MITOCHONDRIA ISOLATED FROM MESENCHYMAL STROMAL CELLS REDUCE LUNGAND DISTAL ORGAN INJURY IN EXPERIMENTAL SEPSIS

Abstract

<h3>Background</h3> Although mesenchymal stromal cells (MSC) administration has demonstrated beneficial effects in experimental sepsis, cell-free therapeutics based on biologically active products from MSCs have been proposed to circumvent inherent risks related to whole-cell transplantation. As mitochondria transfer has emerged as one of the key mechanisms by which MSCs induce therapeutic actions, we asked whether MSC-isolated mitochondria could reduce lung, kidney, and liver injury, thus improving survival in experimental sepsis. <h3>Methods</h3> Experimental sepsis was induced by cecal ligation and puncture (CLP), while sham-operated animals were used as control. Twenty-four hours after surgery, CLP and Sham animals were further randomized to receive saline or MSC-isolated mitochondria (MT, from 3 × 106 MSCs) intravenously. After additional 24 h, survival rate, peritoneal bacterial load, lung mechanics and histology, kidney and liver injury, kidney function, as well as expression levels of selected mediators in tissue homogenates were analyzed. Moreover, the uptake and effects mitochondria on oxygen consumption rate (OCR) and reactive oxygen species (ROS) production of lung epithelial and endothelial cells were evaluated in vitro. <h3>Results</h3> In vitro exposure of lung epithelial and endothelial cells from CLP animals to MSC-isolated mitochondria resulted in mitochondrial uptake by endothelial cells and restored OCR and reduced total ROS production. Systemic administration of MSC-isolated mitochondria led to reduction of bacterial load, static lung elastance, alveolar collapse, neutrophil count, collagen and elastic fiber content as well as expression of interleukin (IL)-1β, keratinocyte chemoattractant, indoleamine 2,3-dioxygenase (IDO)-2 and programmed cell death protein 1 (PD-1) in lung tissue, while increasing KGF levels and survival rate in CLP-induced sepsis. Mitochondria therapy also reduced kidney and liver injury, decreasing plasma creatinine levels, mRNA expression of IL-18 in kidney, IL-6, IDO-2 and PD-1 in liver and increasing mRNA levels of nuclear factor erythroid 2-related factor-2 and superoxide dismutase-2 in kidney and IL-10 in liver. <h3>Conclusions</h3> Mitochondria therapy enabled the recovery of host mitochondrial function and reduced inflammation and oxidative stress, thus decreasing lung, liver, and kidney injury and increasing survival rate in CLP-induced sepsis.