Acidic pH stimulates the production of the angiogenic CXC chemokine, CXCL8 (interleukin‐8), in human adult mesenchymal stem cells via the extracellular signal‐regulated kinase, p38 mitogen‐activated protein kinase, and NF‐κB pathways

Abstract

Blood vessel injury results in limited oxygen tension and diffusion leading to hypoxia, increased anaerobic metabolism, and elevated production of acidic metabolites that cannot be easily removed due to the reduced blood flow. Therefore, an acidic extracellular pH occurs in the local microenvironment of disrupted bone. The potential role of acidic pH and glu-leu-arg (ELR(+)) CXC chemokines in early events in bone repair was studied in human mesenchymal stem cells (hMSCs) treated with medium of decreasing pH (7.4, 7.0, 6.7, and 6.4). The cells showed a reciprocal increase in CXCL8 (interleukin-8, IL-8) mRNA levels as extracellular pH decreased. At pH 6.4, CXCL8 mRNA was induced >60x in comparison to levels at pH 7.4. hMSCs treated with osteogenic medium (OGM) also showed an increase in CXCL8 mRNA with decreasing pH; although, at a lower level than that seen in cells grown in non-OGM. CXCL8 protein was secreted into the medium at all pHs with maximal induction at pH 6.7. Inhibition of the G-protein-coupled receptor alpha, G(alphai), suppressed CXCL8 levels in response to acidic pH; whereas phospholipase C inhibition had no effect on CXCL8. The use of specific mitogen-activated protein kinase (MAPK) signal transduction inhibitors indicated that the pH-dependent increase in CXCL8 mRNA is due to activation of ERK and p38 pathways. The JNK pathway was not involved. NF-kappaB inhibition resulted in a decrease in CXCL8 levels in hMSCs grown in non-OGM. However, OGM-differentiated hMSCs showed an increase in CXCL8 levels when treated with the NF-kappaB inhibitor PDTC, a pyrrolidine derivative of dithiocarbamate.

MSC response to pH levels found in degenerating intervertebral discs

“…The decrease in anabolicand anti-catabolic mRNA measurements as well as the general lack of change (or increase) in MMP-2 expression at all but the lowest pH level suggested a shift to a more catabolic response. In a study by Bischoff et al, it was shown that a drop in pH can stimulate IL-8 production (via p38 and NFκB pathways) [20] and certain cytokines are known to influence matrix protein expression and production [21], which may be a potential mechanism for findings in this study, although more investigation is necessary to determine underlying pathways for our observed changes.…”

Autologous Mesenchymal Stromal Cells and Kidney Transplantation

“…Instead, CD44 and CD105 double-positive MSCs were found in the graft, bona fide from the autologous cells previously infused in the transplant recipient, because no MSCs were documented in untransplanted kidneys or kidney from a patient with early acute graft rejection. Despite the well known anti-inflammatory properties of MSCs (30), the various soluble factors produced by MSCs also include proinflammatory mediators (31)(32)(33), which eventually may have contributed to the intragraft recruitment of granulocytes and slow progressive deterioration of renal function. Patients 1 and 2 are in good health with stable graft function after 360 and 180 days posttransplantation, respectively, and are still on follow-up.…”

Immunomodulatory effects of mesenchymal stromal cells in solid organ transplantation

“…MSCs suppress IL-2 and IL-15-driven NK-cell proliferation and IFN-g production [34,[73][74][75]. On the other hand, MSCs secrete soluble factors such as monocyte chemoattractant protein-1, macrophageinflammatory protein, IFN-inducible protein 10, and IL-8, all of which may attract other immune cells such as monocytes, macrophages, and neutrophils [42,76,77]. However, the relevance of MSC production of these factors to the function of monocytes, macrophages, and neutrophils in an inflammatory environment is unknown.…”