Therapeutic effects of extracellular vesicles obtained from bone marrow-derived, adipose tissue-derived, and lung-derived mesenchymal stromal cells on the lung and distal organs in experimental sepsis

Abstract

Background & Aim The beneficial effects of mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) in experimental sepsis have been described. However, to date, there is no information regarding the best source of MSC-EVs to enhance survival rate and mitigate lung and distal organ damage in sepsis. In this context, we compared the effects of MSC-EVs obtained from bone marrow (BM), adipose tissue (AD), and lung (L) on mortality rate and lung and distal organ histology and molecular biology in a murine model of experimental polymicrobial sepsis. Methods, Results & Conclusion Twenty-four C57BL/6 mice (weight 20-25g) underwent cecal ligation and puncture (CLP) to induce sepsis. A sham-operated group was used as control (SHAM). Animals received antibiotics (imipenem/cilastatin, 10 mg/kg) at 6 and 24 hours. Twenty-four hours after CLP induction, mice were treated with saline (SAL) or EVs from 3 × 106 BM-, AD- or L-derived MSCs. Total protein content, intensity, and hydrodynamic diameter of the EV fraction were measured and compared according to source. Twenty-four hours after therapy, lung, liver, and kidney samples were obtained for histology and molecular biology. Tumor-necrosis factor (TNF)-α protein level was measured in lung tissue. Interleukin (IL)-18, kidney injury molecule (KIM)-1 and heme oxygenase-1 (HO)-1 mRNA expressions were measured in kidney. Survival rate was evaluated at 48 hours. EVs from BM-, AD-, and L-derived MCs exhibited similar total protein content and hydrodynamic diameters. In septic mice, EVs from all sources were able to reduce TNF-α in lung tissue, neutrophils in alveolar septa, and diffuse alveolar damage compared to SAL (p<0.01). BM-EVs reduced liver congestion (p=0.01) and Kupffer cells in sinusoids (p=0.03). EVs from all sources decreased interstitial edema in kidney (p<0.001), but only BM-EVs were able to preserve the brush border, which is damaged in sepsis. Regarding kidney inflammation, BM-EVs and L-EVs, but not AD-EVs, reduced mRNA expression of IL-18 and KIM-1 (p<0.0125). HO-1 (p<0.0125), a marker of acute kidney injury in mice, increased only after administration of AD-EVs. In addition, AD-EVs were associated with a trend (p=0.10) toward lower survival (60%) compared to groups treated with BM- (89%) and L- (88%) derived EVs. In the model of sepsis used herein, EVs obtained from BM-derived MSCs seem to be associated with reduced lung, liver, and kidney damage compared with EVs obtained from AD- and L-MSCs. The beneficial effects of mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) in experimental sepsis have been described. However, to date, there is no information regarding the best source of MSC-EVs to enhance survival rate and mitigate lung and distal organ damage in sepsis. In this context, we compared the effects of MSC-EVs obtained from bone marrow (BM), adipose tissue (AD), and lung (L) on mortality rate and lung and distal organ histology and molecular biology in a murine model of experimental polymicrobial sepsis. Twenty-four C57BL/6 mice (weight 20-25g) underwent cecal ligation and puncture (CLP) to induce sepsis. A sham-operated group was used as control (SHAM). Animals received antibiotics (imipenem/cilastatin, 10 mg/kg) at 6 and 24 hours. Twenty-four hours after CLP induction, mice were treated with saline (SAL) or EVs from 3 × 106 BM-, AD- or L-derived MSCs. Total protein content, intensity, and hydrodynamic diameter of the EV fraction were measured and compared according to source. Twenty-four hours after therapy, lung, liver, and kidney samples were obtained for histology and molecular biology. Tumor-necrosis factor (TNF)-α protein level was measured in lung tissue. Interleukin (IL)-18, kidney injury molecule (KIM)-1 and heme oxygenase-1 (HO)-1 mRNA expressions were measured in kidney. Survival rate was evaluated at 48 hours.