The objective of this proposal is to test the hypothesis that maternal microchimerism is involved in the pathogenesis of acute and chronic renal disease. Acute renal failure leads to tubular injury and inflammation followed by regeneration with subsequent recovery of near normal renal function. However, even recovered patients have poor long-term prognoses, with high mortality and sometimes chronic renal failure. Recent experiments in stem cell transplantation suggest that after renal injury stem cells migrate to the kidney and differentiate into tubular epithelial and endothelial cells. It is not clear, however, whether the new cells in the kidney are helpful or harmful, or how they affect long-term renal function. Moreover, non-host cells may also be derived from pregnancy, when maternal cells pass into the fetus and fetal cells into the mother, leading to persistent fetal and maternal microchimerism (FMC, MMC). Thus, FMC and/or MMC could also participate in renal injury and/or regeneration, with long-term consequences. The PI has documented FMC and MMC in the kidney, as well as other target organs of autoimmunity, including liver, heart, lung, and pancreas. The PI has also discovered that maternal cells can differentiate into renal tubular epithelial cells. Thus after injury foreign stem cells may be recruited to aid in tissue regeneration. However, they also provide a potential source of renewable foreign antigen with the potential to trigger chronic inflammation. This proposal aims to test the hypothesis that MMC plays a pathogenic and/or regenerative role in renal disease.
In Specific Aim 1 we will test the hypothesis that acute renal injury induces the expansion and differentiation of maternal cells in the kidney in two mouse models, renal ischemia and rhabdomyolysis. Chimeric maternal cells will be quantified and characterized before, during and after injury.
Specific Aim 2 will test the hypothesis that MMC contributes to the pathogenesis of an inflammatory renal disease, glomerulonephritis. MMC in the kidney will be studied at different stages of disease in the BXSB lupus mouse. Maternal cells increased prior to onset of disease would suggest a primary pathogenic role for MMC. Maternal cells increased after disease onset would suggest a secondary role for MMC in inflammation or tissue regeneration. The data derived from this project will establish mouse systems in which to address mechanisms of maternal cell action in the kidney, as well as to develop and test treatments for acute renal failure based on maternal cells. ? ?
| López-Guisa, Jesús M; Howsmon, Rebecca; Munro, Andrew et al. (2011) Chimeric maternal cells in offspring do not respond to renal injury, inflammatory or repair signals. Chimerism 2:42-9 |
