In vivo tracking of the tropism of mesenchymal stem cells to malignant gliomas using reporter gene‐based MR imaging

Abstract

Mesenchymal stem cells (MSCs) have emerged as a promising cellular vehicle for gene therapy of malignant gliomas due to their property of tumor tropism. However, MSCs may show bidirectional and divergent effects on tumor growth. Therefore, a robust surveillance system with a capacity for noninvasive monitoring of the homing, distribution and fate of stem cells in vivo is highly desired for developing stem cell-based gene therapies for tumors. In this study, we used ferritin gene-based magnetic resonance imaging (MRI) to track the tumor tropism of MSCs in a rat orthotopic xenograft model of malignant glioma. MSCs were transduced with lentiviral vectors expressing ferritin heavy chain (FTH) and enhanced green fluorescent protein (eGFP). Intra-arterial, intravenous and intertumoral injections of these FTH transgenic MSCs (FTH-MSCs) were performed in rats bearing intracranial orthotopic C6 gliomas. The FTH-MSCs were detected as hypointense signals on T2- and T2*-weighted images on a 3.0 T clinical MRI. After intra-arterial injection, 17% of FTH-MSCs migrated toward the tumor and gradually diffused throughout the orthotopic glioma. This dynamic process could be tracked in vivo by MRI up to 10 days of follow-up, as confirmed by histology. Moreover, the tumor tropism of MSCs showed no appreciable impact on the progression of the tumor. These results suggest that FTH reporter gene-based MRI can be used to reliably track the tropism and fate of MSCs after their systemic transplantation in orthotopic gliomas. This real-time in vivo tracking system will facilitate the future development of stem cell-based therapies for malignant gliomas.

Vimentin-Induced Cardiac Mesenchymal Stem Cells Proliferate in the Acute Ischemic Myocardium

“…This so-called "reporter gene imaging" (incorporating a reporter gene into a specific cell in vitro prior to in vivo transplantation) enables targeted studies of cell-specific biology, differentiation, and environmental interactions. The vimentin-CreER model used in this study allows for the visualization of the reporter gene after successful transplantation and in vivo induction of its expression by tamoxifen [Massoud and Gambhir, 2003;Inubushi and Tamaki, 2007;Rodriguez-Porcel et al, 2012;Cao et al, 2017]. We aimed to characterize cardiac MSCs by GFM without the need for in vitro cell labeling based on our recent results indicating that strong vimentin induction occurred in proliferating cardiac endogenous MSCs in the early peri-infarction area after MI [Klopsch et al, 2017].…”

Magnetic resonance imaging of enhanced nerve repair with mesenchymal stem cells combined with microenvironment immunomodulation in neurotmesis

“…Subgroups A and D received a single dose of subepineurial microinjection of LPS (1.0 μL, 2 μg/μL; Sigma‐Aldrich, St Louis, Missouri) at the site of the lesion immediately after surgical coaptation, 10,13 subepineurial injection of 5 × 10 5 bone marrow–derived enhanced green fluorescent protein (GFP)‐labeled MSCs suspended in 2.0 μL of phosphate‐buffered saline (PBS) 1 week later, followed by a subcutaneous injection of FK506 (5 mg/kg/d; Sigma‐Aldrich) for 7 days continuously after transplantation of GFP‐MSCs 12,13 . The GFP‐MSCs were obtained by transducing MSCs from adolescent SD rats with a lentivirus encoding GFP, as described elsewhere 31,32 . Subgroups B and E received only subepineurial microinjections of 5 × 10 5 GFP‐MSCs 1 week postoperatively.…”

MRI‐Visible siRNA Nanomedicine Directing Neuronal Differentiation of Neural Stem Cells in Stroke

“…T2 maps were obtained using single‐section multispin‐echo sequences to acquired T2 relaxation times. The detailed acquisition parameters were described previously . All experiments were conducted in triplicate.…”