Mesothelial-to-mesenchymal transition drives visceral adipose tissue remodeling in human obesity

Résumé fourni par la source

The cellular origins of pathogenic visceral adipose tissue (vAT) remodeling in obesity remain unclear. Having previously identified mesothelial cells as the vAT population most strongly linked to metabolic disease, we now define the adipose mesothelium as a central regulator of tissue plasticity. A single-nucleus transcriptomic atlas of 14,000 mesothelial cells from 53 individuals, integrated with a MERSCOPE spatial map of human vAT, resolved nine functionally distinct subclusters, spanning barrier formation, lubricant production, immune modulation, and stromal niche support, and was validated across three additional independent cohorts. Combined in vivo analyses of the human adipose mesothelium and in vitro models of primary mesothelial cells identify mesothelial-to-mesenchymal transition (MMT) as the principal driver of this plasticity. Importantly, the extent of MMT activation correlates with donor metabolic health. Intermediate states generate the observed subcluster diversity and confer tissue-protective fibrinolytic and niche-remodeling functions. Full transition, in contrast, yields mesenchymal cells competent for differentiation, proliferation, and migration, and sustained activation commits these cells to a pathogenic myofibroblast fate that accumulates in disease. While mesenchymal drifts are increasingly recognized as a hallmark of cancer and aging, we define this process for the first time in the adipose mesothelium and in the context of metabolic disease. This positions the mesothelium as a bidirectional regulator of vAT remodeling and a tractable therapeutic target in obesity-associated disease.

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