Perspective: Imagings Expanding Role in Stem Cell Therapy
“Molecular imaging is playing a key role in direct visualization of stem cells that would allow monitoring of homing and engraftment and survival of transplanted cells in the target tissues,” says Antti Saraste, MD, PhD, a cardiologist at Turku PET Centre, Turku University Hospital in Finland. “Understanding these basic mechanisms of stem cell therapy is essential to optimize delivery of therapeutic cells and in understanding the clinical effects of therapy.”
However, the duration of cell tracking is limited “from a few hours with 18F-FDG-PET to seven days after injection with 111In with SPECT/CT in an experimental model,” Saraste notes.
Magnetic resonance imaging (MRI) can visualize stem cells labeled with paramagnetic or fluorinated nanoparticles before transplantation without affecting viability of the cells. “High spatial resolution and the absence of ionizing radiation make MRI very attractive for experimental and clinical research. However, signals from nanoparticles are not directly related to cell viability as they lose specificity after cell death and phagocytosis by macrophages,” Saraste notes.
The main concerns over genetic-based labeling are potential immunogenicity and random integration into cellular chromosomes. Since reporter gene imaging requires genetic modification of stem cells, its application to clinical research will require further documentation of suitability and safety to pass regulatory hurdles, asserts Saraste.
Furthermore, hybrid imaging could combine the presence of stem cells with functional effects, such as “perfusion, presence of viable tissue and function,” Saraste says. Future developments in imaging modalities would increase the sensitivity as well as the resolution of images, and there would be more incorporation of different imaging modalities, says Wu.
At present, the most important use of molecular imaging comes in investigating the means to prevent premature death of transplanted cells. Saraste predicts, that in the future, molecular imaging holds promise in developing reproducible stem cell protocols for clinical use. Molecular imaging has the potential to accelerate research progress in stem cell therapy by evaluation of “optimal cell type, delivery route and safety of therapy,” says Saraste.
Imaging strategies
There are different types of imaging approaches. “Choosing the exact approach would depend on the exact biological question that you want to ask,” says Joseph Wu, MD, PhD, assistant professor of medicine and radiology at Stanford University School of Medicine in California. “For example, if you want to know how long the cells will survive after two to three months, it is better to use a genetic-labeled approach. If you want to know short-term effects, like where the cells are located, then it is better to use magnetic resonance. And if you want to know quantitatively how many cells reside in the area, it is possibly better to go with radioactive labeling”, shares Wu.Short-term visualization
Direct labeling of stem cells with radionuclides—such as Indium-111-oxine, 99mTc-exametazime (HMPAO), or 18F-fluorodeoxyglucose (FDG)—before transplantation allows their visualization with SPECT or PET.However, the duration of cell tracking is limited “from a few hours with 18F-FDG-PET to seven days after injection with 111In with SPECT/CT in an experimental model,” Saraste notes.
Magnetic resonance imaging (MRI) can visualize stem cells labeled with paramagnetic or fluorinated nanoparticles before transplantation without affecting viability of the cells. “High spatial resolution and the absence of ionizing radiation make MRI very attractive for experimental and clinical research. However, signals from nanoparticles are not directly related to cell viability as they lose specificity after cell death and phagocytosis by macrophages,” Saraste notes.
Long-term visualization
Monitoring of cell survival and differentiation requires imaging techniques that are linked to integrity of the cells, tissue-specific gene expression patterns allowing studies over longer period of time, shares Saraste. “Reporter gene imaging is a potential technique for this purpose,” he says. “A reporter gene construct, such as herpes simplex virus thymidine kinase enzyme, sodium-iodide symporter, or firefly lu-ciferase, is introduced to stem cells before their transplantation. After transplantation, cells can be visualized by an intravenously administered radioactive or optical reporter probe, which is specific for the reporter gene and accumulates only in the transplanted cells,” he says.The main concerns over genetic-based labeling are potential immunogenicity and random integration into cellular chromosomes. Since reporter gene imaging requires genetic modification of stem cells, its application to clinical research will require further documentation of suitability and safety to pass regulatory hurdles, asserts Saraste.
Furthermore, hybrid imaging could combine the presence of stem cells with functional effects, such as “perfusion, presence of viable tissue and function,” Saraste says. Future developments in imaging modalities would increase the sensitivity as well as the resolution of images, and there would be more incorporation of different imaging modalities, says Wu.
At present, the most important use of molecular imaging comes in investigating the means to prevent premature death of transplanted cells. Saraste predicts, that in the future, molecular imaging holds promise in developing reproducible stem cell protocols for clinical use. Molecular imaging has the potential to accelerate research progress in stem cell therapy by evaluation of “optimal cell type, delivery route and safety of therapy,” says Saraste.