“Cardioimmunotherpy” – A Paradigm Shifting Concept: Engineering Cardio-Reparative Macrophages by Cardiac Specific Exosomes

Cardiovascular disease is the most common cause of death in the United States and developed world.

The human heart suffers loss of viable tissue and contractile function following myocardial infarction and this leads to heart failure, recurrent hospitalization, arrhythmias, and death. Unfortunately, the heart has limited intrinsic regenerative potential.

This project proposes a new direction of research, “cardio-immunotherapy”, with the long-term goal of restoring cardiac function by activating immune cells known as alternatively activated (M2) macrophages.  These unique cells promote cellular preservation and proliferation including tissue regeneration.

The project is based on the concept that cardiac-specific M2 macrophages can be bioengineered by conditioning circulating monocytes with cardiac fibroblast (supportive cells in the heart that surround cardiomyocytes) derived exosomes (compact vesicles containing signaling proteins and RNA). These macrophages are called Cardiac Fibroblast Exosome Educated Macrophages (CExM2) and they have a unique cell surface immune-phenotype that is different than any other known macrophage population.

The project aims to better understand the signaling involved in macrophage activation, demonstrate safety and efficacy of CExM2 administration in ischemic heart failure, and develop a “disease in a dish” model of human ischemic myocardium to test the efficacy of CExM2 administration for the treatment of diseased human tissue. This prototype construct will be used as a testing environment to inform CExM2 selection and dose optimization for human trials. While restoring heart function following myocardial infarction is the direction of this project, there is potential to use this same approach for treating other conditions such as stroke or diseases of the lung, liver, or kidney.

Co-Principal Investigators

• Peiman Hematti
  Professor of Medicine
• Amish Raval
  Associate Professor of Medicine
  

Co-Investigators

• John Kink
  Scientist in the Carbone Comprehensice Cancer Center
• Eric Schmuck
  Assistant Scientist in Medicine
• Sydney Walker
  Research Associate in Medicine

Collaborators

• David Beebe
  Professor of Biomedical Engineering
• Timothy Hacker
  Senior Scientist at the Cardiovascular Research Center and Director of the Cardiovascular Physiology Core Facility
• Timothy Kamp
  Professor of Medicine