Human Mesenchymal Stem Cells Inhibit Neutrophil Apoptosis: A Model for Neutrophil Preservation in the Bone Marrow Niche

Abstract

Antibody neutralization experiments demonstrated that the key MSCderived soluble factor responsible for neutrophil protection from apoptosis was IL-6, which signaled by activating STAT-3 transcription factor. Furthermore, IL-6 expression was detected in MSC by real-time reverse transcriptionpolymerase chain reaction and enzyme-linked immunosorbent assay. Finally, recombinant IL-6 was found to protect neutrophils from apoptosis in a dose-dependent manner. MSC had no effect on neutrophil phagocytosis, expression of adhesion molecules, and chemotaxis in response to IL-8, f-MLP, or C5a. These results support the following conclusions: (a) in the bone marrow niche, MSC likely protect neutrophils of the storage pool from apoptosis, preserving their effector functions and preventing the excessive or inappropriate activation of the oxidative metabolism, and (b) a novel mechanism whereby the inflammatory potential of activated neutrophils is harnessed by inhibition of apoptosis and reactive oxygen species production without impairing phagocytosis and chemotaxis has been identified. STEM CELLS 2008;26:151-162 Disclosure of potential conflicts of interest is found at the end of this article.

Effect of low oxygen tension on the biological characteristics of human bone marrow mesenchymal stem cells

“…Interestingly, the expression of IL6 was maintained in MSCs from some donors cultured under hypoxia at levels similar to those in MSCs cultured under normoxia, but it was downregulated in MSCs from other donors. IL6 is involved in the inhibition of monocyte differentiation toward DCs, decreasing their stimulatory effect on T cells (Djouad et al 2007;Jiang et al 2005), while the secretion of IL6 by MSCs delays apoptosis of lymphocytes and neutrophils (Raffaghello et al 2008;Xu et al 2007). Through further investigation, it will be important to determine whether the relative differences in the levels of gene expression between different donors under hypoxia are a critical factor for the selection of potent MSCs.…”

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

“…In vitro, both MSCs and MSC supernatant have been reported to have notable anti-apoptotic eff ects on resting and activated neutrophils. 52 This eff ect does not require direct contact between cells and seems to be mediated partly by MSC production of the anti-apoptotic cytokine interleukin 6 (fi gure). 52 MSC production of FGF7 has also been postulated to inhibit apoptosis of monocytes, leading to increased bacterial killing.…”

“…52 This eff ect does not require direct contact between cells and seems to be mediated partly by MSC production of the anti-apoptotic cytokine interleukin 6 (fi gure). 52 MSC production of FGF7 has also been postulated to inhibit apoptosis of monocytes, leading to increased bacterial killing. 41 Future research will hopefully illuminate the extent and signifi cance of this pathway.…”

Caffeine alters the effects of bone marrow-derived mesenchymal stem cells on neutrophils

“…Similar to the present study, some former studies also used the bone marrow derived MSCs to investigate the interaction between MSCs and neutrophils. 11,27 Neutrophil homeostasis and turnover are highly regulated in the body. Circulating neutrophils have a short life span of 6-10 h, after which the cells undergo apoptosis.…”

“…Previous studies indicated that MSCs diminish the mitochondrial pro-apoptotic protein, Bax in neutrophils through IL-6 secretion. 27 It is also known that adenosine produced by MSCs can stimulate the A2B receptors through autocrine or paracrine routs, and potently stimulates IL-6 secretion. 23 According to the antagonistic effects of caffeine on adenosine receptor, it is possible that Fig.…”