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Principal Investigator Focus: Mark Majesky, PhD

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From Seattle Children's Research Institute's Interaction Research News.

Following the Path from Origins to Cures: Principal Investigator Mark Majesky Uses Developmental Genetics As the Foundation for Discovery

Majesky

Mark Majesky, PhD, director of the Myocardial Regeneration Initiative, Center for Tissue and Cell Sciences 

“The rapid advances being made in the field of developmental genetics are driving new technologies for stem and progenitor cell-based therapeutics,” said Mark Majesky, PhD, one of the newest members of Seattle Children’s Research Institute’s team of world-class principal investigators. “A detailed understanding of the molecules and mechanisms utilized in embryonic development of the heart and vascular system will provide the tools necessary to open doors to very exciting therapeutic opportunities based on reprogramming one cell type into another.”

Majesky began his research training at the University of Washington and now returns to the Pacific Northwest to join the Center for Tissue and Cell Sciences to lead its groundbreaking program in stem cell biology and regenerative medicine as the Director of the Myocardial Regeneration Initiative.

“A long-range goal of our program is to be able to take a patient’s own cells, convert one cell type (the adipocyte) to another (the cardiac myoblast) and then reintroduce them into the original patient, thus producing a fully immunologically matched cell-based graft.”

Stem cell biology and regenerative medicine program

“The program started with the energy and foundation provided by Robert J. Boucek, MD, MS.” Majesky continued, “Our team is now made up of Dr. Boucek; Mark B. Lewin, MD, clinical co-director of Seattle Children’s Heart Center; Tim McQuinn, MD; and me. We are in the process of recruiting three more principal investigators to join us at the research institute. When we are fully constituted we will have enough investigators focused in the area of heart and vascular development to provide the synergy and interaction to be self-propelling towards discovery and application.”

Majesky and his team are taking a close look at how the heart and coronary vasculature develop. “A long range goal of our program is to be able to take a patient’s own cells, convert one cell type (the adipocyte) to another (the cardiac myoblast) and then reintroduce them into the original patient, thus producing a fully immunologically matched cell-based graft.”

Majesky explained, “We will start with detailed studies of development of the heart and coronary vessels. As we acquire this knowledge, we will work with our collaborators at the Institute for Stem Cell and Regenerative Medicine at the University of Washington, and our clinical colleagues at Seattle Children’s Hospital, to translate this knowledge into clinical applications.”

Areas of focus

The program’s current research is focused in two areas:

  1. the basic mechanisms of development of the epicardium and coronary vessels; and
  2. the functions of resident stem cells in the adventitial layer of developing blood vessels.

In studying the basic mechanisms of coronary vessel development, the focus will be on the epicardium — the outer layer of the heart. “Fate mapping studies in embryos point to these cells giving rise to cells that build the coronary vasculature,” explained Majesky. “A critical step in the developmental sequence for coronary vessel formation is known as epithelial to mesenchymal transition (EMT) of the epicardium. EMT is a highly regulated and essential process in developing hearts. Studying EMT in detail will identify what promotes and at the same time what prevents the process from occurring in embryonic epicardial cells. Knowledge of the pathways that prevent EMT as the epicardium matures will provide the tools we need to reprogram postnatal epicardial cells to re-express their developmental potentials and contribute to cardiac repair and regeneration.”

The second focus area relates to the discovery of resident stem cells in the outer layers of artery walls. “The adventitia is a complex and poorly studied layer of the artery wall,” shared Majesky. “We are applying genetic approaches to better understand the potentials of these resident stem cells to contribute to coronary artery repair, remodeling and disease.”

Building the team

“The real work here will come from the formation of a multidisciplinary team of basic scientists and clinical colleagues to convert possibility into reality,” Majesky emphasized. “Our team will eventually consist of experts in developmental biology, genetics, bioengineering, pathology and clinical pediatrics drawn from Seattle Children’s and partner institutions in the Seattle area. The resources and support provided by the goal-oriented leadership at Seattle Children’s Research Institute is making this possible. This is a unique opportunity to translate what we find in laboratory studies to opportunities for therapeutic application in the areas of congenital defects in heart formation and cardiac insufficiency.”

 

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