The mission of our research program is to investigate the mechanisms of stem cell differentiation, especially in the context of the cardiovascular system. Driven by this mission, we also seek to generate new technologies that advance stem cell biology and promote translation of stem cell research into clinical practice.
A primary strength of our program is the ability to span multiple subdisciplines within both basic science (i.e., stem cell biology, cell-cell fusion, and extracellular matrices) and engineering (cytometry instrumentation and microfabrication) fields. Equally important is the high caliber of our team and the wonderful momentum they have built with hard work, strong intellect, and scientific curiosity. Below we describe the primary research projects within our research program.
Stem cell differentiation via cell fusion
Stem cell or progenitor cell transplantation has been proposed as a means to recover heart muscle function with damage or disease. However, recent experience has taught that most transplanted cells do not successfully engraft and do not become integral components of the myocardium.
Our group was among the first to discover that fusion between donor stem cells and recipient cardiomyocytes promotes stem cell engraftment, survival, and differentiation. Thus, we hypothesize that cardiac differentiation of stem cells and ultimately myocardial repair after infarction might be stimulated by the transplantation of stem cells poised to fuse with cardiomyocytes of the damaged ventricle.
Stem cell differentiation via extracellular matrix (ECM) interactions
ECM-based scaffolds have been proposed as a "bio-inspired" means to deliver stem cells to damaged myocardial tissue. However, our knowledge of the impact of cell-ECM interactions on cell fate processes of stem cells is limited. Particularly lacking is a clear understanding of the impact of 3D stem cell-ECM interactions on induction or repression of differentiation.
We hypothesize that ECM interactions alone are capable of driving lineage-specific differentiation of stem cells. Our group is particularly interested in differentiation of cardiac cell types in this context.
Multiphoton flow cytometry to guide stem cell transplantation
The future of stem cell transplantation depends on identifying noninvasive biomarkers to characterize cells and cell aggregates prior to transplantation. Characterization is needed minimally to define cell state and ideally to predict those cells best poised to contribute to a specific tissue type.
We hypothesize that intrinsic metabolic signatures detected with multiphoton microscopy provide noninvasive biomarkers indicative of stem cell state.
We have recently coupled multiphoton optics to a flow cytometry system (MPFC) that can analyze such intrinsic signatures of single cell and multicell aggregates in a high-throughput manner. This system is also the first of its kind to detect extrinsic fluorescent labels and dyes of cells within multicell aggregates or microtissues in a high-throughput manner.
Hanson K, Jung J, Tran Q, Hsu SP, Iida R, Eliceiri K, Squirrell J, Lyons G and Ogle BM. Spatial and temporal analysis of extracellular matrix proteins in the developing murine heart: a blueprint for regeneration. Tissue Engineering Epub ahead of print. 2013.
Tran QA*, Su PJ*, Fong JJ, Eliceiri KW, Ogle BM, Campagnola PJ. Mesenchymal stem cell interactions with 3D ECM modules fabricated via multiphoton excited photochemistry. Biomacromolecules 13(9):2917-2925. 2012.
Squirrell JM, Buschke DG, Lyons G, Kamp TJ, Eliceiri KW and Ogle BM. Intrinsic fluorescence of pluripotent stem cells predictably identifies differentiation state. PLoS ONE 7(8):e43708. 2012.
Kouris NA, Schaefer JA, Hatta M, Kawaoka Y, Kamp TJ and Ogle BM. Directed fusion of mesenchymal stem cells with cardiomyocytes via VSV-G facilitates stem cell programming. Stem Cells International AI 414038. 2012.
Buschke DG, Resto P, Schumacher N, Cox B, Tallavajhula A, Vivekanandan A, Eliceiri KW, Williams J and Ogle BM. Microfluidic sorting of microtissues. Biomicrofluidics 6(1):14116-1411611. 2012.
Buschke DG, Squirrell JM, Fong J, Eliceiri KW and Ogle BM. Cell death, noninvasively assessed by intrinsic fluorescence intensity of NADH, is a predictive indicator of functional differentiation of embryonic stem cells. Biology of the Cell 104:352-364. 2012.
Jung, J, Squirrell JM, Lyons G, Eliceiri KW and Ogle BM. Imaging cardiac extracellular matrices: a blueprint for regeneration. Trends in Biotechnology 30(4):233-40. 2012.
Sprangers AJ, Freeman B, Kouris KA and Ogle BM. A cre-loxP recombination approach for the detection of cell fusion in vivo. Journal of Visualized Experiments 4(59):e3581. 2012.
Sprangers AJ, Freeman B, and Ogle BM. Electroporation can efficiently transfect hESC-derived mesenchymal stem cells without inducing differentiation. Open Stem Cell Journal 3:62-66. 2011.
Kouris, NA, Squirrell, JM, Jung, JP, Pehlke, CA, Hacker, T, Eliceiri, KW, and Ogle BM. A non-denatured, non-crosslinked collagen matrix to deliver stem cells to the heart. Regenerative Medicine 6(5):569-582. 2011.
Hudulla G, Kouris NA, Koepsel J, Ogle BM and Murphy WL. Sequestering proteoglycans from serum amplifies growth factor signaling and enhances mesenchymal stem cell proliferation and differentiation. Integrative Biology 3(8):832-42. 2011.
McConnico A, Butters K, Lien K, Knudsen BE, Wu X, Platt JL and Ogle BM. In utero cell transfer between porcine littermates. Reproduction, Fertility and Development 23:297-302. 2010.
Lin HP, Vincenz C, Kerppola T and Ogle BM. Bimolecular complementation analysis of eukaryotic fusion products. Biology of the Cell 102:525-537. 2010.
Buschke DG, Ansari H, Smith M, Lyons, G, Kamp TJ, Eliceiri K and Ogle BM. Multiphoton flow cytometry to assess intrinsic and extrinsic fluorescence in cellular aggregates: applications to stem cells. Microscopy and Microanalysis 15:238-255. 2010.
Santiago J, Pogemiller R and Ogle BM. Heterogeneous differentiation of human mesenchymal stem cells in response to extended culture in extracellular matrices. Tissue Engineering 15(12):3911-3922. 2009.