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Early-Phase Luciferase Signals of Islet Grafts Predicts Successful Subcutaneous Site Transplantation in Rats

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Abstract

Purpose

The transplantation of pancreatic islets is a promising cell replacement therapy for type 1 diabetes. Subcutaneous islet transplantation is currently under investigation as a means to circumvent problems associated with standard intra-hepatic islet transplantation. As modifications are being developed to improve the efficacy of subcutaneous islet transplantation, it is important to have robust methods to assess engraftment. Experimentally, ATP-dependent bioluminescence imaging using luciferase reporter genes has been effective for non-invasively tracking engraftment. However, it was heretofore unknown if the bioluminescence of subcutaneously transplanted luciferase-expressing islet grafts correlates with diabetes reversal, a primary outcome of transplantation.

Procedures

A retrospective analysis was conducted using data obtained from subcutaneous islet transplantations in Lewis rats. The analysis included transplantations from our laboratory in which islet donors were transgenic rats ubiquitously expressing luciferase and recipients were wild type, streptozotocin-induced diabetic rats. Data from 79 bioluminescence scans were obtained from 27 islet transplantations during the post-transplant observation period (up to 6 weeks). The bioluminescence intensity of the subcutaneously transplanted grafts, captured after the intravenous administration of luciferin, was correlated with diabetes reversal.

Results

After subcutaneous transplantation, islet bioluminescence decreased over time, dropping > 50 % from 1 to 3 weeks post-transplant. Bioluminescence intensity in the early post-transplant phase (1–2 weeks) correlated with the subsequent reversal of diabetes; based on optimized bioluminescence cutoff values, the bioluminescence intensity of islets at 1 and 2 weeks predicted successful transplantations. However, intensity in the late post-transplant phase (≥ 4 weeks) did not reflect transplantation outcomes.

Conclusions

Early-phase bioluminescence imaging of luciferase-expressing islets could serve as a useful tool to predict the success of subcutaneous islet transplantations by preceding changes in glucose homeostasis.

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References

  1. Shapiro AM, Ricordi C, Hering BJ et al (2006) International trial of the Edmonton protocol for islet transplantation. N Engl J Med 355:1318–1330

    Article  CAS  Google Scholar 

  2. Rezania A, Bruin JE, Arora P, Rubin A, Batushansky I, Asadi A, O'Dwyer S, Quiskamp N, Mojibian M, Albrecht T, Yang YHC, Johnson JD, Kieffer TJ (2014) Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol 32:1121–1133

    Article  CAS  Google Scholar 

  3. Chhabra P, Brayman KL (2013) Stem cell therapy to cure type 1 diabetes: from hype to hope. Stem Cells Transl Med 2:328–336

    Article  CAS  Google Scholar 

  4. Soon-Shiong P, Heintz RE, Merideth N, Yao QX, Yao Z, Zheng T, Murphy M, Moloney MK, Schmehl M, Harris M, Mendez R, Mendez R, Sandford PA (1994) Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation. Lancet 343:950–951

    Article  CAS  Google Scholar 

  5. de Vos P, Spasojevic M, Faas MM (2010) Treatment of diabetes with encapsulated islets. Adv Exp Med Biol 670:38–53

    Article  Google Scholar 

  6. Luan NM, Iwata H (2014) Long-term allogeneic islet graft survival in prevascularized subcutaneous sites without immunosuppressive treatment. Am J Transplant 14:1533–1542

    Article  CAS  Google Scholar 

  7. Kawakami Y, Iwata H, Gu Y, Miyamoto M, Murakami Y, Yamasaki T, Cui W, Ikada Y, Imamura M, Inoue K (2000) Modified subcutaneous tissue with neovascularization is useful as the site for pancreatic islet transplantation. Cell Transplant 9:729–732

    Article  CAS  Google Scholar 

  8. Gibly RF, Zhang X, Graham ML, Hering BJ, Kaufman DB, Lowe WL Jr, Shea LD (2011) Extrahepatic islet transplantation with microporous polymer scaffolds in syngeneic mouse and allogeneic porcine models. Biomaterials 32:9677–9684

    Article  CAS  Google Scholar 

  9. Golocheikine A, Tiriveedhi V, Angaswamy N, Benshoff N, Sabarinathan R, Mohanakumar T (2010) Cooperative signaling for angiogenesis and neovascularization by VEGF and HGF following islet transplantation. Transplantation 90:725–731

    Article  CAS  Google Scholar 

  10. Brady AC, Martino MM, Pedraza E, Sukert S, Pileggi A, Ricordi C, Hubbell JA, Stabler CL (2013) Proangiogenic hydrogels within macroporous scaffolds enhance islet engraftment in an extrahepatic site. Tissue Eng Part A 19:2544–2552

