Molecular imaging: a promising tool to monitor islet transplantation

Abstract

Replacement of insulin production by pancreatic islet transplantation has great potential as a therapy for type 1 diabetes mellitus. At present, the lack of an effective approach to islet grafts assessment limits the success of this treatment. The development of molecular imaging techniques has the potential to fulfill the goal of real-time noninvasive monitoring of the functional status and viability of the islet grafts. We review the application of a variety of imaging modalities for detecting endogenous and transplanted beta-cell mass. The review also explores the various molecular imaging strategies for assessing islet delivery, the metabolic effects on the islet grafts as well as detection of immunorejection. Here, we highlight the use of combined imaging and therapeutic interventions in islet transplantation and the in vivo monitoring of stem cells differentiation into insulin-producing cells.

Figure 1

Transverse T2-weighted magnetic resonance images of transplanted labeled and nonlabeled human islets 14, 23, 37, 58, 97, and 188 d after transplantation under the kidney capsule in nude (nu/nu) mice. The dark area in the left kidney represents a labeled graft (red outline). No darkening was reported for the right kidney with unlabeled graft. S: stomach; SC: spinal cord, reproduced with permission from Nature Publishing Group [67].

Figure 2

In vivo imaging of intrahepatically transplanted human islets. (a) Representative images of NOD.scid mice with transplanted islets. On in vivo images, Feridex-labeled islets appeared as signal voids scattered throughout the liver. (b) Nonlabeled islets were not detectable using the same imaging parameters. (c) In vivo time course imaging of immune rejection in immunocompetent (upper row) and immunocompromised (lower row) animals. Representative images are shown from days 2, 10, and 14 after transplantation. Note that the signal voids (arrows) representing labeled islets/islet clusters tend to disappear faster in Balb/c mice, reproduced with permission from American Diabetes Association [78].

Figure 3

(a) Representative in vivo MRI of islet transplantation showing MN-siCaspase-3-treated islets implanted under the left kidney (inset) and parental MN-treated islets implanted under the right kidney. The dark area outlined under both kidney capsules represents the labeled grafts (day 3 shown). (b) Semiquantitative assessment of the relative changes in graft volumes revealed protective effect in MN-siCaspase-3-labeled grafts (*day 7, P < 0.05; **day 14, P < 0.05). (c) Fluorescence microscopy revealed higher expression of insulin and lower expression of caspase-3 in MN-siCaspase-3-treated grafts compared with MN-labeled islet grafts on the 14th day after-transplantation (Tx) (green, insulin; red, cleaved caspase-3; blue, DAPI nuclear stain) (magnification bar = 50 mm). (d): TUNEL assay on insulin-stained sections confirmed lower apoptotic rate and higher insulin expression in islets treated with MN-siCaspase-3 compared with islets treated with MN on the 14th day post-Tx (red, insulin; green, TUNEL; blue, DAPI nuclear stain) (magnification bar = 50 μm), reproduced with permission from American Diabetes Association [91].