Stem cell imaging: from bench to bedside

Abstract

Although cellular therapies hold great promise for the treatment of human disease, results from several initial clinical trials have not shown a level of efficacy required for their use as a first line therapy. Here we discuss how in vivo molecular imaging has helped identify barriers to clinical translation and potential strategies that may contribute to successful transplantation and improved outcomes, with a focus on cardiovascular and neurological diseases. We conclude with a perspective on the future role of molecular imaging in defining safety and efficacy for clinical implementation of stem cell therapies.

Figure 1

Cell labeling strategies and detectors for stem cell imaging. For direct labeling (in green), cells are incubated with imaging probes that enter the cell via transporter uptake (i.e., ¹⁸F FDG, ¹⁸F-FESP, and ¹⁸F-FHBG), endocytosis (i.e., SPIONs, QDs, Au NPS, and microbubbles), or passive diffusion (i.e., ¹¹¹In-ox). In reporter gene imaging (in blue), cells are transfected or transduced with the reporter gene construct. Transcription of the reporter gene under the control of a promoter followed by translation of its mRNA, leads to accumulation of different reporter proteins such as receptors (i.e., D2R), enzymes (HSVtk, FLuc, RLuc, GFP, and RFP), and transporter proteins (NIS). Introduction of a reporter gene probe (i.e., ¹⁸F-FESP, D-luciferin, coelenterazine) results in signal generation. Labeled cells are detected by imaging systems such as PET, MRI, CT, and ultrasound. Abbreviations: ¹⁸F-FDG, ¹⁸F-fluorodeoxyglucose; ¹⁸F-FESP, 3-(2′-[18F]-fluoroethyl)-spiperone; ¹⁸F-FHBG, 9-(4-18Ffluoro-3-[hydroxymethyl]butyl) guanine; SPIONs, superparamagnetic iron oxide nanoparticles; QDs, quantum dots; Au NSPs, gold nanoparticles; ¹¹¹In-ox, indium oxine; Asp, aspartic acid; Ser, serine; NIS, sodium iodide symporter; I, iodine; ^99mTcO ⁻₄, technetium pertechnetate; D2R, dopamine 2 receptor; HSV-ttk, herpes simplex virus truncated thymidine kinase; FLuc, firefly luciferase; RLuc, renilla luciferase; GFP, green fluorescent protein; RFP, red fluorescent protein); PET, positron emission tomography; MRI, magnetic resonance imaging; CT, computed tomography; SPECT, single photon emission computed tomography; GLUT1, glucose transport type I.

Figure 2

Barriers to clinical translation. A variety of stem cell types (e.g., adult somatic cells, induced pluripotent stem cells, and embryonic stem cells) are available for transplantation, each with their advantages and disadvantages. Adult somatic stem cells are most commonly transplanted directly into the recipient, whereas embryonic and induced pluripotent stem cells undergo in vitro differentiation prior to transplantation. Regardless of the stem cell type, their successful application in regenerative therapy faces similar clinical hurdles, including: 1) limited engraftment, survival, and proliferation; 2) poor differentiation, maturation and integration; 3) immunogenicity with allogeneic transplantation; and 4) potential tumorigenicity with pluripotent stem cell derivatives. Cell imaging plays a pivotal role in overcoming these hurdles and will help guide the translation of this promising therapy.

Figure 3

A step-by-step approach to successful routine application of stem cell therapy. Step 1: Stem cell isolation and purification. Stem cells must be initially isolated and purified from a tissue source. Because of poor in vivo differentiation, cells are often differentiated in vitro prior to implantation. These techniques, however, are imperfect and can result in a mixture of undifferentiated and differentiated cells. Cell sorting is then required to select for the cell population that can be safely transplanted with maximal therapeutic benefit. Step 2: Cell labeling and transplantation. Prior to transplantation, cells are labeled to track cell fate. Selected cells are labeled in vitro using direct labeling or reporter gene techniques and then implanted at the bedside via intravenous delivery or in the operating room/angiography suite, via intra-lesional or intra-arterial delivery, respectively. Step 3: Serial imaging for safety and efficacy monitoring. After delivery, labeled cells are tracked using PET/MRI, which provides high sensitivity for cell detection as well as excellent spatial localization. Cells can be tracked serially to determine whether they engraft, survive, and proliferate in the target organ. Cells can also be monitored for any potential unwanted effects including tumor formation and migration to other sites. In addition, PET/MRI can provide serial data on the functional and structural recovery of damaged tissues.