Mesenchymal stem/stromal cells (MSCs) and their role in the pathogenesis of preeclampsia. (#145)
Afterbirth tissues such as the placenta, umbilical cord, fetal membranes and decidua are readily available, abundant sources of MSCs. MSCs from these sources are already used in human preclinical trials to assess their potential therapeutic use in regenerative medicine. But we know little about the role MSCs play in these tissues, or their in vivo microenvironments (i.e. the niches), or whether MSCs contribute to clinically important pregnancy pathologies.
We provided evidence for the MSC niche in two different placental tissue environments; the fetal chorionic villi, and the maternal decidua that comprises an important part of the placental bed. Immunodetection studies with stem cell antibody markers located MSCs around vessels in both the chorionic villi and the decidua. We isolated, enriched and characterised primary MSCs from the placental chorionic villi (CMSCs) and decidua (DMSCs). Expression of MSC cell surface markers was found to be similar between CMSCs and DMSCs. However, gene expression comparisons between CMSCs and DMSCs showed significant differences.
Our current focus is on whether MSCs contribute to the development and/or progression of preeclampsia (PE), which is the most important clinical disorder of human pregnancy. In the latter stages of PE, the decidua is a major source of oxidative stress products, which damage the endothelial cells that line decidual vessels. DMSCs are closely associated with endothelial cells and thus are exposed to the same oxidative stress products that cause endothelial cell damage. A variety of stress response pathways are activated in this environment including the aldehyde dehydrogenase (ALDH) family of enzymes, which detoxify aldehydes. We showed ALDH is expressed in DMSCs. Many studies show high ALDH enzyme activity is a marker for stem/progenitor cells and is critical for long-term stem cell survival.
We hypothesised that ALDH activity would be reduced in PE-affected DMSCs (PE-DMSCs) compared with control DMSCs and that this would contribute to the pathogenesis of PE by reducing the ability of PE-DMSCs to respond to oxidative stress, and by decreasing PE-DMSC survival. The fluorescence-based “Aldefluor” assay was used to determine the percentage of MSCs with high ALDH activity (ALDHbr cells). PE-DMSCs had a significantly lower percentage of ALDHbr cells compared with DMSCs. The reduced proportion of ALDHbr PE-DMSCs suggests a detrimental effect of oxidative stress on DMSCs and a role for ALDH in protecting DMSCs from oxidative stress damage. We are using ALDH-specific siRNA gene inactivation to determine the functional consequences of reduced ALDH expression on DMSC proliferation and apoptosis.