Journal
ADVANCED SCIENCE
Volume 8, Issue 16, Pages -Publisher
WILEY
DOI: 10.1002/advs.202100106
Keywords
adipose stem cells; fat cells; lipidomics; organotypic cell culture; preadipocytes; stromal vascular fraction; transcriptomics
Categories
Funding
- European Research Council (ERC) Synergy Grant SPHERES under the European Union's Horizon 2020 research and innovation program [856404]
- Swedish Research Council [2016-01153, 2016-01154, 2018-02488, 2019-01837]
- EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN) [875510]
- Strategic Research Programme in Stem Cells and Regenerative Medicine (SFO StratRegen)
- Margareta af Uggla's Foundation
- Novo Nordisk Foundation (Tripartite Immuno-metabolism Consortium) [NNF15CC0018486]
- Novo Nordisk Foundation (MeRIAD consortium) [0064142]
- Novo Nordisk Foundation (MSAM Consortium) [NNF15SA0018346, NNF20OC0061149]
- Knut and Alice Wallenberg Foundation
- CIMED
- Swedish Diabetes Foundation
- Fondation pour la Recherche Medicale [DEQ20170336720]
- Agence Nationale de la Recherche [ANR-17-CE14-0015]
- AstraZeneca France
- Strategic Research Programme in Diabetes (SFO Diabetes)
- Stockholm County Council
- Vinnova [2018-02488] Funding Source: Vinnova
- Agence Nationale de la Recherche (ANR) [ANR-17-CE14-0015] Funding Source: Agence Nationale de la Recherche (ANR)
- Swedish Research Council [2018-02488] Funding Source: Swedish Research Council
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A scaffold-free versatile 3D adipocyte culture platform was developed in this study, accurately recapitulating adipogenesis with mature molecular and cellular phenotypes.
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 beta signaling, that links the organotypic microenvironment in 3D culture to the activation and reinforcement of PPAR gamma and CEBP activity resulting in improved adipogenesis.
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