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

Author:
Alon, Lina, Kraitchman, DaraL., Schär, Michael, Cortez, Angel, Yadav, NirbhayN., Krimins, Rebecca, Johnston, PeterV., McMahon, MichaelT., van Zijl, PeterC. M., Nimmagadda, Sridhar, Pomper, MartinG., Bulte, JeffW. M., Gilad, AssafA.
Source:
Biotechnology and bioprocess engineering 2018 v.23 no.2 pp. 208-217
ISSN:
1226-8372
Subject:
CXCR4 receptor, animal models, cell death, cell movement, chemokine CXCL12, disease course, gene expression, heart, hematopoiesis, herpes simplex, humans, hypoxia, image analysis, iodine, magnetic resonance imaging, monitoring, myocardial infarction, neoplasms, reporter genes, scanners, stem cells, swine, therapeutics, tissue repair, viruses
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.
Agid:
5967102