    Article  CAS  Google Scholar 

  11. Evgenov NV, Medarova Z, Dai G, Bonner-Weir S, Moore A (2006) In vivo imaging of islet transplantation. Nat Med 12:144–148

    Article  CAS  Google Scholar 

  12. Li J, Rawson J, Chea J, Tang W, Miao L, Sui F, Li L, Poku E, Shively JE, Kandeel F (2019) Evaluation of [(68)Ga]DO3A-VS-Cys(40)-Exendin-4 as a PET probe for imaging human transplanted islets in the liver. Sci Rep 9:5705

    Article  Google Scholar 

  13. van der Kroon I, Andralojc K, Willekens SM et al (2016) Noninvasive imaging of islet transplants with 111In-Exendin-3 SPECT/CT. J Nucl Med 57:799–804

    Article  Google Scholar 

  14. Sakata N, Sax N, Yoshimatsu G, Tsuchiya H, Kato S, Aoki T, Ishida M, Katayose Y, Egawa S, Kodama T, Unno M (2015) Enhanced ultrasonography using a nano/microbubble contrast agent for islet transplantation. Am J Transplant 15:1531–1542

    Article  CAS  Google Scholar 

  15. Morciano G, Sarti AC, Marchi S, Missiroli S, Falzoni S, Raffaghello L, Pistoia V, Giorgi C, di Virgilio F, Pinton P (2017) Use of luciferase probes to measure ATP in living cells and animals. Nat Protoc 12:1542–1562

    Article  CAS  Google Scholar 

  16. Berger F, Paulmurugan R, Bhaumik S, Gambhir SS (2008) Uptake kinetics and biodistribution of 14C-D-luciferin--a radiolabeled substrate for the firefly luciferase catalyzed bioluminescence reaction: impact on bioluminescence based reporter gene imaging. Eur J Nucl Med Mol Imaging 35:2275–2285

    Article  Google Scholar 

  17. Contag CH, Bachmann MH (2002) Advances in in vivo bioluminescence imaging of gene expression. Annu Rev Biomed Eng 4:235–260

    Article  CAS  Google Scholar 

  18. Virostko J, Radhika A, Poffenberger G, Chen Z, Brissova M, Gilchrist J, Coleman B, Gannon M, Jansen ED, Powers AC (2010) Bioluminescence imaging in mouse models quantifies beta cell mass in the pancreas and after islet transplantation. Mol Imaging Biol 12:42–53

    Article  Google Scholar 

  19. Chen X, Zhang X, Larson CS, Baker MS, Kaufman DB (2006) In vivo bioluminescence imaging of transplanted islets and early detection of graft rejection. Transplantation 81:1421–1427

    Article  Google Scholar 

  20. Fowler M, Virostko J, Chen Z, Poffenberger G, Radhika A, Brissova M, Shiota M, Nicholson WE, Shi Y, Hirshberg B, Harlan DM, Jansen ED, Powers AC (2005) Assessment of pancreatic islet mass after islet transplantation using in vivo bioluminescence imaging. Transplantation 79:768–776

    Article  Google Scholar 

  21. Cao YA, Bachmann MH, Beilhack A, Yang Y, Tanaka M, Swijnenburg RJ, Reeves R, Taylor-Edwards C, Schulz S, Doyle TC, Fathman CG, Robbins RC, Herzenberg LA, Negrin RS, Contag CH (2005) Molecular imaging using labeled donor tissues reveals patterns of engraftment, rejection, and survival in transplantation. Transplantation 80:134–139

    Article  Google Scholar 

  22. Sunaga A, Sugawara Y, Katsuragi-Tomioka Y, Kobayashi E (2013) The fate of nonvascularized fat grafts: histological and bioluminescent study. Plast Reconstr Surg Glob Open 1:e40

    Article  Google Scholar 

  23. Komatsu H, Cook CA, Gonzalez N, Medrano L, Salgado M, Sui F, Li J, Kandeel F, Mullen Y, Tai YC (2018) Oxygen transporter for the hypoxic transplantation site. Biofabrication 11:015011

    Article  Google Scholar 

  24. Komatsu H, Rawson J, Barriga A, Gonzalez N, Mendez D, Li J, Omori K, Kandeel F, Mullen Y (2018) Posttransplant oxygen inhalation improves the outcome of subcutaneous islet transplantation: a promising clinical alternative to the conventional intrahepatic site. Am J Transplant 18:832–842

    Article  CAS  Google Scholar 

  25. Komatsu H, Gonzalez N, Salgado M, Cook CA, Li J, Rawson J, Omori K, Tai YC, Kandeel F, Mullen Y (2020) A subcutaneous pancreatic islet transplantation platform using a clinically applicable, biodegradable Vicryl mesh scaffold - an experimental study. Transpl Int 33:806–818

