Acidic mesenchymal stem cells

Los Angeles, CA -

Tissue injury is known to cause mobilization of various types of stem cells. For example, after patients have a heart attack, CD34 stem cells, and other types of stem cells are known to mobilize from the bone marrow and enter systemic circulation. Mobilization involves chemoattractants released from the site of injury, but also requires various aspects of the immune system.

In a recent paper (Bischoff et al. 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-kappaB pathways. J Cell Biochem. 2008 Feb 14) the effect of tissue acidification on mesenchymal stem cells was examined. The reason for exposing mesenchymal stem cells to conditions of low pH was because in general, injured tissue is more acidic as compared to healthy tissue. This is in part because injury is associated with reduced blood flow, and reduced blood flow causes lack of oxygen and accumulation of carbon dioxide, which lowers the pH. Primarily the investigators were interested in bone injury.

The study involved exposing human bone marrow derived mesenchymal stem cells to various levels of acidity (7.4, 7.0, 6.7, and 6.4) and assessing their ability to generate the pro-inflammatory chemotactic cytokine IL-8. The study also investigated the generation of IL-8 in response to acidity in mesenchymal stem cells cultured in media that induces differentiation into the osteoblast lineage.

It was found that at the lowest pH (6.4) maximal IL-8 transcript was detected. This was also confirmed by assessment of IL-8 protein.

Induction of IL-8 by low pH was dependent on G-protein-coupled receptor alpha, as well as on active ERK and p38 pathways.

Although the investigators in this study were primarily interested in bone, the findings are applicable to a variety of biological scenarios. For example, various types of tumors are known to express a lower pH than non-malignant tissues (De Milito et al. Tumor acidity, chemoresistance and proton pump inhibitors. Future Oncol. 2005 Dec;1(6):779-86). So if one administers mesenchymal stem cells into a patient with a tumor, would the lower acidity of the tumor stimulate IL-8, and the IL-8 will call in neutrophils to cause inflammatory eradication of the tumor?

Another interesting question is that since hypoxia is associated with acidity, would the bone marrow niches where primitive hematopoietic stem cells preferentially reside actually have a different pH than the systemic circulation?