TY - JOUR
T1 - Human Organotypic Cultured Cardiac Slices
T2 - New Platform For High Throughput Preclinical Human Trials
AU - Kang, C.
AU - Qiao, Y.
AU - Li, G.
AU - Baechle, K.
AU - Camelliti, P.
AU - Rentschler, S.
AU - Efimov, I. R.
N1 - Funding Information:
The authors wish to thank Washington Regional Transplant Community, Washington DC and Mid-America Transplant Services, St. Louis, MO. We are grateful to Dr. Michael Pasque from Washington University School of Medicine, and the families of donors for donating cardiac tissues, which enables this research program. We also would like to thank Barnes Jewish Hospital's and Inova Fairfax Hospital's cardiothoracic transplant teams and donors for procurement of failing human hearts. We would like to acknowledge David Curiel for providing adenovirus, and Benjamin S. Gillers for his assistance in slice culture experiments. We gratefully acknowledge funding: R01 HL114395 and HL126802 (I.E.), CIMED P&F funds (I.E. and S.R.), AHA GIA 14GRNT19510011 (S.R.). Seed Grant from the Center of Regenerative Medicine (S.R.). S.R. holds a Career Award for Medical Scientists from the Burroughs Wellcome Foundation. P.C. acknowledges support from the UK physiological society.
PY - 2016/6/30
Y1 - 2016/6/30
N2 - Translation of novel therapies from bench to bedside is hampered by profound disparities between animal and human genetics and physiology. The ability to test for efficacy and cardiotoxicity in a clinically relevant human model system would enable more rapid therapy development. We have developed a preclinical platform for validation of new therapies in human heart tissue using organotypic slices isolated from donor and end-stage failing hearts. A major advantage of the slices when compared with human iPS-derived cardiomyocytes is that native tissue architecture and extracellular matrix are preserved, thereby allowing investigation of multi-cellular physiology in normal or diseased myocardium. To validate this model, we used optical mapping of transmembrane potential and calcium transients. We found that normal human electrophysiology is preserved in slice preparations when compared with intact hearts, including slices obtained from the region of the sinus node. Physiology is maintained in slices during culture, enabling testing the acute and chronic effects of pharmacological, gene, cell, optogenetic, device, and other therapies. This methodology offers a powerful high-throughput platform for assessing the physiological response of the human heart to disease and novel putative therapies.
AB - Translation of novel therapies from bench to bedside is hampered by profound disparities between animal and human genetics and physiology. The ability to test for efficacy and cardiotoxicity in a clinically relevant human model system would enable more rapid therapy development. We have developed a preclinical platform for validation of new therapies in human heart tissue using organotypic slices isolated from donor and end-stage failing hearts. A major advantage of the slices when compared with human iPS-derived cardiomyocytes is that native tissue architecture and extracellular matrix are preserved, thereby allowing investigation of multi-cellular physiology in normal or diseased myocardium. To validate this model, we used optical mapping of transmembrane potential and calcium transients. We found that normal human electrophysiology is preserved in slice preparations when compared with intact hearts, including slices obtained from the region of the sinus node. Physiology is maintained in slices during culture, enabling testing the acute and chronic effects of pharmacological, gene, cell, optogenetic, device, and other therapies. This methodology offers a powerful high-throughput platform for assessing the physiological response of the human heart to disease and novel putative therapies.
UR - http://www.scopus.com/inward/record.url?scp=84977071176&partnerID=8YFLogxK
U2 - 10.1038/srep28798
DO - 10.1038/srep28798
M3 - Article
C2 - 27356882
AN - SCOPUS:84977071176
SN - 2045-2322
VL - 6
JO - Scientific reports
JF - Scientific reports
M1 - 28798
ER -