    Article  CAS  Google Scholar 

  26. Hakamata Y, Murakami T, Kobayashi E (2006) “Firefly rats” as an organ/cellular source for long-term in vivo bioluminescent imaging. Transplantation 81:1179–1184

    Article  Google Scholar 

  27. Ito T, Itakura S, Todorov I, Rawson J, Asari S, Shintaku J, Nair I, Ferreri K, Kandeel F, Mullen Y (2010) Mesenchymal stem cell and islet co-transplantation promotes graft revascularization and function. Transplantation 89:1438–1445

    Article  Google Scholar 

  28. Salgado M, Gonzalez N, Medrano L et al (2020) Semi-automated assessment of human islet viability predicts transplantation outcomes in a diabetic mouse model. Cell Transplant 29:963689720919444

    Article  Google Scholar 

  29. Youden WJ (1950) Index for rating diagnostic tests. Cancer 3:32–35

    Article  CAS  Google Scholar 

  30. Dionne KE, Colton CK, Yarmush ML (1993) Effect of hypoxia on insulin secretion by isolated rat and canine islets of Langerhans. Diabetes 42:12–21

    Article  CAS  Google Scholar 

  31. Komatsu H, Kang D, Medrano L, Barriga A, Mendez D, Rawson J, Omori K, Ferreri K, Tai YC, Kandeel F, Mullen Y (2016) Isolated human islets require hyperoxia to maintain islet mass, metabolism, and function. Biochem Biophys Res Commun 470:534–538

    Article  CAS  Google Scholar 

  32. Koster JC, Permutt MA, Nichols CG (2005) Diabetes and insulin secretion: the ATP-sensitive K+ channel (K ATP) connection. Diabetes 54:3065–3072

    Article  CAS  Google Scholar 

  33. Wang P, Medarova Z, Moore A (2011) Molecular imaging: a promising tool to monitor islet transplantation. J Transplant 2011:202915

    PubMed  PubMed Central  Google Scholar 

  34. Zambrowicz BP, Imamoto A, Fiering S, Herzenberg LA, Kerr WG, Soriano P (1997) Disruption of overlapping transcripts in the ROSA beta geo 26 gene trap strain leads to widespread expression of beta-galactosidase in mouse embryos and hematopoietic cells. Proc Natl Acad Sci U S A 94:3789–3794

    Article  CAS  Google Scholar 

  35. Gross JB, Hanken J, Oglesby E, Marsh-Armstrong N (2006) Use of a ROSA26:GFP transgenic line for long-term Xenopus fate-mapping studies. J Anat 209:401–413

    Article  CAS  Google Scholar 

  36. Edinger M, Cao YA, Hornig YS, Jenkins DE, Verneris MR, Bachmann MH, Negrin RS, Contag CH (2002) Advancing animal models of neoplasia through in vivo bioluminescence imaging. Eur J Cancer 38:2128–2136

    Article  CAS  Google Scholar 

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Acknowledgments

We thank Dr. Eiji Kobayashi for providing the LUC-Tg Lewis rat strain. We also thank Drs. Hsun Teresa Ku, Jeffrey Isenberg, and Kerin Higa for their critical reading and editing of the manuscript.

Funding

This study was supported by a grant from the Nora Eccles Treadwell Foundation (Title of Grant: CURE OF DIABETES, Grant Period: July 1, 2012–June 30, 2020, P.I.: Yoko Mullen, MD, PhD).

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Authors and Affiliations

  1. Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, 91010, USA

    Hirotake Komatsu, Nelson Gonzalez, Jose Ortiz, Jeffrey Rawson, Keiko Omori, Fouad Kandeel & Yoko Mullen

Authors
  1. Hirotake Komatsu
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  2. Nelson Gonzalez
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  3. Jose Ortiz
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  4. Jeffrey Rawson
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  5. Keiko Omori
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  6. Fouad Kandeel
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  7. Yoko Mullen
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Contributions

H.K. designed the study, collected and analyzed data, and wrote the manuscript; N.G., J.O., and J.R. collected the data; K.O., F.K., and Y.M. reviewed and edited the manuscript.

Corresponding author

Correspondence to Hirotake Komatsu.

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Komatsu, H., Gonzalez, N., Ortiz, J. et al. Early-Phase Luciferase Signals of Islet Grafts Predicts Successful Subcutaneous Site Transplantation in Rats. Mol Imaging Biol 23, 173–179 (2021). https://doi.org/10.1007/s11307-020-01560-2

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  • DOI: https://doi.org/10.1007/s11307-020-01560-2

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