Development of vascularized adipose organoids from PBMSCs and their application in evaluating Celastrol's effects.

Abstract

Obesity lacks physiologically relevant human models, which constrains in-depth investigation into its underlying mechanisms and hampers the development of effective therapeutic strategies for obesity and its associated comorbidities. Here, we developed vascularized adipose organoids (VAOs) from peripheral blood mesenchymal stem cells (PBMSCs) using a standardized three-dimensional dynamic culture system that sequentially induces angiogenesis and adipogenesis. These VAOs mimic native adipose tissue with coexisting adipocytes and endothelial cells. Transcriptomic analysis shows that vascularization alters genes linked to inflammation and redox homoeostasis, yielding distinct metabolic and inflammatory profiles in VAOs versus non-vascularized controls. Notably, upon TNF-α stimulation, VAOs exhibit markedly reduced IL-6 secretion relative to non-vascularized adipose organoids (NVAOs). Importantly, Celastrol simultaneously inhibits angiogenesis and adipogenesis in VAOs and broadly modulates the expression of genes associated with mitochondrial metabolic processes. This study establishes PBMSC-derived VAOs as a scalable, patient-accessible model for investigating adipose development, metabolism, and inflammation. The system also provides a platform for mechanistic research and high-throughput drug screening in obesity and related metabolic diseases.