Nav: Home

Functional heart muscle regenerated in decellularized human hearts

March 11, 2016

Massachusetts General Hospital (MGH) researchers have taken some initial steps toward the creation of bioengineered human hearts using donor hearts stripped of components that would generate an immune response and cardiac muscle cells generated from induced pluripotent stem cells (iPSCs), which could come from a potential recipient. The investigators described their accomplishments - which include developing an automated bioreactor system capable of supporting a whole human heart during the recellularization process -- earlier this year in Circulation Research.

"Generating functional cardiac tissue involves meeting several challenges," says Jacques Guyette, PhD, of the MGH Center for Regenerative Medicine (CRM), lead author of the report. "These include providing a structural scaffold that is able to support cardiac function, a supply of specialized cardiac cells, and a supportive environment in which cells can repopulate the scaffold to form mature tissue capable of handling complex cardiac functions."

The research team is led by Harald Ott, MD, of the MGH CRM and the Department of Surgery, senior author of the paper. In 2008, Ott developed a procedure for stripping the living cells from a donor organ with a detergent solution and then repopulating the remaining extracellular matrix scaffold with organ-appropriate types of cells. Since then his team has used the approach to generate functional rat kidneys and lungs and has decellularized large-animal hearts, lungs and kidneys. This report is the first to conduct a detailed analysis of the matrix scaffold remaining after decellularization of whole human hearts, along with recellularization of the cardiac matrix in three-dimensional and whole-heart formats.

The study included 73 human hearts that had been donated through the New England Organ Bank, determined to be unsuitable for transplantation and recovered under research consent. Using a scaled-up version of the process originally developed in rat hearts, the team decellularized hearts from both brain-dead donors and from those who had undergone cardiac death. Detailed characterization of the remaining cardiac scaffolds confirmed a high retention of matrix proteins and structure free of cardiac cells, the preservation of coronary vascular and microvascular structures, as well as freedom from human leukocyte antigens that could induce rejection. There was little difference between the reactions of organs from the two donor groups to the complex decellularization process.

Instead of using genetic manipulation to generate iPSCs from adult cells, the team used a newer method to reprogram skin cells with messenger RNA factors, which should be both more efficient and less likely to run into regulatory hurdles. They then induced the pluripotent cells to differentiate into cardiac muscle cells or cardiomyocytes, documenting patterns of gene expression that reflected developmental milestones and generating cells in sufficient quantity for possible clinical application. Cardiomyocytes were then reseeded into three-dimensional matrix tissue, first into thin matrix slices and then into 15 mm fibers, which developed into spontaneously contracting tissue after several days in culture.

The last step reflected the first regeneration of human heart muscle from pluripotent stem cells within a cell-free, human whole-heart matrix. The team delivered about 500 million iPSC-derived cardiomyocytes into the left ventricular wall of decellularized hearts. The organs were mounted for 14 days in an automated bioreactor system developed by the MGH team that both perfused the organ with nutrient solution and applied environmental stressors such as ventricular pressure to reproduce conditions within a living heart. Analysis of the regenerated tissue found dense regions of iPSC-derived cells that had the appearance of immature cardiac muscle tissue and demonstrated functional contraction in response to electrical stimulation.

"Regenerating a whole heart is most certainly a long-term goal that is several years away, so we are currently working on engineering a functional myocardial patch that could replace cardiac tissue damaged due a heart attack or heart failure," says Guyette. "Among the next steps that we are pursuing are improving methods to generate even more cardiac cells - recellularizing a whole heart would take tens of billions -- optimizing bioreactor-based culture techniques to improve the maturation and function of engineered cardiac tissue, and electronically integrating regenerated tissue to function within the recipient's heart."

Team leader Ott, an assistant professor of Surgery at Harvard Medical School, adds, "Generating personalized functional myocardium from patient-derived cells is an important step towards novel device-engineering strategies and will potentially enable patient-specific disease modeling and therapeutic discovery. Our team is excited to further develop both of these strategies in future projects."
-end-
Additional coauthors of the Circulation Research report are Jonathan Charest, MS, Bernhard Jank, MD, Philipp Moser, MD, Sarah Gilpin, PhD, Tatsuya Okamoto, MD, PhD, and Gabriel Gonzalez, PhD, MGH Center for Regenerative Medicine; Robert Mills, PhD, and David J. Milan, MD, MGH Cardiovascular Research Center; and Joshua Gershlak and Glenn Gaudette, PhD, Worcester Polytechnic Institute. The study was supported by National Institutes of Health Director's New Innovator Award DP2 OD008749-01, and by National Heart Lung and Blood Institute grants R21 HL108663-2 and R01 HL115282.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $800 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2015, MGH returned into the number one spot on the 2015-16 U.S. News & World Report list of "America's Best Hospitals."

