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

肥胖症是一种日益严重的流行病，影响着世界上大量的人口，并且是糖尿病、心脏病和癌症等许多疾病的风险。它的特点是大量的脂肪组织沉积在体内和器官周围。这种脂肪组织主要由专门的细胞组成，这些细胞储存能量，如脂肪细胞和免疫细胞，称为巨噬细胞。巨噬细胞作为免疫哨兵，识别异物和病原体并消除它们。然而，在肥胖个体的脂肪组织中，巨噬细胞被认为引起慢性炎症，这是发展肥胖相关并发症如糖尿病的主要机制。脂肪组织中有两种类型的巨噬细胞。组织驻留巨噬细胞（TRM），在胎儿中形成，并迁移到组织中，在个体的一生中创造自我更新的细胞。第二种类型的巨噬细胞是骨髓源性巨噬细胞（BMG），它们在成人的骨髓中产生，并响应于炎症被募集到组织中。为了研究这些巨噬细胞在肥胖和糖尿病等代谢疾病中的作用，该项目将开发一种含有两种巨噬细胞来源的人体脂肪组织的组织工程3D打印模型。为了模拟BRM，我们将从人血液中分离骨髓来源的细胞，并将其分化为巨噬细胞;为了模拟TRM，我们将使用具有胚胎特性的人干细胞，其可以在胚胎发育期间遵循相同的过程分化为巨噬细胞;最后，为了模拟脂肪组织环境，我们将从人脂肪组织中分离脂肪细胞。这三个细胞将被3D生物打印到生物材料结构中，以允许细胞在3D中相互作用。细胞和生物材料水凝胶的结合将使我们能够用两种类型的巨噬细胞组织工程人类脂肪组织模型。该模型可用于更密切地研究巨噬细胞与脂肪细胞的相互作用，以及这种相互作用如何在肥胖症中改变并导致代谢疾病。一旦建立，该模型系统可用于探测炎症的影响（例如，通过硬化水凝胶性质-以模拟肥胖脂肪组织中脂肪细胞增加的纤维沉积-或引入炎性化学刺激），以确定这如何影响巨噬细胞对脂肪细胞的反应和与脂肪细胞的相互作用。该模型还可用于测试药物或确定开发肥胖和2型糖尿病治疗的新靶点。

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.