterial hydrogels will enable us to tissue-engineer a model of human fat tissue with the two types of macrophages. This model could be used to study more closely the interaction of macrophages with adipocytes and how this alters in obesity and results in metabolic diseases. Once established this model system could be used to probe the effects of inflammation (e.g. by stiffening the hydrogel properties- to model increased fiber deposition by adipocytes in obese fat tissue- or introducing inflammatory chemical stimuli) to determine how this influences macrophages response to and interaction with adipocytes. This model could also be used to test drugs or identify new targets for developing treatments for obesity and type 2 diabetes.