Stem cell therapies for the treatment of radiation-induced normal tissue side effects

Abstract

Significance: Targeted irradiation is an effective cancer therapy but damage inflicted to normal tissues surrounding the tumor may cause severe complications. While certain pharmacologic strategies can temper the adverse effects of irradiation, stem cell therapies provide unique opportunities for restoring functionality to the irradiated tissue bed.

Recent advances: Preclinical studies presented in this review provide encouraging proof of concept regarding the therapeutic potential of stem cells for treating the adverse side effects associated with radiotherapy in different organs. Early-stage clinical data for radiation-induced lung, bone, and skin complications are promising and highlight the importance of selecting the appropriate stem cell type to stimulate tissue regeneration.

Critical issues: While therapeutic efficacy has been demonstrated in a variety of animal models and human trials, a range of additional concerns regarding stem cell transplantation for ameliorating radiation-induced normal tissue sequelae remain. Safety issues regarding teratoma formation, disease progression, and genomic stability along with technical issues impacting disease targeting, immunorejection, and clinical scale-up are factors bearing on the eventual translation of stem cell therapies into routine clinical practice.

Future directions: Follow-up studies will need to identify the best possible stem cell types for the treatment of early and late radiation-induced normal tissue injury. Additional work should seek to optimize cellular dosing regimes, identify the best routes of administration, elucidate optimal transplantation windows for introducing cells into more receptive host tissues, and improve immune tolerance for longer-term engrafted cell survival into the irradiated microenvironment.

FIG. 1.

Stem cell transplantation for ameliorating radiation-induced cognitive dysfunction. Immunocompromised athymic rats are subjected to cranial irradiation, while human stem cells are grown in parallel. At specified times (2 days, 2 or 4 weeks) after irradiation, animals are subjected to hippocampal transplantation with fixed numbers of human stem cells. At specific times (1 or 4 months) after irradiation, animals are then evaluated for cognitive performance using NPR and FC tasks. Irradiated animals transplanted with stem cells (IRR+hNSC) exhibit higher exploration ratios in NPR and increased time spent freezing in the context phase of FC, demonstrating improved hippocampal-dependent performance. After completion of cognitive testing, the brains of animals are analyzed for engrafted cell survival, migration, differentiated fate (NeuN-neuronal fate, GFAP-astroglial fate), and functional integration by the expression of the Arc. Asterisks represent significance (p<0.05) compared to irradiated groups. Arc, activity-regulated cytoskeleton-associated protein; FC, fear conditioning; hNSC, human neural stem cell; NPR, novel place recognition.

FIG. 2.

Transplantation of salivary gland stem cells rescues mice from radiation-induced hyposalivation. Salivary gland tissue is dispersed to a cell solution and allowed to form salispheres in culture. From these salispheres, c-Kit expressing stem cells are selected and injected into locally irradiated glands to improve saliva secretion [adapted from Gao et al. (75)]. n.d., not determined.

FIG. 3.

Bone marrow grafts treated with BCP. Histologic section reveals healing of defective bone, shown as the BCP substitute associated with the bone marrow graft in the irradiated bone area. New bone formation (yellow, ←) in contact with the BCP (gray, *). Rich bone marrow (red, ⇒) in contact with the BCP. BCP, biphasic calcium phosphate.

FIG. 4.

ADSC for the resolution of skin injury. ADSC exhibit marked plasticity toward keratinocyte and endothelial cells. Stem cells of the adipose lineage have the ability to differentiate into epithelial cells, acquire a functional keratinocyte phenotype, and differentiate into vascular cells. These cells can be used to facilitate the repair of radiation-induced skin injury as well as other pathological conditions of the skin. ADSC, adipose-derived stem cells.

FIG. 5.

Preparative liver irradiation for hepatocyte transplantation. The anterior half of the right lobe of liver was irradiated with a single fraction of 50 Gray in C57Bl/6 mice, followed by intrasplenic transplantation of 1×10⁶ beta-galactosidase-proficient hepatocytes isolated from congeneic Rosa mouse, 1 day after irradiation. Hepatic mitogenic signal was provided by intravenous administration of an adenovirus expressing recombinant human HGF within 1 h after liver irradiation. Animals were sacrificed 16 weeks after hepatocyte transplantation. Data show beta-galactosidase staining of a fresh frozen section of the right lobe of the liver 16 weeks after hepatocyte transplantation. Note preferential repopulation of the donor beta-galactosidase-positive hepatocytes (blue) in the irradiated liver lobe. HGF, hepatocyte growth factor.

FIG. 6.

Radiation-induced myocardial damage and stem cell treatments. Irradiation causes microvascular damage and capillary loss, which leads to inadequate perfusion of the tissue and may result in myocardial infarct. Bone marrow progenitor cells can either be mobilized to the blood using growth factors, or extracted and cultured in vitro to enrich populations of endothelial progenitor cells. Mobilized or injected progenitor cells home to the infarct area and stimulate surviving cells to proliferate and regenerate damaged tissue.