Mitochondria-Rich Fraction Isolated From Mesenchymal Stromal Cells Reduces Lung and Distal Organ Injury in Experimental Sepsis*

Abstract

OBJECTIVES: To ascertain whether systemic administration of mitochondria-rich fraction isolated from mesenchymal stromal cells would reduce lung, kidney, and liver injury in experimental sepsis. DESIGN: Animal study. SETTING: Laboratory investigation. SUBJECTS: Sixty C57BL/6 male mice. INTERVENTIONS: Sepsis was induced by cecal ligation and puncture; sham-operated animals were used as control. At 24 hours after surgery, cecal ligation and puncture and Sham animals were further randomized to receive saline or mitochondria-rich fraction isolated from mesenchymal stromal cells (3 × 106) IV. At 48 hours, survival, peritoneal bacterial load, lung, kidney, and liver injury were analyzed. Furthermore, the effects of mitochondria on oxygen consumption rate and reactive oxygen species production of lung epithelial and endothelial cells were evaluated in vitro. MEASUREMENTS AND MAIN RESULTS: In vitro exposure of lung epithelial and endothelial cells from cecal ligation and puncture animals to mitochondria-rich fraction isolated from mesenchymal stromal cells restored oxygen consumption rate and reduced total reactive oxygen species production. Infusion of exogenous mitochondria-rich fraction from mesenchymal stromal cells (mitotherapy) reduced peritoneal bacterial load, improved lung mechanics and histology, and decreased the expression of interleukin-1β, keratinocyte chemoattractant, indoleamine 2,3-dioxygenase-2, and programmed cell death protein 1 in lung tissue, while increasing keratinocyte growth factor expression and survival rate in cecal ligation and puncture-induced sepsis. Mitotherapy also reduced kidney and liver injury, plasma creatinine levels, and messenger RNA expressions of interleukin-18 in kidney, interleukin-6, indoleamine 2,3-dioxygenase-2, and programmed cell death protein 1 in liver, while increasing nuclear factor erythroid 2-related factor-2 and superoxide dismutase-2 in kidney and interleukin-10 in liver. CONCLUSIONS: Mitotherapy decreased lung, liver, and kidney injury and increased survival rate in cecal ligation and puncture-induced sepsis.

Mitochondria in Focus: From Function to Therapeutic Strategies in Chronic Lung Diseases

“…Mitochondrial therapy, using isolated mitochondria from C57BL/6J gastrocnemius muscle, has also shown efficacy in a murine model of lung ischemia-reperfusion injury, attenuating lung tissue injury, and mechanical parameters via vascular delivery or nebulization ( 182 ). More recently, systemic mito-therapy using a mitochondria-rich fraction isolated from BMSCs was capable of decreasing lung, liver, and kidney injury and increased the survival rate in cases of cecal ligation and puncture-induced sepsis ( 183 ).…”

Mesenchymal Stromal Cells From Emphysematous Donors and Their Extracellular Vesicles Are Unable to Reverse Cardiorespiratory Dysfunction in Experimental Severe Emphysema

“…In previous studies using experimental models of acute respiratory distress syndrome, mitochondrial transfer from MSCs to host cells was associated with enhanced macrophage phagocytic activity and antimicrobial effects ( Jackson et al, 2016 ; Morrison et al, 2017 ) as well as recovered alveolar ATP concentration ( Islam et al, 2012 ). Systemic administration of a mitochondria-rich fraction isolated from MSCs was also effective at reducing lung, kidney and liver damage in experimental sepsis ( de Carvalho et al, 2021 ). Although both H-MSCs and E-MSCs used here indicated transfer of their mitochondria when co-cultured with AMs, E-MSC mitochondria might be less effective at reducing harmful effects from noxious environment because these demonstrated a senescent phenotype.…”

The Four Pillars for Successful Regenerative Therapy in Endodontics: Stem Cells, Biomaterials, Growth Factors, and Their Synergistic Interactions

“…Beside EVs, the effects of mitochondrial transfer have surfaced as a new cell-free approach for the treatment of inflammatory diseases [ 75 ]. In addition, mitochondrial exchange is currently being considered as one emerging mechanism of action through which MSCs can be beneficial for multiple cellular processes [ 76 ], such as graft versus host disease [ 77 ] and sepsis to regenerate and repair damaged cells or tissues [ 78 ]. It has been evident that this transfer is a major key in immune regulation, healing several diseases related to brain injury, cardiac myopathies, muscle sepsis, lung disorders, and acute respiratory disorders that can be also applied to dental condition where inflammation plays an important trigger role [ 79 ].…”