Regenerative Medicine
Scientists have taken some initial steps toward the creation of bioengineered human hearts using donor hearts stripped of cells and induced pluripotent stem cells. The work could lead to custom grown transplantable organs with near zero rejection rates in the future.
Researchers at Massachusetts General Hospital have taken the initial steps toward the creation of bioengineered human hearts using induced pluripotent stem cells (iPSCs) and donor hearts stripped of the elements that would generate an immune response. The work, which includes developing an automated bioreactor system capable of supporting a whole human heart during the recellularization process, was published in the journal Circulation Research.
The scientists are currently developing new approaches to recellularize heart scaffolds to facilitate this regeneration. They are designing and validating novel whole-heart bioreactors that recapitulate cardiac physiology to aid in the maturation of recellularized cardiac matrices.
This project draws from expertise in stem cell biology, developmental biology, physiology, cardiology, and biomedical engineering in pursuit of creating a bioartificial heart that will one day provide a viable treatment option for patients in need of heart transplants.
"Generating functional cardiac tissue involves meeting several challenges," says Jacques Guyette, PhD, of the MGH Center for Regenerative Medicine (CRM), and 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."
"Regenerating a whole heart is most certainly a long-term goal that is several years away."
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The study included 73 human hearts that had been donated through the New England Organ Bank, found 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.Once treated, 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 Harald Ott, MD, of the MGH CRM and the Department of Surgery, , 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."
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