Faculty DirectoryWilliam M. Miller
Professor of Chemical and Biological Engineering
Director, Master of Science in Biotechnology Program
Contact2145 Sheridan Road
Evanston, IL 60208-3109
Email William Miller
Ph.D. Chemical Engineering, University of California, Berkeley, CA
S.M. Chemical Engineering, MIT, Cambridge, MA
B.S. Chemical Engineering (Hons), Lehigh University, Bethlehem, PA
Cell culture applications, biotechnology and medicine, tissue engineering, bioreactors, cell therapies and organ regeneration
Controlled differentiation of hematopoietic (blood) cells
Our aim is to understand the regulation of hematopoietic stem cell (HSC) self-renewal (division with no loss in stem cell potential) and lineage-specific commitment and maturation. Applications include HSC expansion for transplantation or gene therapy, the selective production of granulocytic and megakaryocytic (Mk) progenitor and mature cells to eliminate the nadirs in neutrophil and platelet counts after bone marrow transplants, the treatment of hematological disorders, and the production of culture-derived platelets for transfusions.
Differentiation of hematopoietic stem cells for in vitro platelet production
Our in vitro culture system is based on aspects of the supportive stem cell niche environment found in the bone marrow. By modulating cytokine, pH, and oxygen levels to mimic in vivo gradients, we can tune the HSC response to produce mature Mks with the potential to give rise to functional platelets. More recently, we have turned our attention to the maturation process following commitment to the Mk lineage. During this phase, Mk cells replicate their DNA in the absence of cytokinesis (polyploidization) before transitioning to terminal maturation when they extend long, branched extensions, called proplatelets, between endothelial cells and into the bone marrow sinusoids. In vivo, the flowing blood shears off platelets, which are then available to respond to sites of injury.
By optimizing the process of in vitro differentiation, we look to provide an alternative supply for platelet transfusions. We aim to increase the yield of platelets per input cell by (1) Studying Mk cell surface interactions and proplatelet formation; (2) Developing a bioreactor for simultaneous cell culture and platelet collection using shear flow; and (3) Adapting a commercial cell washer to isolate platelets from culture.
Exploring molecular mechanisms of megakaryopoiesis
The molecular regulation of Mk commitment, maturation, and polyploidization is not well understood. Previous research from our lab has indicated that sirtuins (SIRT 1-7), a family of deacetylase enzymes, are important in Mk polyploidization, which is positively correlated with platelet production. In an effort to elucidate molecular mechanisms governing this process, we are using novel high-throughput assays to evaluate (1) transcription factor (TF) activity using luciferase reporters (collaboration with Shea lab) and (2) lysine deacetylase (KDAC) activity using acetylated peptides and mass spectrometry (collaboration with Mrksich lab). SIRT1 is a key regulator of transcription, and we are currently evaluating changes in the activity of Mk-relevant TFs in response to SIRT1 silencing, inhibition, or overexpression.
Development of bioreactor systems to support the recellularization of decellularized organs for eventual application in liver and kidney transplantation
Collaboration with Professor Jason Wertheim in Transplant Surgery
"Energy, Water and Fish: Biodiversity Impacts of Energy-Sector Water Demand in the United States Depend on Efficiency and Policy Measures," R.I. McDonald, J.D. Olden, J.J. Opperman, W.M. Miller, J. Fargione, C. Revenga; J.V. Higgins, and J. Powell, PLoS ONE, 7: e50219 (17 pages) (2012).
"Administration of nicotinamide does not increase platelet levels in mice," I.M. Konieczna, S. Panuganti, T.A. DeLuca, E.T. Papoutsakis, E.A. Eklund, and W.M. Miller, Blood Cells, Molecules and Disease, 50: 171–176 (2013).
"Bioreactor design for perfusion-based, highly-vascularized organ regeneration," B.M. Bijonowski, W.M. Miller*, and J.A. Wertheim*, Curr. Opin. Chem. Eng., 2: 32–40 (2013).
"Three-Stage Ex Vivo Expansion of High-Ploidy Megakaryocytic Cells: Towards Large-Scale Platelet Production," S. Panuganti, A.C. Schlinker, P.F. Lindholm, E.T. Papoutsakis, and W.M. Miller, Tissue Eng. A, 19: 998-1014 (2013).
"Synergistic effect of hydrogen peroxide on polyploidization during the megakaryocytic differentiation of K562 leukemia cells by PMA," Y. Ojima, M.T. Duncan, R.W. Nurhayati, M. Taya, and W.M. Miller, Exp. Cell Res., 319: 2205-2215(2013).
"Profiling Deacetylase Activities in Cell Lysates with Peptide Arrays and SAMDI Mass Spectrometry," H.-Y. Kuo, T.A. DeLuca, W.M. Miller*, and M. Mrksich*, Anal. Chem., 85: 10635-10642 (2013) (Editors' Highlight).
"Dynamic transcription factor activity profiles reveal key regulatory interactions during megakaryocyte and erythrocyte differentiation," M.T. Duncan, S. Shin, J.J. Wu, Z. Mays S. Weng, N. Bagheri*, W.M. Miller*, L.D. Shea*, Biotechnol. Bioeng. 111: 2082–2094(2014).
"Human Megakaryocyte Progenitors Derived from Hematopoietic Stem Cells of Normal Individuals are MHC class II-Expressing Professional APC that Enhance Th17 and Th1/Th17 Responses," A. Finkielsztein, A.C. Schlinker, L. Zhang, W.M. Miller, S.K. Datta, Immunol. Lett. 163:84-95 (2015).
"Optimization and critical evaluation of decellularization strategies to develop renal extracellular matrix scaffolds as biological templates for organ engineering and transplantation," M. Caralt, J.S. Uzarski, S. Iacob, K.P. Obergfell, N. Berg, B.M. Bijonowski, K.M. Kiefer, H.H. Ward, A. Wandinger-Ness, W.M. Miller, Z.J. Zhang, M.M. Abecassis, J.A. Wertheim, Am. J. Transplantation 15:64-75 (2015).
"Separation of in-vitro-derived megakaryocytes and platelets using spinning-membrane filtration," A.C. Schlinker, K. Radwanski, C. Wegener, K. Min*, W.M. Miller*, Biotechnol. Bioeng. 112:788-800(2015).
"Design and characterization of dual-purpose bioreactors for recellularization and maintenance culture of bioengineered kidney and liver scaffolds," J.S. Uzarski, B.M. Bijonowski, B. Wang, H.H. Ward, A. Wandinger-Ness, W.M. Miller*, J.A. Wertheim*, Tissue Eng. C. 21: 1032-1043 (2015).
"Epithelial Cell Repopulation and Preparation of Rodent Extracellular Matrix Scaffolds for Renal Tissue Development," J.S. Uzarski, J. Su, Y. Xie, Z.J. Zhang, H.H. Ward, A. Wandinger-Ness, W.M. Miller, J.A. Wertheim, J. Vis. Exp. (102), e53271, doi:10.3791/53271 (2015).