University of Washington (UW) researchers have succeeded in engineering human tissue patches free of some problems that have stymied stem-cell repair for damaged hearts. Pre-formed blood vessels in patches connect to rodents’ heart circulation.
The disk-shaped patches can be fabricated in sizes ranging from less than a millimeter to a half-inch in diameter. Until now, engineering tissue for heart repair has been hampered by cells dying at the transplant core, because nutrients and oxygen reached the edges of the patch but not the center. To make matters worse, the scaffolding materials to position the cells often proved to be harmful.
In contrast to the heart muscle cell-only tissue, which failed to survive transplantation and which remained apart from the rat’s heart circulatory system, the pre-formed vessels in the mixed-cell tissue joined with the rat’s heart circulatory system and delivered rat blood to the transplanted graft.
“The viability of the transplanted graft was remarkably improved,” Murry observed. “We think the gain in viability is due to the ability for the tissue to form blood vessels.”
Equally as exciting, the scientists observed that the patches of engineered tissue actively contracted. Moreover, these contractions could be electronically paced, up to what would translate to 120 beats per minute. Beyond that point, the tissue patch didn’t relax fully and the contractions weakened. However, the average resting adult heart pulses about 70 beats per minute. This suggests that the engineered tissue could, within limits, theoretically keep pace with typical adult heart muscle, according to the study authors.
Another physical quality that made the mixed-cell tissue patches superior to heart muscle-cell patches was their mechanical stiffness, which more closely resembled human heart muscle. This was probably due to the addition of supporting cells, which created connective tissues. Passive stiffness allows the heart to fill properly with blood before it contracts.
When the researchers implanted these mixed celled, pre-vascularized tissue patches into rodents, the patches grew into cell grafts that were ten times larger than the too-small results from tissue composed of heart muscle cells only. The rodents were bred without an immune system that rejects tissue transplants.
Murry noted that these results have significance beyond their contribution to the ongoing search for ways to treat heart attack damage by regenerating heart tissue with stem cells
The study findings, he observed, suggest that researchers consider including blood vessel-generating and vascular-supporting elements when designing human tissues for certain other types of regenerative therapies unrelated to heart disease.
2. Scientists from the Universities of Michigan and Minnesota show in a research report published online in the FASEB Journal that gene therapy may be used to improve an ailing heart’s ability to contract properly. [Scientists Jump-start The Heart By Gene Transfer]
In addition to showing gene therapy’s potential for reversing the course of heart failure, it also offers a tantalizing glimpse of a day when “closed heart surgery” via gene therapy is as commonly prescribed as today’s cocktail of drugs.
To make this advance, Herron and colleagues treated heart muscle cells from the failing hearts of rabbits and humans with a virus (adenovirus) modified to carry a gene which produces a protein that enables heart cells to contract normally (fast molecular motor) or a gene that becomes active in failing hearts, which is believed to be part of the body’s way of coping with its perilous situation (slow molecular motor). Heart cells treated with the gene to express the fast molecular motor contracted better, while those treated with the gene to express the slow molecular motor were unaffected.
“Helping hearts heal themselves, rather than prescribing yet another drug to sustain a failing organ, would be a major advance for doctors and patients alike,” said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. “Equally important, it shows that gene therapy remains one of the most promising approaches to treating the world’s most common and deadliest diseases.”
Current inotropic therapies used to increase cardiac contractility of the failing heart center on increasing the amount of calcium available for contraction, but their long-term use is associated with increased mortality due to fatal arrhythmias. Thus, there is a need to develop and explore novel inotropic therapies that can act via calcium-independent mechanisms. The purpose of this study was to determine whether fast -myosin molecular motor gene transfer can confer calcium-independent positive inotropy in slow -myosin-dominant rabbit and human failing ventricular myocytes. To this end, we generated a recombinant adenovirus (AdMYH6) to deliver the full-length human -myosin gene to adult rabbit and human cardiac myocytes in vitro. Fast -myosin motor expression was determined by Western blotting and immunocytochemical analysis and confocal imaging. In experiments using electrically stimulated myocytes from ischemic failing hearts, AdMYH6 increased the contractile amplitude of failing human [23.9±7.8 nm (n=10) vs. AdMYH6 amplitude 78.4±16.5 nm (n=6)] and rabbit myocytes. The intracellular calcium transient amplitude was not altered. Control experiments included the use of a green fluorescent protein or a -myosin heavy chain adenovirus. Our data provide evidence for a novel form of calcium-independent positive inotropy in failing cardiac myocytes by fast -myosin motor protein gene transfer.—Herron, T. J., Devaney, E., Mundada, L., Arden, E., Day, S., Guerrero-Serna, G., Turner, I., Westfall, M., Metzger, J. M. Ca2+-independent positive molecular inotropy for failing rabbit and human cardiac muscle by -myosin motor gene transfer.
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