Massachusetts General Hospital

Related Immune Response Articles:

Discovering the early age immune response in foals
Researchers at the Cornell University College of Veterinary Medicine have discovered a new method to measure tiny amounts of antibodies in foals, a finding described in the May 16 issue of PLOS ONE.
Nixing the cells that nix immune response against cancer
For first time, study characterizes uptick of myeloid-derived suppressor cells in the spleens of human cancer patients, paving the way for therapies directed against these cells that collude with cancer.
Jumbled chromosomes may dampen the immune response to tumors
How well a tumor responds to immunotherapy may depend in part on whether its chromosomes are intact or in a state of disarray, a new study reports.
Tailored organoid may help unravel immune response mystery
Cornell and Weill Cornell Medicine researchers report on the use of biomaterials-based organoids in an attempt to reproduce immune-system events and gain a better understanding of B cells.
Tweaking the immune response might be a key to combat neurodegeneration
Patients with Alzheimer's or other neurodegenerative diseases progressively loose neurons yet cannot build new ones.
Estrogen signaling impacted immune response in cancer
New research from The Wistar Institute showed that estrogen signaling was responsible for immunosuppressive effects in the tumor microenvironment across cancer types.
No platelets, no immune response
When a virus attacks our organism, an inflammation appears on the affected area.
Malaria: A genetically attenuated parasite induces an immune response
With nearly 3.2 billion people currently at risk of contracting malaria, scientists from the Institut Pasteur, the CNRS and Inserm have experimentally developed a live, genetically attenuated vaccine for Plasmodium, the parasite responsible for the disease.
New finding will help target MS immune response
Researchers have made another important step in the progress towards being able to block the development of multiple sclerosis and other autoimmune diseases.
Flu infection reveals many paths to immune response
A new study of influenza infection in an animal model broadens understanding of how the immune system responds to flu virus, showing that the process is more dynamic than usually described, engaging a broader array of biological pathways.

Related Immune Response Reading:

The Immune Response: Basic and Clinical Principles
by Tak W. Mak (Author), Mary E. Saunders (Author), Wendy Lynn Tamminen (Editor), Maya Rani Chaddah (Editor)

The Immune Response is a unique reference work covering the basic and clinical principles of immunology in a modern and comprehensive fashion. Written in an engaging conversational style, the book conveys the broad scope and fascinating appeal of immunology. The book is beautifully illustrated with superb figures as well as many full color plates. This extraordinary work will be an invaluable resource for lecturers and graduate students in immunology, as well as a vital reference for research scientists and clinicians studying related areas in the life and medical sciences.Current and... View Details


The Lyme Solution: A 5-Part Plan to Fight the Inflammatory Auto-Immune Response and Beat Lyme Disease
by Darin Ingels (Author), Amy Myers MD (Foreword)

A comprehensive, natural approach to treating acute and chronic Lyme disease, from a leading naturopathic physician who has managed his symptoms for more than fifteen years.

Lyme disease is one of the fastest-growing infectious diseases in the United States, and millions of people worldwide suffer from its shape-shifting symptoms. Now, in The Lyme Solution, Dr. Darin Ingels shares his revolutionary approach to treating and healing acute and chronic Lyme. Drawing on his experience as a naturopathic physician who has treated thousands of cases, and as a patient,... View Details


The Immune Response to Infection
by Stefan H. E. Kaufmann (Editor), Barry T. Rouse (Editor), David L. Sacks (Editor)

Examines the mechanisms of both the innate and adaptive immune systems as they relate to infection and disease.

Explores the underlying mechanisms of immunity and the many sequelae of host-pathogen interactions, ranging from the sterile eradication of the invader, to controlled chronic infection, to pathologic corollaries of the host-pathogen crosstalk. Discusses the pathogenesis of certain autoimmune disorders and cancers that are induced by infectious agents but then become independent of the infection process. Serves as a resource for immunologists, molecular microbiologists,... View Details


Primer to the Immune Response, Second Edition
by Tak W. Mak (Author), Mary E. Saunders (Author), Bradley D. Jett (Author)

Written in the same engaging conversational style as the acclaimed first edition, Primer to The Immune Response, 2nd Edition is a fully updated and invaluable resource for college and university students in life sciences, medicine and other health professions who need a concise but comprehensive introduction to immunology. The authors bring clarity and readability to their audience, offering a complete survey of the most fundamental concepts in basic and clinical immunology while conveying the subject’s fascinating appeal.

