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Cited by 493Mesenchymal stem cell researchPluripotent Stem Cells ResearchTissue Engineering and Regenerative Medicine

In vivo visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery

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Cao, Feng, Lin, Shuan, Xie, Xiaoyan, Ray, Pritha, Patel, Manishkumar, Zhang, Xianzhong, Drukker, Micha, Dylla, Scott J. +5 more·2006·Circulation
DOI 10.1161/circulationaha.105.588954PMC PMC4701384
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Abstract

Background— Recent studies have shown that stem cell therapy can promote tissue regeneration; however, monitoring stem cells in vivo remains problematic owing to limitations of conventional histological assays and imaging modalities. Methods and Results— Murine embryonic stem (ES) cells were stably transduced with a lentiviral vector carrying a novel triple-fusion (TF) reporter gene that consists of firefly luciferase, monomeric red fluorescence protein, and truncated thymidine kinase (fluc-mrfp-ttk). ES cell viability, proliferation, and differentiation ability were not adversely affected by either reporter genes or reporter probes compared with nontransduced control cells ( P =NS). Afterward, 1×10 7 of ES cells carrying the TF reporter gene (ES-TF) were injected into the myocardium of adult nude rats (n=20). Control animals received nontransduced ES cells (n=6). At day 4, the bioluminescence and positron emission tomography signals in study animals were 3.7×10 7 ±5.8×10 6 photons · s −1 · cm −2 per steradian (sr) and 0.08±0.03% injected dose/g, respectively ( P <0.05 versus control). Both signals increased progressively from week 1 to week 4, which indicated ES cell survival and proliferation in the host. Histological analysis demonstrated the formation of intracardiac and extracardiac teratomas. Finally, animals (n=4) that were treated with intraperitoneal injection of ganciclovir (50 mg/kg) did not develop teratomas when compared with control animals (n=4) treated with saline (1 mL/kg). Conclusion— This is the first study to characterize ES cells that stably express fluorescence, bioluminescence, and positron emission tomography reporter genes and monitor the kinetics of ES cell survival, proliferation, and migration. This versatile imaging platform should have broad applications for basic research and clinical studies on stem cell therapy.

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  • Bioluminescence has been utilized to detect engraftment and hematopoietic reconstitution after transplantation of luciferase-positive HSC populations.

    “Bioluminescence has been utilized to detect engraftment and hematopoietic reconstitution after transplantation of luciferase-positive HSC populations (Welsh and Kay, 2005; Cao et al., 2006”

    From Transparent Adult Zebrafish as a Tool for In Vivo Transplantation Analysis (2008) · cites this paper as Cao et al., 2006

    The Results (page not provided) report using bioluminescence to assess engraftment after transplantation of luciferase-expressing embryonic stem cells into rat hearts. The source does not report transplantation of hematopoietic stem cell (HSC) populations or detection of hematopoietic reconstitution. (LLM, conf=0.88)

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Research works printed but not linked: 30

