From stem cells to viable autologous semilunar heart valve.
BACKGROUND
An estimated 275,000 patients undergo heart valve replacement each year. However, existing solutions for valve replacement are complicated by the morbidity associated with lifelong anticoagulation of mechanical valves and the limited durability of bioprostheses. Recent advances in tissue engineering and our understanding of stem cell biology may provide a lifelong solution to these problems.


RESULTS
Mesenchymal stem cells were isolated from ovine bone marrow and characterized by their morphology and antigen expression through immunocytochemistry, flow cytometry, and capacity to differentiate into multiple cell lineages. A biodegradable scaffold was developed and characterized by its tensile strength and stiffness as a function of time in cell-conditioned medium. Autologous semilunar heart valves were then created in vitro using mesenchymal stem cells and the biodegradable scaffold and were implanted into the pulmonary position of sheep on cardiopulmonary bypass. The valves were evaluated by echocardiography at implantation and after 4 months in vivo. Valves were explanted at 4 and 8 months and examined by histology and immunohistochemistry. Valves displayed a maximum instantaneous gradient of 17.2+/-1.33 mm Hg, a mean gradient of 9.7+/-1.3 mm Hg, an effective orifice area of 1.35+/-0.17 cm2, and trivial or mild regurgitation at implantation. Gradients changed little over 4 months of follow-up. Histology showed disposition of extracellular matrix and distribution of cell phenotypes in the engineered valves reminiscent of that in native pulmonary valves.


CONCLUSIONS
Stem-cell tissue-engineered heart valves can be created from mesenchymal stem cells in combination with a biodegradable scaffold and function satisfactorily in vivo for periods of >4 months. Furthermore, such valves undergo extensive remodeling in vivo to resemble native heart valves.
Sutherland
Fraser W H
FW
Department of Cardiothoracic Surgery, Children's Hospital, Boston, Mass, USA. fraser.sutherland@northglasgow.scot.nhs.uk
Perry
Tjorvi E
TE
Yu
Ying
Y
Sherwood
Megan C
MC
Rabkin
Elena
E
Masuda
Yutaka
Y
Garcia
G Alejandra
GA
McLellan
Dawn L
DL
Engelmayr
George C
GC
Sacks
Michael S
MS
Schoen
Frederick J
FJ
Mayer
John E
JE
D000818:Animals; D001672:Biocompatible Materials; D001705:Bioprosthesis; D002454:Cell Differentiation; D019070:Cell Lineage; D004452:Echocardiography; D006350:Heart Valve Prosthesis; D019918:Heart Valve Prosthesis Implantation; D016130:Immunophenotyping; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D039904:Pluripotent Stem Cells; D011664:Pulmonary Valve; D012756:Sheep; D023822:Tissue Engineering / Q000379:methods*; D014182:Transplantation, Autologous
D001672:Biocompatible Materials