Multiple Dosing and Preactivation of Mesenchymal Stromal Cells Enhance Efficacy in Established Pneumonia Induced by Antimicrobial-Resistant Klebsiella pneumoniae in Rodents

Antimicrobial-resistant (AMR) bacteria, such as Klebsiella species, are an increasingly common cause of hospital-acquired pneumonia, resulting in high mortality and morbidity. Harnessing the host immune response to AMR bacterial infection using mesenchymal stem cells (MSCs) is a promising approach to bypass bacterial AMR mechanisms. The administration of single doses of naive MSCs to ARDS clinical trial patient cohorts has been shown to be safe, although efficacy is unclear. The study tested whether repeated MSC dosing and/or preactivation, would attenuate AMR Klebsiella pneumonia-induced established pneumonia. Rat models of established K. pneumoniae-induced pneumonia were randomised to receive intravenous naive or cytomix-preactivated umbilical cord MSCs as a single dose at 24 h post pneumonia induction with or without a subsequent dose at 48 h. Physiological indices, bronchoalveolar lavage (BAL), and tissues were obtained at 72 h post pneumonia induction. A single dose of naive MSCs was largely ineffective, whereas two doses of MSCs were effective in attenuating Klebsiella pneumosepsis, improving lung compliance and oxygenation, while reducing bacteria and injury in the lung. Cytomix-preactivated MSCs were superior to naive MSCs. BAL neutrophil counts and activation were reduced, and apoptosis increased. MSC therapy reduced cytotoxic BAL T cells, and increased CD4(+)/CD8(+) ratios. Systemically, granulocytes, classical monocytes, and the CD4(+)/CD8(+) ratio were reduced, and nonclassical monocytes were increased. Repeated doses of MSCs-particularly preactivated MSCs-enhance their therapeutic potential in a clinically relevant model of established AMR K. pneumoniae-induced pneumosepsis.

Automated summary

Antimicrobial-resistant bacteria, such as Klebsiella species, are a common cause of hospital-acquired pneumonia, leading to high mortality and morbidity. Using mesenchymal stem cells (MSCs) to harness the host immune response to these bacteria shows promise in bypassing antimicrobial resistance mechanisms. This study tested the efficacy of repeated doses and preactivated MSCs in attenuating Klebsiella pneumonia-induced pneumonia in rat models. Two doses of MSCs were effective in improving lung function and reducing bacteria and injury, with preactivated MSCs showing superior results. MSC therapy also affected immune cell populations both locally and systemically. Repeated doses of MSCs, particularly preactivated MSCs, enhance their therapeutic potential in treating antimicrobial-resistant Klebsiella pneumonia.