Article

Improvement of mouse cardiac function by hESC-derived cardiomyocytes correlates with vascularity but not graft size.

Heart Lung Center Utrecht, The Netherlands.
Stem cell research (impact factor: 3.39). 07/2009; 3(2-3):106-12. DOI:10.1016/j.scr.2009.05.004 pp.106-12
Source: PubMed

ABSTRACT Transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CM) has been shown to improve the function of the rodent heart 1 month after myocardial infarction (MI). However, the mechanistic basis and optimal delivery strategies are unclear. We investigated the influence of the number of injected cells, resulting graft size, and possible paracrine mechanisms in this process. MI was induced in NOD-SCID mice (n=84) followed by injection of enriched hESC-CM at different dosages, hESC-non-CM derivatives, culture medium, or no injection. Cardiac function was monitored for 12 weeks with 9.4 T MRI (n=70). Grafts were identified by epifluorescence of a transgenic GFP marker and characterized by immunofluorescence. Vascularity and paracrine effects were investigated immunohistochemically. Transplantation of differentiated hESCs improved short, mid-, and long-term cardiac performance and survival, although only cardiomyocytes formed grafts. A mid-term (4 weeks) cardiomyocyte-specific enhancement was associated with elevated vascular density around the graft and attenuated compensatory remodeling. However, increasing the number of hESC-CM for injection did not enhance heart function further. Moreover, we observed that small graft size was associated with a better functional outcome. HESC-CM increased myocardial vascularization and enhanced heart function in mice after MI, but larger graft size was associated with reduced functional improvement. Future studies should focus on advanced delivery strategies and mechanisms of action rather than increasing graft size.

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Keywords

4 weeks
 
Cardiac function
 
enriched hESC-CM
 
functional outcome
 
graft size
 
heart function
 
hESC-non-CM derivatives
 
larger graft size
 
mechanistic basis
 
mice
 
mid-
 
myocardial vascularization
 
NOD-SCID mice
 
optimal delivery strategies
 
paracrine effects
 
possible paracrine mechanisms
 
rodent heart 1 month
 
small graft size
 
transgenic GFP marker
 
vascular density