Embryonic Stem Cells Overexpressing Pitx2 Engraft in Infarcted Myocardium and Improve Cardiac Function

• Published in: International heart journal Vol. 50; no. 6; pp. 783 - 799
• Main Authors: Guddati, AK, Otero, José Javier, Kessler, Eric, Aistrup, Gary, Wasserstrom, J. Andrew, Han, Xiaoqiang, Lomasney, Jon W., Kessler, John A.
• Format: Journal Article
• Language: English
• Published: 01-11-2009
• ISSN: 1349-2365; 1349-3299

This study investigated the effects on cardiomyocyte differentiation of
embryonic stem cells by the overexpression of the transcription factor, Pitx2c,
and examined the effects of transplantation of these differentiated cells on
cardiac function in a mouse model of myocardial infarction. Pitx2c
overexpressing embryonic stem cells were characterized for cardiac
differentiation by immunocytochemistry, RNA analysis, and electrophysiology.
Differentiated cells were transplanted by directed injection into the infarcted
murine myocardium and functional measurements of blood pressure, contractility,
and relaxation were performed. Histochemistry and FISH analysis performed on
these mice confirmed the engraftment and cardiac nature of the transplanted
cells.
Pitx2c overexpressing embryonic stem cells robustly differentiated into
spontaneously contracting cells which acquired cardiac protein markers and
exhibited action potentials resembling that of cardiomyocytes. These cells could
also be synchronized to an external pacemenker. Significant improvements (p
< 0.01) in blood pressure (56%), contractility (57%) and relaxation (59%)
were observed in infarcted mice with transplants of these differentiated cells
but not in mice which were transplanted with control cells. The Pitxx2c
overexpressing cells secrete paracrine factors which when absorbed into a
heparinated gel and injected into the infarcted myocardium produce a comparable
and significant (p < 0.01) functional recovery.
Pitx2c overexpression is a valuable method for producing cardiomycytes
from embryonic stem cells, and transplantation of these cardiomyocytes into
infarcted myocardium restores cardia function through multiple mechanisms.