Multimodal imaging of pancreatic beta cells in vivo by targeting transmembrane protein 27 (TMEM27).
OBJECTIVE
Non-invasive diagnostic tools specific for pancreatic beta cells will have a profound impact on our understanding of the pathophysiology of metabolic diseases such as diabetes. The objective of this study was to use molecular imaging probes specifically targeting beta cells on human samples and animal models using state-of-the-art imaging modalities (fluorescence and PET) with preclinical and clinical perspective.


METHODS
We generated a monoclonal antibody, 8/9-mAb, targeting transmembrane protein 27 (TMEM27; a surface N-glycoprotein that is highly expressed on beta cells), compared its expression in human and mouse pancreas, and demonstrated beta cell-specific binding in both. In vivo imaging was performed in mice with subcutaneous insulinomas overexpressing the human TMEM27 gene, or transgenic mice with beta cell-specific hTMEM27 expression under the control of rat insulin promoter (RIP-hTMEM27-tg), using fluorescence and radioactively labelled antibody, followed by tissue ex vivo analysis and fluorescence microscopy.


RESULTS
Fluorescently labelled 8/9-mAb showed beta cell-specific staining on human and mouse pancreatic sections. Real-time PCR on islet cDNA indicated about tenfold higher expression of hTMEM27 in RIP-hTMEM27-tg mice than in humans. In vivo fluorescence and PET imaging in nude mice with insulinoma xenografts expressing hTMEM27 showed high 8/9-mAb uptake in tumours after 72 h. Antibody homing was also observed in beta cells of RIP-hTMEM27-tg mice by in vivo fluorescence imaging. Ex vivo analysis of intact pancreas and fluorescence microscopy in beta cells confirmed these findings.


CONCLUSIONS
hTMEM27 constitutes an attractive target for in vivo visualisation of pancreatic beta cells. Studies in mouse insulinoma models and mice expressing hTMEM27 demonstrate the feasibility of beta cell-targeted in vivo imaging, which is attractive for preclinical investigations and holds potential in clinical diagnostics.
Animal Imaging Center, Institute for Biomedical Engineering, ETH, Wolfgang Pauli Strasse 10, 8093 Zurich, Switzerland.
D
D
Vats
H
H
Wang
D
D
Esterhazy
K
K
Dikaiou
C
C
Danzer
M
M
Honer
F
F
Stuker
H
H
Matile
C
C
Migliorini
E
E
Fischer
J
J
Ripoll
R
R
Keist
W
W
Krek
R
R
Schibli
M
M
Stoffel
M
M
Rudin
D000818:Animals; D006801:Humans; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence / Q000379:methods*; D057054:Molecular Imaging; D010179:Pancreas / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*
C429534:CLTRN protein, human; D008562:Membrane Glycoproteins; C504407:Tmem27 protein, mouse