Pre-Clinical Research
Imaging Survival and Function of Transplanted Cardiac Resident Stem Cells

https://doi.org/10.1016/j.jacc.2008.12.036Get rights and content
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Objectives

The goal of this study is to characterize resident cardiac stem cells (CSCs) and investigate their therapeutic efficacy in myocardial infarction by molecular imaging methods.

Background

CSCs have been isolated and characterized in vitro.These cells offer a provocative method to regenerate the damaged myocardium. However, the survival kinetics and function of transplanted CSCs have not been fully elucidated.

Methods

CSCs were isolated from L2G85 transgenic mice (FVB strain background) that constitutively express both firefly luciferase and enhanced green fluorescence protein reporter gene. CSCs were characterized in vitro and transplanted in vivo into murine infarction models. Multimodality noninvasive imaging techniques were used to assess CSC survival and therapeutic efficacy for restoration of cardiac function.

Results

CSCs can be isolated from L2G85 mice, and fluorescence-activated cell sorting analysis showed expression of resident CSC markers (Sca-1, c-Kit) and mesenchymal stem cell markers (CD90, CD106). Afterwards, 5 × 105CSCs (n = 30) or phosphate-buffered saline control (n = 15) was injected into the hearts of syngeneic FVB mice undergoing left anterior descending artery ligation. Bioluminescence imaging showed poor donor cell survival by week 8. Echocardiogram, invasive hemodynamic pressure-volume analysis, positron emission tomography imaging with fluorine-18-fluorodeoxyglucose, and cardiac magnetic resonance imaging demonstrated no significant difference in cardiac contractility and viability between the CSC and control group. Finally, postmortem analysis confirmed transplanted CSCs integrated with host cardiomyocytes by immunohistology.

Conclusions

In a mouse myocardial infarction model, Sca-1–positive CSCs provide no long-term engraftment and benefit to cardiac function as determined by multimodality imaging.

Key Words

molecular imaging
cardiac stem cells
ischemic heart disease
differentiation
cell fate

Abbreviations and Acronyms

BLI
bioluminescence imaging
BM-MSC
bone marrow-derived mesenchymal stem cell
CSC
cardiac stem cell(s)
DAPI
4′6-diamidino-2-phenylindole
DiI-ac-LDL
DiI acetylated low-density lipoprotein
EF
ejection fraction
eGFP
enhanced green fluorescence protein
FBS
fetal bovine serum
Fluc
firefly luciferase
FS
fractional shortening
%ID/g
injected dose per gram of heart
LAD
left anterior descending artery
LVEDd
left ventricular end-diastolic diameter
LVESd
left ventricular end-systolic diameter
MI
myocardial infarction
MRI
magnetic resonance imaging
PBS
phosphate-buffered saline
PET
positron emission tomography
PV
pressure-volume
ROI
region of interest
RT-PCR
reverse transcription-polymerase chain reaction
[18F]-FDG
fluorine-18-fluorodeoxyglucose

Cited by (0)

This work was supported, in part, by grants from the National Institutes of Health HL089027 (to Dr. Wu), the Burroughs Wellcome Foundation Career Award for Medical Scientists (to Dr. Wu), Stanford Cardiovascular Institute (to Dr. Wu), and the Society of Nuclear Medicine Pilot Research Award (to Dr. Li).