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Gene-Augmented Mesenchymal Stem Cells in Bone Repair

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Gene-Augmented Mesenchymal Stem Cells in Bone Repair GENE-AUGMENTED MESENCHYMAL STEM CELLS IN BONE REPAIR DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Terri A. Zachos, DVM * * * * * The Ohio State University 2006 Dissertation Committee: Approved by Professor Alicia Bertone, Adviser Professor Jeffrey Bartlett _________________________________________ Adviser Professor Clifford Les Graduate Program in Veterinary Clinical Sciences Professor Thomas Rosol Copyright by Terri A. Zachos 2006 ABSTRACT Complicated healing of articular fractures represents a clinical challenge and a financial burden on the health care system. Biologic repair systems are being evaluated, in both in vitro and in vivo experimental models, to augment healing of musculoskeletal connective tissues to address this problem. Bone marrow-derived mesenchymal stem cells (BMDMSC) hold promise for targeted osteogenic differentiation and can be augmented by delivery of genes encoding bone morphogenetic proteins (BMP). The feasibility of promoting osteogenic differentiation of BMDMSC was investigated using two BMP genes in monolayer and three-dimensional alginate culture systems. Cultured BMDMSC were transduced with E1-deleted adenoviral vectors containing either human BMP2 or BMP6 coding sequence under cytomegalovirus (CMV) promotor control and either sustained in monolayer or suspended in 1 ml 1.2% alginate beads for 22 days. Adenovirus (Ad)-BMP-2 and Ad-BMP-6 transduction resulted in abundant BMP-2 and BMP-6 mRNA and ligand expression in monolayer culture and BMP-2 ligand expression in alginate cultures. Ad-BMP-2 and Ad-BMP-6 transduced BMDMSC in monolayer had earlier and robust alkaline phosphatase-positive staining and mineralization and were sustained for a longer duration with morphology scores more consistent with viable cells than untransduced or Ad-ß-galactosidase-transduced cells. Ad-BMP-2- and to a lesser degree Ad-BMP-6-transduced BMDMSC suspended in alginate demonstrated greater mineralization than untransduced cells. Gene expression studies at day 2 confirmed an inflammatory response to the gene delivery process with up-regulation of interleukin 8 and CXCL2. Up- regulation of genes consistent with response to BMP exposure and osteogenic differentiation, specifically endochondral ossification and extracellular matrix proteins, occurred in BMP-transduced cells. These data support that transduction of BMDMSC with Ad-BMP-2 or Ad-BMP-6 can accelerate osteogenic differentiation and mineralization of stem cells in culture, including in three-dimensional culture. BMP-2- transduced stem cells suspended in alginate culture may be a practical carrier system to support bone formation in vivo. BMP-6 induced a less robust cellular response than BMP-2, particularly in alginate. ii In vivo models are valuable to evaluate fracture healing methods. A weight-bearing, distal femoral intercondylar articular osteotomy model was created in the nude rat. Osteotomies were treated with BMDMSC, either wild-type (NoAd) or transduced with an adenoviral-bone morphogenetic protein 2 transgene construct (Ad-BMP-2). Cells were delivered in alginate (ALG) or injected in saline. Controls were empty ALG, saline injections, direct Ad-BMP-2 injection, and untreated osteotomies. Healing was compared using quantitative micro-computed tomography, fluorescent labeling, and histology. At day 14, osteotomy gap area in the Ad-BMP-2 ALG group was significantly greater than any other group (P < 0.0003). The group treated with Ad-BMP-2-transduced cells injected in saline (Ad-BMP-2 cells) had healed with less osteotomy gap area (P < 0.0001) and volume (P < 0.02) than untreated controls. In ALG groups, bone healing was impeded by the development of a chondroid mass most pronounced in the Ad- BMP-2 ALG group. Injection of Ad-BMP-2-transduced BMDMSC in saline accelerated bone healing and reconstituted the articular surface in this distal femoral osteotomy model of articular fracture healing. iii Dedicated to my parents, Evelyn Stasinopoulos Zachos and George H. Zachos, who taught me that “with God all things are possible” (Matthew 19:26). iv ACKNOWLEDGMENTS I sincerely thank my adviser, Dr. Alicia Bertone, for providing exceptional mentorship, advice, and support, and for setting an example that has challenged me to strive for excellence in every endeavor. I thank Dr. Clifford Les for extensive discussions and consultation in the areas of imaging, statistical analysis, and biomechanics, and for his valuable advice on grantsmanship and collaboration. I thank Dr. Les and Drs. Jeffrey Bartlett and Thomas Rosol for their tireless efforts as members of my Doctoral Advisory, Candidacy