Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.
Diabetes Obes Metab. 2019 May;21(5):1146-1157. doi: 10.1111/dom.13628. Epub 2019 Feb 18.
There are many obstacles to overcome in the development of new drugs for metabolic diseases, including efficacy and toxicity problems in later stages of drug development. To overcome these problems and predict efficacy and toxicity in early stages, we constructed a new model of insulin resistance in terms of communication between 3T3-L1 adipocytes and RAW264.7 macrophages by three-dimensional (3D) culture.
In this study, results focused on the functional resemblance between 3D co-culture of adipocytes and macrophages and adipose tissue in diabetic mice. The 3D mono-culture preadipocytes showed good cell viability and induced cell differentiation to adipocytes, without cell confluence or cell-cell contact and interaction. The 3D co-cultured preadipocytes with RAW264.7 macrophages induced greater insulin resistance than two-dimensional and 3D mono-cultured adipocytes. Additionally, we demonstrated that 3D co-culture model had functional metabolic similarity to adipose tissue in diabetic mice. We utilized this 3D co-culture system to screen PPARγ antagonists that might have potential as therapeutic agents for diabetes as demonstrated by an in vivo assay.
This in vitro 3D co-culture system could serve as a next-generation platform to accelerate the development of therapeutics for metabolic diseases.
在开发代谢疾病的新药方面存在许多障碍，包括药物开发后期的疗效和毒性问题。为了克服这些问题并在早期预测疗效和毒性，我们构建了一种新的 3T3-L1 脂肪细胞和 RAW264.7 巨噬细胞之间通过三维（3D）培养进行通讯的胰岛素抵抗模型。
本研究主要关注 3D 共培养的脂肪细胞和巨噬细胞与糖尿病小鼠脂肪组织之间的功能相似性。3D 单培养前体细胞显示出良好的细胞活力，并诱导细胞分化为脂肪细胞，而没有细胞汇合或细胞-细胞接触和相互作用。与二维和 3D 单培养的脂肪细胞相比，3D 共培养的前体细胞与 RAW264.7 巨噬细胞共同诱导的胰岛素抵抗更大。此外，我们证明 3D 共培养模型与糖尿病小鼠的脂肪组织具有功能代谢相似性。我们利用这种 3D 共培养系统筛选了 PPARγ 拮抗剂，这些拮抗剂可能具有作为糖尿病治疗剂的潜力，这在体内试验中得到了证实。
这种体外 3D 共培养系统可以作为一种下一代平台，加速代谢疾病治疗药物的开发。