  1. [2]Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410:701–705. doi: 10.1038/35070587. [DOI] [PubMed] [Google Scholar] · DOI
  2. [3]Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001;7:430–436. doi: 10.1038/86498. [DOI] [PubMed] [Google Scholar] · DOI
  3. [4]Hodgson DM, Behfar A, Zingman LV, Kane GC, Perez-Terzic C, Alekseev AE, Puceat M, Terzic A. Stable benefit of embryonic stem cell therapy in myocardial infarction. Am J Physiol Heart Circ Physiol. 2004;287:H471–H479. doi: 10.1152/ajpheart.01247.2003. [DOI] [PubMed] [Google Scholar] · DOI
  4. [5]Wollert KC, Drexler H. Clinical applications of stem cells for the heart. Circ Res. 2005;96:151–163. doi: 10.1161/01.RES.0000155333.69009.63. [DOI] [PubMed] [Google Scholar] · DOI
  5. [6]Reinlib L, Field L. Cell transplantation as future therapy for cardiovascular disease? A workshop of the National Heart, Lung, and Blood Institute. Circulation. 2000;101:E182–E187. doi: 10.1161/01.cir.101.18.e182. [DOI] [PubMed] [Google Scholar] · DOI
  6. [7]Hofmann M, Wollert KC, Meyer GP, Menke A, Arseniev L, Hertenstein B, Ganser A, Knapp WH, Drexler H. Monitoring of bone marrow cell homing into the infarcted human myocardium. Circulation. 2005;111:2198–2202. doi: 10.1161/01.CIR.0000163546.27639.AA. [DOI] [PubMed] [Google Scholar] · DOI
  7. [8]Bulte JW, Kraitchman DL. Iron oxide MR contrast agents for molecular and cellular imaging. NMR Biomed. 2004;17:484–499. doi: 10.1002/nbm.924. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  8. [9]Ahrens ET, Flores R, Xu H, Morel PA. In vivo imaging platform for tracking immunotherapeutic cells. Nat Biotechnol. 2005;23:983–987. doi: 10.1038/nbt1121. [DOI] [PubMed] [Google Scholar] · DOI
  9. [10]Wu JC, Chen IY, Sundaresan G, Min JJ, De A, Qiao JH, Fishbein MC, Gambhir SS. Molecular imaging of cardiac cell transplantation in living animals using optical bioluminescence and positron emission tomography. Circulation. 2003;108:1302–1305. doi: 10.1161/01.CIR.0000091252.20010.6E. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  10. [11]Boheler KR, Czyz J, Tweedie D, Yang HT, Anisimov SV, Wobus AM. Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circ Res. 2002;91:189–201. doi: 10.1161/01.res.0000027865.61704.32. [DOI] [PubMed] [Google Scholar] · DOI
  11. [12]Ray P, De A, Min JJ, Tsien RY, Gambhir SS. Imaging tri-fusion multimodality reporter gene expression in living subjects. Cancer Res. 2004;64:1323–1330. doi: 10.1158/0008-5472.can-03-1816. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  12. [13]Lois C, Hong EJ, Pease S, Brown EJ, Baltimore D. Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science. 2002;295:868–872. doi: 10.1126/science.1067081. [DOI] [PubMed] [Google Scholar] · DOI
  13. [14]De A, Lewis XZ, Gambhir SS. Noninvasive imaging of lentiviral-mediated reporter gene expression in living mice. Mol Ther. 2003;7:681–691. doi: 10.1016/s1525-0016(03)00070-4. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  14. [15]Maltsev VA, Wobus AM, Rohwedel J, Bader M, Hescheler J. Cardiomyocytes differentiated in vitro from embryonic stem cells developmentally express cardiac-specific genes and ionic currents. Circ Res. 1994;75:233–244. doi: 10.1161/01.res.75.2.233. [DOI] [PubMed] [Google Scholar] · DOI
  15. [16]Pannell D, Osborne CS, Yao S, Sukonnik T, Pasceri P, Karaiskakis A, Okano M, Li E, Lipshitz HD, Ellis J. Retrovirus vector silencing is de novo methylase independent and marked by a repressive histone code. EMBO J. 2000;19:5884–5894. doi: 10.1093/emboj/19.21.5884. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  16. [17]Pfeifer A, Ikawa M, Dayn Y, Verma IM. Transgenesis by lentiviral vectors: lack of gene silencing in mammalian embryonic stem cells and preimplantation embryos. Proc Natl Acad Sci U S A. 2002;99:2140–2145. doi: 10.1073/pnas.251682798. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  17. [18]Ma Y, Ramezani A, Lewis R, Hawley RG, Thomson JA. High-level sustained transgene expression in human embryonic stem cells using lentiviral vectors. Stem Cells. 2003;21:111–117. doi: 10.1634/stemcells.21-1-111. [DOI] [PubMed] [Google Scholar] · DOI
  18. [19]Massoud TF, Gambhir SS. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev. 2003;17:545–580. doi: 10.1101/gad.1047403. [DOI] [PubMed] [Google Scholar] · DOI
  19. [20]Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:154–156. doi: 10.1038/292154a0. [DOI] [PubMed] [Google Scholar] · DOI
  20. [21]Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145–1147. doi: 10.1126/science.282.5391.1145. [DOI] [PubMed] [Google Scholar] · DOI
  21. [22]Frangioni JV, Hajjar RJ. In vivo tracking of stem cells for clinical trials in cardiovascular disease. Circulation. 2004;110:3378–3383. doi: 10.1161/01.CIR.0000149840.46523.FC. [DOI] [PubMed] [Google Scholar] · DOI
  22. [23]Jacobs A, Voges J, Reszka R, Lercher M, Gossmann A, Kracht L, Kaestle C, Wagner R, Wienhard K, Heiss WD. Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas. Lancet. 2001;358:727–729. doi: 10.1016/s0140-6736(01)05904-9. [DOI] [PubMed] [Google Scholar] · DOI
  23. [24]Penuelas I, Mazzolini G, Boan JF, Sangro B, Marti-Climent J, Ruiz M, Ruiz J, Satyamurthy N, Qian C, Barrio JR, Phelps ME, Richter JA, Gambhir SS, Prieto J. Positron emission tomography imaging of adenoviral-mediated transgene expression in liver cancer patients. Gastroenterology. 2005;128:1787–1795. doi: 10.1053/j.gastro.2005.03.024. [DOI] [PubMed] [Google Scholar] · DOI
  24. [25]Yang Y, Nunes FA, Berencsi K, Furth EE, Gonczol E, Wilson JM. Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci U S A. 1994;91:4407–4411. doi: 10.1073/pnas.91.10.4407. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  25. [26]Yaghoubi S, Barrio JR, Dahlbom M, Iyer M, Namavari M, Satyamurthy N, Goldman R, Herschman HR, Phelps ME, Gambhir SS. Human pharmacokinetic and dosimetry studies of [(18)F]FHBG: a reporter probe for imaging herpes simplex virus type-1 thymidine kinase reporter gene expression. J Nucl Med. 2001;42:1225–1234. [PubMed] [Google Scholar]
  26. [27]Min JY, Yang Y, Converso KL, Liu L, Huang Q, Morgan JP, Xiao YF. Transplantation of embryonic stem cells improves cardiac function in postinfarcted rats. J Appl Physiol. 2002;92:288–296. doi: 10.1152/jappl.2002.92.1.288. [DOI] [PubMed] [Google Scholar] · DOI
  27. [28]Min JY, Yang Y, Sullivan MF, Ke Q, Converso KL, Chen Y, Morgan JP, Xiao YF. Long-term improvement of cardiac function in rats after infarction by transplantation of embryonic stem cells. J Thorac Cardiovasc Surg. 2003;125:361–369. doi: 10.1067/mtc.2003.101. [DOI] [PubMed] [Google Scholar] · DOI
  28. [29]Behfar A, Zingman LV, Hodgson DM, Rauzier JM, Kane GC, Terzic A, Puceat M. Stem cell differentiation requires a paracrine pathway in the heart. FASEB J. 2002;16:1558–1566. doi: 10.1096/fj.02-0072com. [DOI] [PubMed] [Google Scholar] · DOI
  29. [30]Phelps ME. Inaugural article: positron emission tomography provides molecular imaging of biological processes. Proc Natl Acad Sci U S A. 2000;97:9226–9233. doi: 10.1073/pnas.97.16.9226. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  30. [31]Wu JC, Tseng JR, Gambhir SS. Molecular imaging of cardiovascular gene products. J Nucl Cardiol. 2004;11:491–505. doi: 10.1016/j.nuclcard.2004.04.004. [DOI] [PubMed] [Google Scholar] · DOI