Examination, and Final Oral Examination, and Dissertation Committees. I gratefully acknowledge Tim Vojt for electronic artwork and animations. I thank Alan Bakaletz, Ruth Berger, Joseph Ielapi, Amanda Johnson, Susie Jones, Dr. Yi-wen Liu-Stratton, and Anne Saulsbery for technical support, and Dr. Kelly Santangelo for managing local anesthesia in in vivo studies. I am grateful for the assistance of Dr. Valerie Samii and Linnea Baumwart with computed tomography in the Veterinary Teaching Hospital. I thank Dr. Steven Weisbrode for histopathologic review and consultation. I am indebted to Alisha Diggs, without whom micro-computed tomography studies would not have been possible, and to Jessica Williams, Colleen Flanagan, and Dr. Scott Hollister for assistance with micro-computed tomography data analysis. Some of the materials employed in this work were provided by the Tulane Center for Gene Therapy through a grant from NCRR of the NIH, Grant # P40RR017447. I thank Roxanne Reger, Margaret Wolfe, and Dr. Darwin Prockop of the Tulane Center for Gene Therapy for proving mesenchymal stem cells and their experience on their biological behavior in vitro. My graduate program and this research were supported by a Ruth L. Kirschstein Individual National Research Service Award from the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (Grant # F32AR050916) and by the Trueman Endowment. v VITA November 4, 1970 . Born in Flushing, NY 1988 . Diploma with Honors, The Peddie School, Hightstown, NJ 1992 . BS with Honors, Cornell University 1996 . DVM, Cornell University 1996-1997 . Intern, Small animal medicine and surgery The Animal Medical Center New York, NY 1997-2000 . Resident, Small animal surgery The Animal Medical Center New York, NY 2000-2002 . Sten-Erik Olsson Fellow in Comparative Orthopaedic Research Michigan State University 2002-2003 . Graduate Research Associate Department of Veterinary Clinical Sciences The Ohio State University 2003-2006 . Graduate Fellow Department of Veterinary Clinical Sciences The Ohio State University PUBLICATIONS 1. Munsterman AS, Bertone AL, Zachos TA, Weisbrode SE. Effects of the omega-3 fatty acid, alpha-linolenic acid, on lipopolysaccharide-challenged and -unchallenged equine synovial explants, American Journal of Veterinary Research, 66: 1503-1508, 2005. 2. Zachos TA, Bertone AL. Growth factors and their potential therapeutic applications for healing of musculoskeletal and other connective tissues, Am J Vet Res, 66: 727-738, 2005. FIELDS OF STUDY Major Field: Veterinary Clinical Sciences vi TABLE OF CONTENTS Page Abstract . .ii Dedication . .iv Acknowledgments . .v Vita . vi List of Tables . x List of Figures . .xi Chapters: 1. Growth factors: interactions and therapeutic implications for musculoskeletal connective tissues . 1 1.1 Summary . .1 1.2 Musculoskeletal and connective tissues: clinical concerns. .1 1.3 Review of terms. .3 1.4 The biology of growth factors . .6 1.5 Biologic functions and signaling interactions among growth factors in musculoskeletal and connective tissues. .8 1.6 Molecular interactions relevant to musculoskeletal and connective tissue development and healing . 17 1.7 Perspectives on the clinical applications of growth factors, disease-modifying agents and biologics . 19 1.8 Clinical implications for new therapies and devices. 20 vii 1.9 Clinically available therapies and devices. .23 1.10 The clinical future for therapies and devices . 26 1.11 Conclusions . .30 2. Gene-mediated osteogenic differentiation of stem cells by BMP2 or BMP6 . .32 2.1 Summary . .32 2.2 Introduction . .33 2.3 Methods . .36 2.4 Results . .41 2.5 Discussion . .50 3. Rodent models for the study of articular fracture healing . 58 3.1 Summary . .58 3.2 Introduction . .59 3.3 Methods . .60 3.4 Results . .68 3.5 Discussion . .71 4. Chondro-osseous differentiation of bone marrow-derived mesenchymal stem cells in alginate cultures induced by BMP-2 and BMP-6 gene delivery . 81 4.1 Summary . .81 4.2 Introduction . .82 4.3 Results . .84 4.4 Discussion . .86 4.5 Methods . .90 viii 5. Mesenchymal stem cell-mediated gene delivery of BMP-2 in an articular fracture model . .102 5.1 Summary . .102 5.2 Introduction . .103 5.3 Results. 106 5.4 Discussion. 110 5.5 Methods. 115 Appendix A: Microarray Data From In Vitro Studies . 139 Appendix B: Supplementary Micro-Computed Tomography Data . 146 Bibliography . .153 ix LIST OF TABLES Table Page 1.1 Classification, origin, and major functions of growth factors relevant to musculoskeletal and connective tissue healing . .7 1.2 Dose of rhBMP and rate of bone healing in various species in the presence of recombinant bone morphogenetic proteins (BMPs) . .22 1.3 Commercially available growth factors and their respective costs (as quoted for purchase on a unit basis) . ..
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