Carbon monoxide-induced autophagy enhances human mesenchymal stromal cell function via paracrine actions in murine polymicrobial sepsis

Narae Hwang; Sailaja Ghanta; Qifei Li; Anthony M Lamattina; Ekaterina Murzin; James A Lederer; Souheil El-Chemaly; Su Wol Chung; Xiaoli Liu; Mark A Perrella

doi:10.1016/j.ymthe.2024.05.018

Carbon monoxide-induced autophagy enhances human mesenchymal stromal cell function via paracrine actions in murine polymicrobial sepsis

Mol Ther. 2024 May 11:S1525-0016(24)00321-6. doi: 10.1016/j.ymthe.2024.05.018. Online ahead of print.

Authors

Affiliations

¹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
² Division of Newborn Medicine, Department of Pediatrics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
³ Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine and Jackson Health System, Miami, FL, USA.
⁴ Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁵ School of Biological Sciences, University of Ulsan, Ulsan, South Korea.
⁶ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Division of Newborn Medicine, Department of Pediatrics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Division of Newborn Medicine, Department of Pediatrics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: mperrella@bwh.harvard.edu.

PMID: 38734903
DOI: 10.1016/j.ymthe.2024.05.018

Abstract

Sepsis is a life-threatening process due to organ dysfunction resulting from severe infections. Mesenchymal stromal cells (MSCs) are being investigated as therapy for sepsis, along with conditioning regimens to improve their function. Carbon monoxide (CO) gas, which is cytoprotective at low doses, induces autophagy and is a mediator of inflammation. We evaluated CO-induced autophagy in human MSCs (hMSCs), and its impact on cell function in murine cecal ligation and puncture. Conditioning of hMSCs with CO ex vivo resulted in enhanced survival and bacterial clearance in vivo, and neutrophil phagocytosis of bacteria in vitro. Decreased neutrophil infiltration and less parenchymal cell death in organs were associated with increased macrophage efferocytosis of apoptotic neutrophils, promoting resolution of inflammation. These CO effects were lost when the cells were exposed to autophagy inhibition prior to gas exposure. When assessing paracrine actions of CO-induced autophagy, extracellular vesicles (EVs) were predominantly responsible. CO had no effect on EV production, but altered their miRNA cargo. Increased expression of miR-145-3p and miR-193a-3p by CO was blunted with disruption of autophagy, and inhibitors of these miRNAs led to a loss of neutrophil phagocytosis and macrophage efferocytosis. Collectively, CO-induced autophagy enhanced hMSC function during sepsis via paracrine actions of MSC-derived EVs.

Keywords: autophagy; carbon monoxide; extracellular vesicles; mesenchymal stromal cells; microRNA; paracrine; sepsis.