Mesenchymal Stromal Cells Improve Survival During Sepsis in the Absence of Heme Oxygenase-1: The Importance of Neutrophils

Abstract

The use of mesenchymal stromal cells (MSCs) for treatment of bacterial infections, including systemic processes like sepsis, is an evolving field of investigation. The present study was designed to investigate the potential use of MSCs, harvested from compact bone, and their interactions with the innate immune system, during polymicrobial sepsis induced by cecal ligation and puncture (CLP). We also wanted to elucidate the role of endogenous HO-1 in MSCs during a systemic bacterial infection. MSCs harvested from the bones of heme oxygenase (HO)-1 deficient (−/−) and wild-type (+/+) mice improved the survival of HO-1−/− and HO-1+/+ recipient mice when administered after the onset of polymicrobial sepsis induced by cecal ligation and puncture (CLP), compared with the administration of fibroblast control cells. The MSCs, originating from compact bone in mice, enhanced the ability of neutrophils to phagocytize bacteria in vitro and in vivo, and to promote bacterial clearance in the peritoneum and blood after CLP. Moreover, after depleting neutrophils in recipient mice, the beneficial effects of MSCs were entirely lost, demonstrating the importance of neutrophils for this MSC response. MSCs also decreased multiple organ injury in susceptible HO-1−/− mice, when administered after the onset of sepsis. Taken together, these data demonstrate that the beneficial effects of treatment with MSCs after the onset of polymicrobial sepsis is not dependent on endogenous HO-1 expression, and that neutrophils are crucial for this therapeutic response.

Effects of bone marrow mesenchymal stem cells on the cardiac function and immune system of mice with endotoxemia

“…MSCs are readily obtained and easy to culture in vitro, with rapid and simple amplification. Previous studies have also shown that MSCs may exert antibiotic action by excreting antimicrobial peptide LL-37, thereby stimulating neutrophil granulocytes (36,37). Another advantage is that their immunogenicity is low, which makes it possible to treat sepsis using allogeneic stem cells.…”

Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis

“…37,38,[48][49][50][51] This antibacterial eff ect is partly mediated by improved phagocytic activity of host immune cells such as macrophages, 38,41 monocytes, 48 neutrophils, 49 and ITGAMpositive cells (monocytes, macrophages, and neutrophils). 38 Studies using ex-vivo human lungs have reported similar fi ndings.…”

Guanylate-binding protein 1 (GBP1) contributes to the immunity of human mesenchymal stromal cells against Toxoplasma gondii

“…Data from murine colitis models have shown that human adipose-derived MSCs protect against dextran-induced colitis by decreasing the secretion of proinflammatory cytokines and chemokines (6). However, the antimicrobial effector molecules in vertebrate MSCs are not universally the same (4)(5)(6)(7)(8)(9)(10)(11). The antimicrobial effect of unstimulated hMSCs is mediated by the cathelicidin, LL-37 (4), as shown both in vitro and in vivo.…”