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PRE-CLINICAL RESEARCH

Imaging Survival and Function of Transplanted Cardiac Resident Stem Cells

Zongjin Li, MD, PhD^_*, Andrew Lee, BS^_*, Mei Huang, PhD^_*, Hyung Chun, MD, Jaehoon Chung, MD, Pauline Chu, MS, Grant Hoyt, BS, Phillip Yang, MD, PhD, Jarrett Rosenberg, PhD^_*, Robert C. Robbins, MD and Joseph C. Wu, MD, PhD^_*,,_*

^_* Department of Radiology and Molecular Imaging Program (MIPS) Stanford University School of Medicine, Stanford, California
Department of Medicine, Division of Cardiology Stanford University School of Medicine, Stanford, California
Department of Cardiothoracic Surgery Stanford University School of Medicine, Stanford, California
Department of Comparative Medicine, Stanford University School of Medicine, Stanford, California

Manuscript received September 26, 2008; revised manuscript received December 1, 2008, accepted December 23, 2008.

^_* Reprint requests and correspondence: Dr. Joseph C. Wu, Stanford University School of Medicine, Edwards Building, R354, Stanford, California 94305-5344. (Email: joewu{at}stanford.edu).

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 x 10⁵ CSCs (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

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