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Authors
Cao, F., Lin, S., Xie, X., Ray, P., Patel, M., Zhang, X., Drukker, M., Dylla, S. J., Connolly, A. J., Chen, X., Weissman, I. L., Gambhir, S. S., & Wu, J. C.
Affiliations
  • Stanford Medicine (US)
  • From the Department of Radiology and Bio-X Program (F.C., S.L., X.X., P.R., M.P., X.Z., X.C., S.S.G., J.C.W.), the Department of Pathology and Developmental Biology (M.D., S.J.D., A.J.C., I.L.W.), the Department of Bioengineering (S.S.G.), and the Department of Medicine, Division of Cardiology (J.C.W.), Stanford University School of Medicine, Stanford, Calif.
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2006-02-21
Volume
113
Issue
7
Pages
1005-1014
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.105.588954
PMC
PMC4701384
OpenAlex
W2115096499
Cited by
493
References
1
Citations by year
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FWCI
24.99
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Site cant be reached (submittedVersion)
Funders
  • National Heart, Lung, and Blood Institute (K08HL074883, R01HL078632)
  • National Cancer Institute
Topics
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
embryonic stem cells, stem cell tracking, in vivo imaging, bioluminescence reporter, firefly luciferase, lentiviral transduction, stem cell survival, stem cell proliferation, stem cell migration, teratoma formation, ganciclovir, stem cell therapy, intramyocardial injection, cardiac regeneration
MeSH terms
Animals, Cell Movement, Cell Survival, Embryo, Mammalian, Humans, Myocardium, Premedication, Regeneration, Stem Cells, Teratoma, Transduction, Genetic, Transplantation, Heterologous, Ganciclovir, Genes, Reporter, Models, Animal, Stem Cell Transplantation, Cell Proliferation, Positron-Emission Tomography, Luminescence, Mice, Rats

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