ISCRM Researchers to Play Pivotal Roles on NIH-Funded Collaboration with Stanford

How subtle mutations in the protein myosin (shown here) lead to bigger changes at the cell and tissue level is a key question for a collaborative research effort involving UW, Stanford, and partner institutions.

Over the last decade, human induced pluripotent stem cells (iPSCs) have become powerful tools of discovery for scientists around the world. Essentially, iPSC technology involves reprogramming adult cells to an early developmental state in which they once again have the potential to become any other type of cell, enabling researchers to study normal biological processes, model diseases, and screen for potential drugs with thrilling speed, scale, and accuracy.

At the Institute for Stem Cell and Regenerative Medicine, for example, iPSCs are yielding valuable new insights about the nature of Alzheimer’s disease, cancer, diabetes, and many other chronic and acute conditions impacting billions of people.

But how faithfully do tissues made from these reprogrammed stem cells actually mimic the structural and functional changes that researchers are attempting to understand? And how do seemingly small mutations at the molecular level become serious health problems at the cell and tissue levels? These are the questions a collaborative research team led by investigators from Stanford University, the University of California Santa Barbara, the Curie Institute in Paris, and the University of Washington are determined to address in a new study funded by a five-year $10 million grant from the National Institute of General Medical Sciences (NIGMS).

Dr. Mike Regnier, Professor of Bioengineering and ISCRM Faculty Member, will lead the UW research team partnering with Stanford in a study funded by the National Institute for General Medical Sciences.

James Spudich PhD, from the Department of Biochemistry at Stanford University is the Principal Investigator for the project. Dr. Spudich is joined by three co-investigators from Stanford and by Dr. Mike Regnier, the UW Washington Research Foundation Professor of Bioengineering and an ISCRM faculty member.

To study how alterations in tissue organization and function can arise from often subtle changes in function at the molecular level, the research team will use iPSCs to model hypertrophic cardiomyopathy (HCM), the most common inherited cardiovascular disorder and a leading cause of sudden death. A focal point in the investigation will be a protein, called myosin, that helps generate the force needed for muscle contractions.

“We know from previous research that mutations in myosin lead to a variety of cardiac and skeletal muscle diseases, including HCM,” explains Regnier. “We want to help fill a knowledge gap by studying how these changes at the molecular level affect heart function in HCM and other diseases.”

The collaborative nature of the research funded by the grant will be crucial for success. The project brings together experts in biophysics, bioengineering, chemical engineering, cardiology, embryology, and stem cell biology. The multidisciplinary approach will also enable the team to develop biological and computational models required for a multi-layered picture of changes that originate from myosin alterations.

Specifically, the Stanford researchers will build platforms that will enable the project team to probe, manipulate, and visualize the mechanisms at work within cardiac and skeletal muscle, while their UW counterparts will conduct the in-depth quantitative analysis at the cellular and subcellular levels and differentiate stem cells into the muscle tissue required for the study.

“The key question is how the whole system respond to mutations,” says Regnier. “Answering that involves people who are working at the protein level, at the sub-cellular and cellular levels and, at the tissue level.  From stem cell-derived muscle in culture, we’ll reconstruct the individual proteins all the way up to engineered tissue.”

The butterfly effect of small mutations in the heart is just one question at the center of the collaboration. The research team will also be comparing and contrasting the impact of these changes on two types of muscle – specifically, cardiac muscle in our hearts and the skeletal muscle that enables us to perform voluntary functions, like walking, breathing, and moving our limbs. To better understand the implications for the full spectrum of muscle disorders, a third thread of the inquiry will focus on differences between myosin mutations that prevent muscles from contracting and other mutations that impair relaxation.

Dr. David Mack, Associate Professor of Rehabilitation Medicine and Bioengineering and ISCRM faculty member, brings expertise growing stem cells into cardiac and skeletal muscle tissue to the collaborative research effort.

Tackling these novel questions will be a group effort. The project partners will share the risk inherent in a large-scale investigation while collectively advancing the field of cardiac and skeletal muscle research. For their part, the UW team will bring a unique skillset that includes developmental biology and bioengineering.

Mike Regnier, the project lead for UW, brings the expertise, and the instrumentation, to measure force, contraction, and relaxation kinetics at scales from single proteins to whole organs –  the functional metrics that will be central to the investigation.

Joining Regnier from UW is Dr. David Mack, an Associate Professor of Rehabilitation Medicine and Bioengineering and an ISCRM faculty member. As a developmental biologist, Mack will differentiate gene-edited stem cells into the cardiac and skeletal muscle tissue that will allow the research team to study the genesis of the disease. “For the most part, we can’t watch development happen in humans,” explains Mack.  But we can use stem cells to make a disease model in a dish. We can then track muscle development, hour by hour.”

The findings of the collaborative study will have real-world implications for human health, starting with HCM. By using iPSCs to develop a more sophisticated understanding of the disease, the research team hopes to produce insights that point to new therapeutic targets for specific HCM mutations, a strategy that could be used by future researchers using IPSCs or animal models to study and treat other human diseases.