Department Seminar

Dystrophin-deficient iPS cell-derived cardiomyocytes: A new tool for drug discovery

Speaker Details:

David Mack
Assistant Professor
Rehabilitation Medicine, University of Washington

Lecture Details:

February 26, 2015
12:30-1:20 p.m.
Foege N130A, Wallace H. Coulter Seminar Room

Abstract:

Modeling a disease in culture typically requires differentiating at least one patient-specific iPS cell line into the functional cell type that will mimic the disease phenotype observed in the patient. Our efforts to create an iPSC-derived disease model for the cardiomyopathy associated with Duchenne Muscular Dystrophy (DMD) will serve as an example of ongoing projects in the laboratory that attempt to improve drug discovery for neuromuscular diseases. There is currently no effective treatment available for DMD cardiomyopathy—a condition responsible for early morbidity and mortality in these patients. Urine-derived iPSCs generated from healthy volunteers and a DMD patient were differentiated into beating cardiomyocytes in monolayer culture using a series of small molecules that modulate the Wnt signaling pathway. Dystrophin-null cardiomyocytes exhibit the following multifaceted phenotype: 1. delay in calcium re-uptake, 2. faster opening mitochondrial permeability pore when under oxidative stress, 3. an increase in mitochondrial basal and oxygen consumption rate as well as maximum and spare capacity, 4. fragility of cardiac cell membrane under osmotic stress leading to the release of two widely accepted cardiac injury markers, CK-MD and cardiac troponin I. Studies currently underway include transitioning these readouts into a high-throughput platform for drug screening purposes, as well attempts to promote cardiomyocyte maturity to better mimic the pathology observed in patients and to serve as secondary or tertiary validation of therapeutic candidates.

Speaker Bio:

Dr. David Mack is an in the Department of Rehabilitation Medicine as well as a faculty member of the Institute for Stem Cell and Regenerative Medicine at the University of Washington. He has a longstanding interest in how stem cells make cell fate decisions during embryonic development by coordinating their intrinsic genetic program with cues from their surrounding microenvironment. The goal of the Mack laboratory is to apply their understanding of this basic question to the development of stem cell and gene therapy treatments for neuromuscular diseases. David’s expertise is rooted at the intersection of genetics, developmental biology, cancer biology and biomaterials, which resulted directly from different phases of his professional training. The foundation is a Ph.D. in molecular genetics from the Indiana University School of Medicine, where he studied transcriptional regulation of T-cell development and how this process goes awry to cause leukemia. As a postdoctoral fellow at the National Cancer Institute in Bethesda, he studied how tissue-specific stem cells interact with their microenvironment and how this impacts cell fate choices during mammary gland development and pregnancy. David then switched from cancer research to the relatively new field of regenerative medicine by accepting a senior postdoc position at the Wake Forest Institute for Regenerative Medicine. Under the leadership of Dr. Anthony Atala, David’s work focused on how to control embryonic and fetal stem cell differentiation by using natural and artificial scaffolds in concert with direct manipulation of the cells’ genetic program. All of these efforts have the overriding purpose of developing therapies to enhance tissue repair and regeneration following injury or disease.