The content of this new edition has been... View Details


Biomaterials and Immune Response: Complications, Mechanisms and Immunomodulation (Devices, Circuits, and Systems)
by Nihal Engin Vrana (Editor)

The interactions of the biomaterials with the host immune system is crucial for their functionality. This book aims to provide the reader with a better understanding of the role of the immune system in biomaterial applications. For this end, the book has dedicated chapters for i) explaining immune cells taking part in immune response to biomaterials/immune systems interface; ii) the effect of biomaterial shape, form and physicochemical properties on the response of immune system; iii) biofilm formation on implanted materials as a failure of immune system/biomaterial interactions; iv)... View Details


Immune Response

On the wet Olympic peninsula of Washington state. Physician's Assistant Rick scales is having problems with some of his terminally-ill patients– –they aren't dying … Along with Makah tribal cop Jasmine Hughes, Scales starts to poke around, and they find way more than they expected. A classic medical mystery, from New York Times Bestselling author Steve Perry. View Details


Nutrient Modulation of the Immune Response
by Susanna Cunningham-Rundles (Editor)

This book demonstrates that nutrients play a direct role as co-factors and regulators of the immune system. The book also shows that modulating the immune response with nutrients can provide a fundamental approach to preventive medicine.;Containing nearly 2300 bibliographic citations as well as illustrative figures, tables, and micrographs, this book is designed to be of interest to clinical immunologists, immunology and vitamin researchers, nutrition specialists, paediatricians, neonatologists, and upper-level undergraduate, graduate, and medical school students in these disciplines. View Details


Somatic Diversification of Immune Responses (Current Topics in Microbiology and Immunology) (Vol 229)
by Garnett Kelsoe (Editor), Martin Flajnik (Editor)

Discovery of the mechanism for V(D)J hypermutation remains a basic goal of immunology despite the best efforts of many labo­ ratories. The existence of catalyzed, site-specific mutation and its exploitation for the somatic evolution of lymphocytes are re­ markable adaptations, yet since the discovery of hypermutation in 1970 (see cover), much hard work has generated little. Indeed, our knowledge of what is probably absolutely required for the mutator's action can be succinctly expressed: /g gene enhancers. Table 1 of Winter et a!.'s chapter puts into a historical perspec­ tive how our... View Details


The Immune Response to Implanted Materials and Devices: The Impact of the Immune System on the Success of an Implant
by Bruna Corradetti (Editor)

This book provides a comprehensive overview of the cascade of events activated in the body following the implant of biomaterials and devices. It is one of the first books to shed light on the role of the host immune response on therapeutic efficacy, and reviews the state-of-the-art for both basic science and medical applications. The text examines advantages and disadvantages of the use of synthetic versus natural biomaterials. Particular emphasis is placed on the role of biomimicry in the development of smart strategies able to modulate infiltrating immune cells, thus reducing side effects... View Details


The Cytokines of the Immune System: The Role of Cytokines in Disease Related to Immune Response
by Zlatko Dembic (Author)

The Cytokines of the Immune System catalogs cytokines and links them to physiology and pathology, providing a welcome and hugely timely tool for scientists in all related fields. In cataloguing cytokines, it lists their potential for therapeutic use, links them to disease treatments needing further research and development, and shows their utility for learning about the immune system. This book offers a new approach in the study of cytokines by combining detailed guidebook-style cytokine description, disease linking, and presentation of immunologic roles.

Supplies new ideas for... View Details

Best Science Podcasts 2018

We have hand picked the best science podcasts for 2018. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

The Person You Become
Over the course of our lives, we shed parts of our old selves, embrace new ones, and redefine who we are. This hour, TED speakers explore ideas about the experiences that shape the person we become. Guests include aerobatics pilot and public speaker Janine Shepherd, writers Roxane Gay and Taiye Selasi, activist Jackson Bird, and fashion executive Kaustav Dey.
Now Playing: Science for the People

#478 She Has Her Mother's Laugh
What does heredity really mean? Carl Zimmer would argue it's more than your genes along. In "She Has Her Mother’s Laugh: The Power, Perversions, and Potential of Heredity", Zimmer covers the history of genetics and what kinship and heredity really mean when we're discovering how to alter our own DNA, and, potentially, the DNA of our children.