Limits...
Assessment of bystander killing-mediated therapy of malignant brain tumors using a multimodal imaging approach.

Leten C, Trekker J, Struys T, Dresselaers T, Gijsbers R, Vande Velde G, Lambrichts I, Van Der Linden A, Verfaillie CM, Himmelreich U - Stem Cell Res Ther (2015)

Bottom Line: Subsequently, ganciclovir (GCV) treatment was commenced and the fate of both the MAPCs and the tumor were followed by multimodal imaging (MRI and bioluminescence imaging).Noteworthy, in some phosphate-buffered saline-treated animals (33 %), a significant decrease in tumor size was seen compared to sham-operated animals, which could potentially also be caused by a synergistic effect of the immune-modulatory stem cells.This treatment could be followed and guided noninvasively in vivo by MRI and bioluminescence imaging.

View Article: PubMed Central - PubMed

Affiliation: Biomedical MRI, Department of Imaging and Pathology, KU Leuven, 3000, Leuven, Belgium. cindy.leten@gmail.com.

ABSTRACT

Introduction: In this study, we planned to assess if adult stem cell-based suicide gene therapy can efficiently eliminate glioblastoma cells in vivo. We investigated the therapeutic potential of mouse Oct4(-) bone marrow multipotent adult progenitor cells (mOct4(-) BM-MAPCs) in a mouse glioblastoma model, guided by multimodal in vivo imaging methods to identify therapeutic windows.

Methods: Magnetic resonance imaging (MRI) of animals, wherein 5 × 10(5) syngeneic enhanced green fluorescent protein-firefly luciferase-herpes simplex virus thymidine kinase (eGFP-fLuc-HSV-TK) expressing and superparamagnetic iron oxide nanoparticle labeled (1 % or 10 %) mOct4(-) BM-MAPCs were grafted in glioblastoma (GL261)-bearing animals, showed that labeled mOct4(-) BM-MAPCs were located in and in close proximity to the tumor. Subsequently, ganciclovir (GCV) treatment was commenced and the fate of both the MAPCs and the tumor were followed by multimodal imaging (MRI and bioluminescence imaging).

Results: In the majority of GCV-treated, but not phosphate-buffered saline-treated animals, a significant difference was found in mOct4(-) BM-MAPC viability and tumor size at the end of treatment. Noteworthy, in some phosphate-buffered saline-treated animals (33 %), a significant decrease in tumor size was seen compared to sham-operated animals, which could potentially also be caused by a synergistic effect of the immune-modulatory stem cells.

Conclusions: Suicide gene therapy using mOct4(-) BM-MAPCs as cellular carriers was effective in reducing the tumor size in the majority of the GCV-treated animals leading to a longer progression-free survival compared to sham-operated animals. This treatment could be followed and guided noninvasively in vivo by MRI and bioluminescence imaging. Noninvasive imaging is of particular interest for a rapid and efficient validation of stem cell-based therapeutic approaches for glioblastoma and hereby contributes to a better understanding and optimization of a promising therapeutic approach for glioblastoma patients.

No MeSH data available.


Related in: MedlinePlus

In vivo assessment of mOct4− BM-MAPCs SPIO labeling. a Analysis of in vivo three-dimensional T2* MR images on day 2 and day 8 postinjection showed hypointense voxel volume of the Endorem®- and ihSPIO-labeled mOct4− BM-MAPCs. b MRI data corresponded to the Masson’s trichrome staining to locate the stem cells and a Prussian blue staining to stain for the presence of iron in the tissue. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. ihSPIO in-house superparamagnetic iron oxide, p.i. postinjection
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4562202&req=5

Fig2: In vivo assessment of mOct4− BM-MAPCs SPIO labeling. a Analysis of in vivo three-dimensional T2* MR images on day 2 and day 8 postinjection showed hypointense voxel volume of the Endorem®- and ihSPIO-labeled mOct4− BM-MAPCs. b MRI data corresponded to the Masson’s trichrome staining to locate the stem cells and a Prussian blue staining to stain for the presence of iron in the tissue. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. ihSPIO in-house superparamagnetic iron oxide, p.i. postinjection

Mentions: Next, we compared the contrast generated by mOct4− BM-MAPCs labeled with ihSPIO particles or Endorem® in vivo. For this, 3 × 105 nonlabeled, 1 × 105 and 3 × 105 Endorem®-labeled, as well as 1 × 105 and 3 × 105 ihSPIO-labeled mOct4− BM-MAPCs were injected into the striatum of C57BL6/j mice after which MRI was performed to assess in vivo contrast generation. Contrast could be detected in vivo on day 2 and day 8 (Fig. 2a) postinjection, with only a slight decrease in contrast from day 2 to day 8 as indicated in Fig. 2a. Three hundred thousand ihSPIO-labeled cells generated a more extensive hypointense contrast compared to mOct4− BM-MAPCs that were labeled with the same amount of Endorem®, indicating that contrast generation with ihSPIO was superior for in vivo cell detection. Masson’s Trichrome and Prussian blue stainings were performed on paraffin sections to confirm the presence of the SPIO particles. The Prussian blue staining confirmed the presence of iron (Fig. 2b) in areas corresponding to the location of hypointense signal in MRI. Both contrast agents generate sufficient contrast to visualize the location of engrafted cells for at least 1 week. Due to its superior imaging properties, cells were labeled with ihSPIO for all subsequent studies.Fig. 2


Assessment of bystander killing-mediated therapy of malignant brain tumors using a multimodal imaging approach.

