Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation

Abstract

Recent observations have demonstrated that one of the functions of mesenchymal stem/stromal cells (MSCs) is to serve as guardians against excessive inflammatory responses. One mode of action of the cells is that they are activated to express the interleukin (IL)-1 receptor antagonist. A second mode of action is to create a negative feedback loop in which tumor necrosis factor-α (TNF-α) and other proinflammatory cytokines from resident macrophages activate MSCs to secrete the multifunctional anti-inflammatory protein TNF-α stimulated gene/protein 6 (TSG-6). The TSG-6 then reduces nuclear factor-κB (NF-κB) signaling in the resident macrophages and thereby modulates the cascade of proinflammatory cytokines. A third mode of action is to create a second negative feedback loop whereby lipopolysaccharide, TNF-α, nitric oxide, and perhaps other damage-associated molecular patterns (DAMPs) from injured tissues and macrophages activate MSCs to secrete prostaglandin E(2) (PGE(2)). The PGE(2) converts macrophages to the phenotype that secretes IL-10. There are also suggestions that MSCs may produce anti-inflammatory effects through additional modes of action including activation to express the antireactive oxygen species protein stanniocalcin-1.

Figures

Figure 1

Anti-inflammatory effects of human mesenchymal stem/stromal cells (hMSCs) activated to secrete tumor necrosis factor-α (TNF-α) stimulated gene/protein 6 (TSG-6) in a mouse model of myocardial infarction. (a) Schematic diagram. (1) hMSCs injected intravenously were trapped in the lungs and activated to secrete TSG-6 (TNF-α stimulated gene/protein 6). (2) The TSG-6 decreased the normal but excessive inflammatory response that damages the heart. (3) The TSG-6 probably further decreased proteolytic damage to the heart by inhibiting matrix metalloproteinases (MMPs) (see refs. 42,43,46). (b) Selected sections through heart. Each heart was cut from apex to base into over 400 sequential 5 µm sections. Every twentieth section is shown. Either hMSCs or hMSCs transduced with the scrambled siRNA (scr siRNA) decreased the size of myocardial infarction examined 3 weeks later. However, hMSCs with an siRNA knockdown of the TSG-6 gene (TSG-6 siRNA) had no effect on infarct size. Intravenous infusion of 100 µg of recombinant human (rh) TSG-6 immediately following the surgery and at 24 hour also decreased infarct size. (a) Reproduced with modifications and with permission from Elsevier. (b) Reprinted with permission from Elsevier.

Figure 2

Dose-dependent effects of tumor necrosis factor-α (TNF-α) stimulated gene/protein 6 (TSG-6) in reducing corneal inflammation and opacity. Sterile inflammation was produced in corneas of Lewis rats by brief exposure to 100% ethanol followed by mechanical debridement of the cornea and limbal epithelium that removed the stem cells located in the limbus. (a) Representative corneal photographs on day 3 postinjury demonstrated that TSG-6 suppressed development of corneal opacity after chemical injury in a dose-dependent manner. (b) The anti-inflammatory effects of TSG-6 were dose-dependent as reflected in clinical grade of corneal opacity and myeloperoxidase (MPO) concentration as a semiquantitative assay of neutrophil infiltration. Values are mean ± SD; n = 3 for each group. (c) Gelatin zymography of corneas for pro-MMP-9 and active matrix metalloproteinase (MMP)-9. (d) Total and active MMP-9 concentration in the cornea as assayed by enzyme-linked immunosorbent assay (ELISA). Values are mean + SD; n = 5 for each group. Significant improvements were observed with dose of 0.002 µg but maximal effects were obtained with 2 µg. Reprinted with permission from National Academy of Sciences, USA.

Figure 3

The anti-inflammatory effects of human mesenchymal stem/stromal cells (hMSCs) and tumor necrosis factor-α (TNF-α) stimulated gene/protein 6 (TSG-6) in a mouse model of zymosan-induced peritonitis. (1) Zymosan-activated nuclear factor-κB (NF-κB) signaling in resident macrophages via Toll-like receptor 2 (TLR2). (2) Activation of the NF-κB signaling pathway increased the production of proinflammatory cytokines to initiate the cascade of proinflammatory cytokines that was amplified by mesothelial cells and other cells of the peritoneum. (3) The proinflammatory cytokines also activated the hMSCs to secrete TSG-6. (4) TSG-6 decreased TLR2/NF-κB signaling in the resident macrophages through a direct interaction with CD44 or in a complex with hyaluronan. The amplification of the proinflammatory signals by mesothelial cells to recruit neutrophils was modulated by a negative feedback loop introduced by hMSCs and TSG-6. Reprinted with permission from the American Society of Hematology.

Figure 4

Schematic for the anti-inflammatory effects of mesenchymal stem/stromal cells (MSCs) based on observations in a mouse model for sepsis. Bacterial toxins such as lipopolysaccharide (LPS) and circulating tumor necrosis factor-α (TNF-α) acted on the TLR4 and TNF receptor-1 (TNFR-1) of MSCs to activate the nuclear factor-κB (NF-κB) signaling. Activation of NF-κB signaling upregulated expression of cyclooxygenase-2 (COX2) and the COX2 increased synthesis of prostaglandin E2 (PGE2). PGE2 was secreted and bound to EP2 and EP4 receptors on macrophages. The PGE2 thereby increased IL-10 secretion by macrophages to reduce the inflammatory response. Reprinted with permission from Macmillan Publishers Ltd.

Figure 5

Summary of some of the anti-inflammatory effects of mesenchymal stem/stromal cells (MSCs). (1) Damage-associated molecular patterns (DAMPs) and interleukin (IL)-1α released by sterile injury or pathogen-associated molecular patterns (PAMPs) released by infectious injury to tissues activate resident macrophages through receptors involving pattern recognition receptors (PRRs). (2) The activated macrophages produce proinflammatory cytokines such as IL-1α, IL-1β, or tumor necrosis factor-α (TNF-α) to initiate the inflammatory cascade. (3) Simultaneously, the proinflammatory cytokines and probably other signals from injured cells activate MSCs to secrete anti-inflammatory factors that include TNF-α stimulated gene/protein 6 (TSG-6), PGE2, and IL-1ra that either modulate the activation of the resident macrophages or decrease the downstream effects of the proinflammatory cytokines. (4) The net effect is to decrease the amplification of the proinflammatory signals by parenchymal cells through the secretion of IL-6, CXCL1, and related factors and as a result to decrease the recruitment of neutrophils.