Molecular Imaging of CXCL12 Promoter-driven HSV1-TK Reporter Gene Expression

Research output: Contribution to journalArticle

Abstract

The C-X-C motif chemokine 12 (CXCL12, SDF1a) and its receptor, CXCR4, play a fundamental role in several biological processes, including hematopoiesis, cardiogenesis, cancer progression, and stem cell migration. Noninvasive monitoring of CXCL12 is highly desirable for optimizing strategies that combine mobilization of therapeutic cells to combat cancer or to assist in cardiac tissue repair after myocardial infarction. Here, we report on an MRI reporter gene system for directly monitoring CXCL12 expression in vivo. Glioma cells and human adipose-derived stem cells (hADSC) were transduced with the herpes simplex virus type-1-thymidine kinase (HSV1- tk) reporter gene expressed under the CXCL12 promoter. HSV1-tk expression resulted in accumulation of the PET tracer [125I]FIAU in vitro and in vivo and induced cell death after ganciclovir treatment. Furthermore, the results show that conditional expression of the reporter gene can be induced by hypoxia in transduced cells. Transduced hADSC were incubated with the CEST MRI probe 5-methyl-5, 6- dihydrothymidine (5-MDHT) and transplanted into swine heart. Transplanted cells were clearly visible on Chemical Exchange Saturation Transfer (CEST) MRI using a 3T clinical scanner. Therefore, we conclude that it is possible to image CXCL12 expression with MRI in a large animal model, opening up a possible route to clinical translation.

Original languageEnglish (US)
Pages (from-to)208-217
Number of pages10
JournalBiotechnology and Bioprocess Engineering
Volume23
Issue number2
DOIs
StatePublished - Mar 1 2018

Fingerprint

Molecular imaging
Molecular Imaging
Reporter Genes
Gene expression
Magnetic resonance imaging
Stem cells
Gene Expression
Genes
Stem Cells
CXCR4 Receptors
Biological Phenomena
Chemokine CXCL12
CXC Chemokines
Ganciclovir
Neoplastic Stem Cells
Thymidine Kinase
Monitoring
Hematopoiesis
Human Herpesvirus 1
Cell death

Keywords

  • CXCL12
  • herpes simplex virus type-1 thymidine kinase (HSV1-tk)
  • hypoxia
  • magnetic resonance imaging (MRI)
  • reporter gene

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Applied Microbiology and Biotechnology
  • Biomedical Engineering

Cite this

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title = "Molecular Imaging of CXCL12 Promoter-driven HSV1-TK Reporter Gene Expression",
abstract = "The C-X-C motif chemokine 12 (CXCL12, SDF1a) and its receptor, CXCR4, play a fundamental role in several biological processes, including hematopoiesis, cardiogenesis, cancer progression, and stem cell migration. Noninvasive monitoring of CXCL12 is highly desirable for optimizing strategies that combine mobilization of therapeutic cells to combat cancer or to assist in cardiac tissue repair after myocardial infarction. Here, we report on an MRI reporter gene system for directly monitoring CXCL12 expression in vivo. Glioma cells and human adipose-derived stem cells (hADSC) were transduced with the herpes simplex virus type-1-thymidine kinase (HSV1- tk) reporter gene expressed under the CXCL12 promoter. HSV1-tk expression resulted in accumulation of the PET tracer [125I]FIAU in vitro and in vivo and induced cell death after ganciclovir treatment. Furthermore, the results show that conditional expression of the reporter gene can be induced by hypoxia in transduced cells. Transduced hADSC were incubated with the CEST MRI probe 5-methyl-5, 6- dihydrothymidine (5-MDHT) and transplanted into swine heart. Transplanted cells were clearly visible on Chemical Exchange Saturation Transfer (CEST) MRI using a 3T clinical scanner. Therefore, we conclude that it is possible to image CXCL12 expression with MRI in a large animal model, opening up a possible route to clinical translation.",
keywords = "CXCL12, herpes simplex virus type-1 thymidine kinase (HSV1-tk), hypoxia, magnetic resonance imaging (MRI), reporter gene",
author = "Lina Alon and Dara Kraitchman and Michael Schar and Angel Cortez and Yadav, {Nirbhay N.} and Rebecca Krimins and Johnston, {Peter V} and Mcmahon, {Michael T} and {Van Zijl}, {Peter C} and Sridhar Nimmagadda and Pomper, {Martin Gilbert} and Bulte, {Jeff W} and Gilad, {Assaf A.}",
year = "2018",
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T1 - Molecular Imaging of CXCL12 Promoter-driven HSV1-TK Reporter Gene Expression