Leten C, Trekker J, Struys T, Dresselaers T, Gijsbers R, Vande Velde G, Lambrichts I, Van Der Linden A, Verfaillie CM, Himmelreich U - Stem Cell Res Ther (2015)

In vivo assessment of mOct4− BM-MAPCs SPIO labeling. a Analysis of in vivo three-dimensional T2* MR images on day 2 and day 8 postinjection showed hypointense voxel volume of the Endorem®- and ihSPIO-labeled mOct4− BM-MAPCs. b MRI data corresponded to the Masson’s trichrome staining to locate the stem cells and a Prussian blue staining to stain for the presence of iron in the tissue. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. ihSPIO in-house superparamagnetic iron oxide, p.i. postinjection
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4562202&req=5

Fig2: In vivo assessment of mOct4− BM-MAPCs SPIO labeling. a Analysis of in vivo three-dimensional T2* MR images on day 2 and day 8 postinjection showed hypointense voxel volume of the Endorem®- and ihSPIO-labeled mOct4− BM-MAPCs. b MRI data corresponded to the Masson’s trichrome staining to locate the stem cells and a Prussian blue staining to stain for the presence of iron in the tissue. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. ihSPIO in-house superparamagnetic iron oxide, p.i. postinjection
Mentions: Next, we compared the contrast generated by mOct4− BM-MAPCs labeled with ihSPIO particles or Endorem® in vivo. For this, 3 × 105 nonlabeled, 1 × 105 and 3 × 105 Endorem®-labeled, as well as 1 × 105 and 3 × 105 ihSPIO-labeled mOct4− BM-MAPCs were injected into the striatum of C57BL6/j mice after which MRI was performed to assess in vivo contrast generation. Contrast could be detected in vivo on day 2 and day 8 (Fig. 2a) postinjection, with only a slight decrease in contrast from day 2 to day 8 as indicated in Fig. 2a. Three hundred thousand ihSPIO-labeled cells generated a more extensive hypointense contrast compared to mOct4− BM-MAPCs that were labeled with the same amount of Endorem®, indicating that contrast generation with ihSPIO was superior for in vivo cell detection. Masson’s Trichrome and Prussian blue stainings were performed on paraffin sections to confirm the presence of the SPIO particles. The Prussian blue staining confirmed the presence of iron (Fig. 2b) in areas corresponding to the location of hypointense signal in MRI. Both contrast agents generate sufficient contrast to visualize the location of engrafted cells for at least 1 week. Due to its superior imaging properties, cells were labeled with ihSPIO for all subsequent studies.Fig. 2

Bottom Line: Subsequently, ganciclovir (GCV) treatment was commenced and the fate of both the MAPCs and the tumor were followed by multimodal imaging (MRI and bioluminescence imaging).Noteworthy, in some phosphate-buffered saline-treated animals (33 %), a significant decrease in tumor size was seen compared to sham-operated animals, which could potentially also be caused by a synergistic effect of the immune-modulatory stem cells.This treatment could be followed and guided noninvasively in vivo by MRI and bioluminescence imaging.

View Article: PubMed Central - PubMed

Affiliation: Biomedical MRI, Department of Imaging and Pathology, KU Leuven, 3000, Leuven, Belgium. cindy.leten@gmail.com.

ABSTRACT

Introduction: In this study, we planned to assess if adult stem cell-based suicide gene therapy can efficiently eliminate glioblastoma cells in vivo. We investigated the therapeutic potential of mouse Oct4(-) bone marrow multipotent adult progenitor cells (mOct4(-) BM-MAPCs) in a mouse glioblastoma model, guided by multimodal in vivo imaging methods to identify therapeutic windows.

Methods: Magnetic resonance imaging (MRI) of animals, wherein 5 × 10(5) syngeneic enhanced green fluorescent protein-firefly luciferase-herpes simplex virus thymidine kinase (eGFP-fLuc-HSV-TK) expressing and superparamagnetic iron oxide nanoparticle labeled (1 % or 10 %) mOct4(-) BM-MAPCs were grafted in glioblastoma (GL261)-bearing animals, showed that labeled mOct4(-) BM-MAPCs were located in and in close proximity to the tumor. Subsequently, ganciclovir (GCV) treatment was commenced and the fate of both the MAPCs and the tumor were followed by multimodal imaging (MRI and bioluminescence imaging).

Results: In the majority of GCV-treated, but not phosphate-buffered saline-treated animals, a significant difference was found in mOct4(-) BM-MAPC viability and tumor size at the end of treatment. Noteworthy, in some phosphate-buffered saline-treated animals (33 %), a significant decrease in tumor size was seen compared to sham-operated animals, which could potentially also be caused by a synergistic effect of the immune-modulatory stem cells.

Conclusions: Suicide gene therapy using mOct4(-) BM-MAPCs as cellular carriers was effective in reducing the tumor size in the majority of the GCV-treated animals leading to a longer progression-free survival compared to sham-operated animals. This treatment could be followed and guided noninvasively in vivo by MRI and bioluminescence imaging. Noninvasive imaging is of particular interest for a rapid and efficient validation of stem cell-based therapeutic approaches for glioblastoma and hereby contributes to a better understanding and optimization of a promising therapeutic approach for glioblastoma patients.

No MeSH data available.


Related in: MedlinePlus