Brown adipose-derived mesenchymal stromal cells improve sepsis-induced multiorgan dysfunction more than white adipose cells in obese rats.

Abstract

Sepsis remains a leading cause of mortality worldwide and is driven by a dysregulated host response to infection. Mesenchymal stromal cells (MSCs) derived from white adipose tissue (WAT) have shown therapeutic potential in sepsis; however, the properties of brown adipose tissue (BAT)-derived MSCs remain poorly characterized, particularly in obesity, a condition known to alter MSC phenotype and function. We compared the therapeutic efficacy of MSCs isolated from brown versus white adipose depots of obese donors in a clinically relevant model of sepsis in obese rats. Obesity was induced in Wistar rats through a high-fat diet. MSCs were isolated from brown and white adipose tissue and characterized by plastic adherence, surface marker expression, and gene expression profiling. Sepsis was induced by cecal ligation and puncture (CLP). Twenty-four hours after CLP, animals received saline, WAT-MSCs, or BAT-MSCs (1 × 10⁶ cells). Primary outcomes were 48-h survival and bacterial burden. Secondary outcomes included blinded histological assessment and molecular analyses of lung, kidney, and liver injury, focusing on inflammatory cytokines, fibrotic signaling, and oxidative stress. Both MSC populations met established characterization criteria. BAT-MSCs exhibited higher baseline expression of anti-inflammatory and antioxidant genes. In obese septic rats, treatment with BAT-MSCs significantly improved 48-h survival compared with WAT-MSCs and reduced bacterial burden more effectively. Histological analyses demonstrated greater protection across organs, including reduced alveolar collapse, renal brush-border injury, and hepatic necrosis. Molecular analyses showed more pronounced suppression of interleukin-6, interleukin-1β, and transforming growth factor-β signaling, along with reduced collagen deposition and oxidative stress (all P < 0.05). In obese septic rats, BAT-MSCs provided superior early survival benefit and multi-organ protection compared with WAT-MSCs. These findings identify brown adipose tissue as a promising MSC source for sepsis therapy and support further translational and mechanistic investigation.