Our laboratory uses a variety of molecular, biochemical, and genetic approaches to study the basic biology of mesenchymal stem cells (MSCs). A main focus of the lab is to gain a better understanding of the molecular mechanisms that confer stem/progenitor and effector (angiogenic, anti-inflammatory, immuno-modulatory) phenotypes onto cells. By adapting this knowledge to basic principles of stem cell biology, we are building an expanded MSC hierarchy that more accurately models the functional complexity of populations and predicts how procurement and culture expansion methods alter therapeutic potency. Because MSCs reside within bone marrow in a low oxygen environment, we are also actively studying how oxidative stress impacts MSC function and how such stress may contribute to disease pathophysiology of the skeletal system. Our lab has made several important contributions to the field in these regards. One example of our work was the cataloging of the MSC transcriptome via serial analysis of gene expression (SAGE), which represented one of the first comprehensive analyses of gene expression in MSCs (see Tremain N et al., Stem Cells 2001; 19:408 & Phinney DG et al. Stem Cells 2006; 24:186). These findings fostered other studies by our laboratory showing that MSCs promote survival and induce neurite outgrowth in cultured neurons and DRG explants (see Crigler et al., Exp. Neurol. 2006; 198:54) and also protect mice against bleomycin-induced lung injury (see Ortiz LA et al Proc. Natl. Adac. Sci. USA 2007; 104:11002.). The latter study was one of the first to demonstrate that MSCs exhibit anti-inflammatory activity in vivo. Our laboratory also developed a reliable method to isolate primary MSCs from mouse bone marrow (Phinney DG, Methods Mol. Biol. 2008; 449:171) and showed that these cells exhibit hypersensitivity to oxidative stress via a P53 dependent mechanism, thereby providing an important link between oxidative stress and cellular immortalization (Boregowda SV et al. Stem Cells 2012; 30:975). Our lab is currently funded by the National Institutes of Health to provide primary MSCs from inbred, transgenic, and knockout mice to the larger scientific community (please click here for information on how to obtain cells).
Our study of MSCs has also fostered new avenues of investigation for the lab. For example, in an effort to identify microRNAs that modulate MSC function we discovered a microRNA cluster at the imprinted DLKI-DIO3 genomic locus that is epigenetically silenced during the early stages of breast cancer (see Haga C et al. J. Biol. Chem. 2012; 287:42695). Closer scrutiny of this cluster identified several microRNAs that target signaling pathways important in tumor metastasis and that regulate metabolic adaptation of tumor cells to hypoxic stress. In collaboration with the Disney laboratory, we are developing novel chemical probes to interrogate how dysregulated expression of these microRNAs contribute to cancer, which also serve as novel RNA-targeting lead therapeutics.