AU - Alon, Lina

AU - Kraitchman, Dara

AU - Schar, Michael

AU - Cortez, Angel

AU - Yadav, Nirbhay N.

AU - Krimins, Rebecca

AU - Johnston, Peter V

AU - Mcmahon, Michael T

AU - Van Zijl, Peter C

AU - Nimmagadda, Sridhar

AU - Pomper, Martin Gilbert

AU - Bulte, Jeff W

AU - Gilad, Assaf A.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - The C-X-C motif chemokine 12 (CXCL12, SDF1a) and its receptor, CXCR4, play a fundamental role in several biological processes, including hematopoiesis, cardiogenesis, cancer progression, and stem cell migration. Noninvasive monitoring of CXCL12 is highly desirable for optimizing strategies that combine mobilization of therapeutic cells to combat cancer or to assist in cardiac tissue repair after myocardial infarction. Here, we report on an MRI reporter gene system for directly monitoring CXCL12 expression in vivo. Glioma cells and human adipose-derived stem cells (hADSC) were transduced with the herpes simplex virus type-1-thymidine kinase (HSV1- tk) reporter gene expressed under the CXCL12 promoter. HSV1-tk expression resulted in accumulation of the PET tracer [125I]FIAU in vitro and in vivo and induced cell death after ganciclovir treatment. Furthermore, the results show that conditional expression of the reporter gene can be induced by hypoxia in transduced cells. Transduced hADSC were incubated with the CEST MRI probe 5-methyl-5, 6- dihydrothymidine (5-MDHT) and transplanted into swine heart. Transplanted cells were clearly visible on Chemical Exchange Saturation Transfer (CEST) MRI using a 3T clinical scanner. Therefore, we conclude that it is possible to image CXCL12 expression with MRI in a large animal model, opening up a possible route to clinical translation.

AB - The C-X-C motif chemokine 12 (CXCL12, SDF1a) and its receptor, CXCR4, play a fundamental role in several biological processes, including hematopoiesis, cardiogenesis, cancer progression, and stem cell migration. Noninvasive monitoring of CXCL12 is highly desirable for optimizing strategies that combine mobilization of therapeutic cells to combat cancer or to assist in cardiac tissue repair after myocardial infarction. Here, we report on an MRI reporter gene system for directly monitoring CXCL12 expression in vivo. Glioma cells and human adipose-derived stem cells (hADSC) were transduced with the herpes simplex virus type-1-thymidine kinase (HSV1- tk) reporter gene expressed under the CXCL12 promoter. HSV1-tk expression resulted in accumulation of the PET tracer [125I]FIAU in vitro and in vivo and induced cell death after ganciclovir treatment. Furthermore, the results show that conditional expression of the reporter gene can be induced by hypoxia in transduced cells. Transduced hADSC were incubated with the CEST MRI probe 5-methyl-5, 6- dihydrothymidine (5-MDHT) and transplanted into swine heart. Transplanted cells were clearly visible on Chemical Exchange Saturation Transfer (CEST) MRI using a 3T clinical scanner. Therefore, we conclude that it is possible to image CXCL12 expression with MRI in a large animal model, opening up a possible route to clinical translation.

KW - CXCL12

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KW - hypoxia

KW - magnetic resonance imaging (MRI)

KW - reporter gene

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