Investigating the use of multipotent adult progenitor cells for treatment of Duchenne muscular dystrophy: a translational approach.

University of Minnesota Ph.D. dissertation. August 2008. Major Biomedical Engineering. Advisors: Catherine M. Verfaillie, MD and Paul A. Iaizzo, PhD. 1 computer file (PDF); viii, 125 pages.Taking a “translational” approach to developing clinical therapies is a two step process that requires: 1) Basic science research on clinical diseases; and 2) application of knowledge gained or resultant therapeutics from that research to patient care. The collaboration of basic sciences and clinical sciences will result in greater advancement of knowledge within each field. There are many diseases that have no cure, even with the tools that modern medicine has to offer. A good example of this is Duchenne muscular dystrophy (DMD). Unfortunately, there is no cure and no effective long-term treatment to delay the progression of DMD; modern medicine can only ameliorate the symptoms and attempt to give the patient the best quality of life possible. It may one day be possible to cure patients if even one of the many experimental therapies for DMD, aimed at restoring dystrophin in skeletal muscle and shown to improve muscle function in dystrophic animals, could be developed clinically. One such therapy is stem cell therapy. The stem cells used in this work are multipotent adult progenitor cells (MAPC). MAPC were first discovered in the Verfaillie lab here at the University of Minnesota- Twin Cities. It was traditionally believed that adult stem cells like hematopoietic stem cells and mesenchymal stem cells could not differentiate into cells outside the mesodermal lineage; however there are currently numerous reports that challenge this thought. This thesis presents the application of a three-step translational approach toward development of stem cell therapy for treatment of DMD. The three steps are: 1) In vitro study of MAPC myogenic potential; 2) in vivo study of MAPC myogenic potential; and 3) development of a system to measure functional effects of therapies. Chapter 2 describes multifactorial testing of different cytokines in an effort to develop a protocol aimed at directing myogenic induction. Chapter 3 describes methods developed and subsequently tested to enhance MAPC engraftment in the DMD model mouse upon intramuscular injection. Chapter 4 describes the development and testing of a system aimed at detecting functional differences due to therapy