Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium.
Cellular cardiomyoplasty is an attractive option for the treatment of severe heart failure. It is, however, still unclear and controversial which is the most promising cell source. Therefore, we investigated and examined the fate and functional impact of bone marrow (BM) cells and embryonic stem cell (ES cell)-derived cardiomyocytes after transplantation into the infarcted mouse heart. This proved particularly challenging for the ES cells, as their enrichment into cardiomyocytes and their long-term engraftment and tumorigenicity are still poorly understood. We generated transgenic ES cells expressing puromycin resistance and enhanced green fluorescent protein cassettes under control of a cardiac-specific promoter. Puromycin selection resulted in a highly purified (>99%) cardiomyocyte population, and the yield of cardiomyocytes increased 6-10-fold because of induction of proliferation on purification. Long-term engraftment (4-5 months) was observed when co-transplanting selected ES cell-derived cardiomyocytes and fibroblasts into the injured heart of syngeneic mice, and no teratoma formation was found (n = 60). Although transplantation of ES cell-derived cardiomyocytes improved heart function, BM cells had no positive effects. Furthermore, no contribution of BM cells to cardiac, endothelial, or smooth muscle neogenesis was detected. Hence, our results demonstrate that ES-based cell therapy is a promising approach for the treatment of impaired myocardial function and provides better results than BM-derived cells.
Kolossov
Eugen
E
Axiogenesis AG, 50931 Cologne, Germany. eugen.kolossov@axiogenesis.com
Bostani
Toktam
T
Roell
Wilhelm
W
Breitbach
Martin
M
Pillekamp
Frank
F
Nygren
Jens M
JM
Sasse
Philipp
P
Rubenchik
Olga
O
Fries
Jochen W U
JW
Wenzel
Daniela
D
Geisen
Caroline
C
Xia
Ying
Y
Lu
Zhongju
Z
Duan
Yaqi
Y
Kettenhofen
Ralf
R
Jovinge
Stefan
S
Bloch
Wilhelm
W
Bohlen
Heribert
H
Welz
Armin
A
Hescheler
Juergen
J
Jacobsen
Sten Eirik
SE
Fleischmann
Bernd K
BK
D000818:Animals; D016026:Bone Marrow Transplantation; D017931:DNA Primers; D004594:Electrophysiology; D053595:Embryonic Stem Cells / Q000166:cytology*; D049452:Green Fluorescent Proteins; D007150:Immunohistochemistry; D051379:Mice; D009200:Myocardial Contraction / Q000502:physiology*; D009203:Myocardial Infarction / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000637:transplantation*; D011691:Puromycin; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D011691:Puromycin