Islet-1 gene delivery improves myocardial performance after experimental infarction.
OBJECTIVE
The LIM-homeobox transcription factor Isl1 plays a crucial role during heart embryogenesis and later on gives rise to adult resident cardiac stem cells. In this study, we aimed to discover new extra cardiac populations of Isl1 stem cells. We then investigated endogenous Isl1 kinetics after myocardial infarction (MI), and the effect of intra-myocardial gene transfer of naked DNA encoding Isl1 on functional recovery after MI.


METHODS
We used the transgenic mice Isl1/cre/Z/EG for lineage tracing of extra cardiac Isl1 stem cells. Non transgenic mice were used to study Isl1 kinetics post-MI by RT-PCR and FACS analysis. MI was induced in non transgenic mice by permanent ligation of the left anterior descending coronary artery (LAD). Naked DNA encoding Isl1 was injected to the peri-infarct region. Evaluation of cardiac performance was conducted by echocardiogram. Analysis of myocardial fibrosis and number of vessels was performed on histological cryosections.


CONCLUSIONS
Isl1 gives rise to subpopulations of progenitors in both the bone marrow and spleen, and is re-expressed in the spleen and left ventricle following MI. Intramyocardial gene transfer of Isl1 to the border zone of the infarcted hearts resulted in partial salvage of left ventricular function, enhanced vascularization, and reduced myocardial fibrosis. The Isl1 gene appears to be an attractive reparative target for future management of myocardial dysfunction.
The Cardiology Department, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Aya
A
Barzelay
Edith
E
Hochhauser
Michal
M
Entin-Meer
Yelena
Y
Chepurko
Einat
E
Birk
Arnon
A
Afek
Iris
I
Barshack
Lidya
L
Pinhas
Yulia
Y
Rivo
Jeremy
J
Ben-Shoshan
Sofia
S
Maysel-Auslender
Gad
G
Keren
Jacob
J
George
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D019070:Cell Lineage; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005355:Fibrosis; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D007267:Injections; D007700:Kinetics; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D016133:Polymerase Chain Reaction; D020127:Recovery of Function; D013154:Spleen / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014463:Ultrasonography; D016277:Ventricular Function, Left
D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1