3D Adipose Tissue Culture Links the Organotypic Microenvironment to Improved Adipogenesis. Issue 16 (24th June 2021)

• Record Type: Journal Article
• Authors: Shen, Joanne X.; Couchet, Morgane; Dufau, Jérémy; de Castro Barbosa, Thais; Ulbrich, Maximilian H.; Helmstädter, Martin; Kemas, Aurino M.; Zandi Shafagh, Reza; Marques, Marie‐Adeline; Hansen, Jacob B.; Mejhert, Niklas; Langin, Dominique; Rydén, Mikael; Lauschke, Volker M.
• Is Part Of: Advanced science. Volume 8:Issue 16(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-06-24
• Subjects: adipose stem cells -- fat cells -- lipidomics -- organotypic cell culture -- preadipocytes -- stromal vascular fraction -- transcriptomics; Science -- Periodicals; 505
• DOI: 10.1002/advs.202100106
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: Obesity and type 2 diabetes are strongly associated with adipose tissue dysfunction and impaired adipogenesis. Understanding the molecular underpinnings that control adipogenesis is thus of fundamental importance for the development of novel therapeutics against metabolic disorders. However, translational approaches are hampered as current models do not accurately recapitulate adipogenesis. Here, a scaffold‐free versatile 3D adipocyte culture platform with chemically defined conditions is presented in which primary human preadipocytes accurately recapitulate adipogenesis. Following differentiation, multi‐omics profiling and functional tests demonstrate that 3D adipocyte cultures feature mature molecular and cellular phenotypes similar to freshly isolated mature adipocytes. Spheroids exhibit physiologically relevant gene expression signatures with 4704 differentially expressed genes compared to conventional 2D cultures (false discovery rate < 0.05), including the concerted expression of factors shaping the adipogenic niche. Furthermore, lipid profiles of >1000 lipid species closely resemble patterns of the corresponding isogenic mature adipocytes in vivo ( R 2 = 0.97). Integration of multi‐omics signatures with analyses of the activity profiles of 503 transcription factors using global promoter motif inference reveals a complex signaling network, involving YAP, Hedgehog, and TGF β signaling, that links the organotypic microenvironment in 3D culture to the activation and reinforcement of PPAR γ and CEBP activity resulting in improved adipogenesis. Abstract : A scaffold‐free high‐throughput compatible 3D human adipocyte culture platform in chemically defined media is presented. The model is long‐term stable and closely resembles human adipocytes in vivo on transcriptomic, lipidomic, and functional level. Furthermore, transcription factor activity analysis reveals a complex signaling network that links the organotypic microenvironment to improved adipogenesis.