title: Stimulation of adult resident cardiac progenitor cells by durable myocardial expression of thymosin beta 4 with ultrasound-targeted microbubble delivery.
abstract: It has been proposed that thymosin beta 4 (TB4)-protein delivery stimulates differentiation of resident adult WT1-positive cardiac progenitor cells, but with very low efficiency. We determined whether gene therapy with human TB4 stimulates proliferation of resident adult cardiac progenitor cells in normal rat heart. Ultrasound-targeted microbubble destruction (UTMD) was used to deliver the human TB4 gene under a piggybac transposon plasmid to normal rat heart. The rat hearts were assayed by quantitative reverse transcription-PCR and immunohistology with a confocal microscope at 1, 2, 3, 4 and 12 weeks after UTMD. Exogenous TB4 stimulation resulted in the presence of WT1-positive cardiac progenitor cells from epicardium to endocardium. TB4 stimulated angiogenesis and arteriogenesis. One month after TB4 gene therapy by UTMD, the percentage of NKX2.5-positive cardiomyocytes was 5.5±1.0% and NKX2.5 mRNA was 24-fold higher than in the control groups (P<0.001). Similar results were found for ISL-1, BrDu, Ki-67, PHH3 and aurora B (P<0.001). Cardiac-specific delivery of exogenous human TB4 gene efficiently stimulates proliferation and differentiation of resident WT1-positive adult cardiac progenitor cells into three intact cardiac cell lineages-vascular endothelial cells, coronary artery smooth muscle cells and cardiac muscle cells in normal adult rat heart.
authors.affiliation: Baylor Research Institute, Dallas, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Shimoda
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: P A
authors.initials: PA
authors.lastname: Grayburn
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D003331:Coronary Vessels / Q000166:cytology; D004251:DNA Transposable Elements / Q000235:genetics; D042783:Endothelial Cells / Q000166:cytology; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D045423:Microbubbles; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D009389:Neovascularization, Pathologic; D010957:Plasmids / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D013947:Thymosin / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099201:Thymosin beta(4)
chemical_list: D004251:DNA Transposable Elements; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D013947:Thymosin; D014157:Transcription Factors; D000099201:Thymosin beta(4); C524161:Nkx2-5 protein, rat