Noninvasive in vivo cell tracking using molecular imaging: A useful tool for developing mesenchymal stem cell-based cancer treatment

Abstract

Mounting evidence has emphasized the potential of cell therapies in treating various diseases by restoring damaged tissues or replacing defective cells in the body. Cell therapies have become a strong therapeutic modality by applying noninvasive in vivo molecular imaging for examining complex cellular processes, understanding pathophysiological mechanisms of diseases, and evaluating the kinetics/dynamics of cell therapies. In particular, mesenchymal stem cells (MSCs) have shown promise in recent years as drug carriers for cancer treatment. They can also be labeled with different probes and tracked in vivo to assess the in vivo effect of administered cells, and to optimize therapy. The exact role of MSCs in oncologic diseases is not clear as MSCs have been shown to be involved in tumor progression and inhibition, and the exact interactions between MSCs and specific cancer microenvironments are not clear. In this review, a multitude of labeling approaches, imaging modalities, and the merits/demerits of each strategy are outlined. In addition, specific examples of the use of MSCs and in vivo imaging in cancer therapy are provided. Finally, present limitations and future outlooks in terms of the translation of different imaging approaches in clinics are discussed.

Keywords: Cell therapy; Drug delivery; In vivo molecular imaging; Mesenchymal stem cells; Superparamagnetic iron oxide.

Figure 1

Schematic illustration of labeling mesenchymal stem cells for in vivo non-invasive imaging. SPIO: Small superparamagnetic iron oxide; NIS: Sodium iodide symporter; HSV-TK: Herpes simplex virus-thymidine kinase; EGFP: Enhanced green fluorescent protein; [¹⁸F]FHBG: 9-(4-[F]fluoro-3-hydroxymethylbutyl) guanine.

Figure 2

Schematic illustration of the labeling strategy for in vivo tracking of mesenchymal stem cells by optical imaging. A: After fluorescent protein (enhanced green fluorescent protein) transduction into mesenchymal stem cells (MSCs) or binding of lipophilic labeling agents (e.g., fluorescent nanoparticles and VivoTrack 680) to the membrane of MSCs, cells are injected into the tumor-bearing mice, and their migration is visualized with the use of in vivo fluorescent imaging; B: After the bioluminescent protein (Firefly or Renilla luciferase) transduction into MSCs, cells are injected into the tumor-bearing mice. The light emitted due to the interaction between luciferase and its substrates (D-luciferin or coelenterazine) is captured by in vivo bioluminescent imaging. MSCs: Mesenchymal stem cells; EGFP: Enhanced green fluorescent protein; Fluc: Firefly luciferase; Rluc: Renilla luciferase.

Figure 3

Schematic illustration of the labeling strategy for in vivo tracking of mesenchymal stem cells by nuclear and magnetic resonance imaging. A: Gene transduction of sodium iodide symporter (NIS) or herpes simplex virus-thymidine kinase (HSV-TK) into mesenchymal stem cells (MSCs) can aid radiotracers (¹²³I, ¹²⁴I and ^99mTc) in entering MSCs. MSCs-NIS are injected into tumor-bearing mice followed by the injection of radiotracers. In vivo nuclear imaging (positron-emission tomography, camera imaging, and single-photon emission computed tomography) can visualize migration of the MSCs; B: MSCs can be incubated with molecules including small superparamagnetic iron oxide (SPIO) or SPIO coated with gold-nanoparticles (SPIO@Au-NPs). SPIO-labeled MSCs are injected into tumor-bearing mice, and in vivo magnetic resonance imaging can visualize migration of the MSCs. MSCs: Mesenchymal stem cells; NIS: Sodium iodide symporter; HSV-TK: Herpes simplex virus-thymidine kinase; ^99mTc: Technetium-99m; [¹⁸F]FHBG: 9-(4-[F]fluoro-3-hydroxymethylbutyl) guanine; SPIO: Superparamagnetic iron oxide.