Mobilization of Bone Marrow Stem Cells by Granulocyte Colony-Stimulating Factor Ameliorates Radiation-Induced Damage to Salivary Glands

Abstract

Purpose: One of the major reasons for failure of radiotherapeutic cancer treatment is the limitation in dose that can be applied to the tumor because of coirradiation of the normal healthy tissue. Late radiation-induced damage reduces the quality of life of the patient and may even be life threatening. Replacement of the radiation-sterilized stem cells with unirradiated autologous stem cells may restore the tissue function. Here, we assessed the potential of granulocyte colony-stimulating factor (G-CSF)–mobilized bone marrow–derived cells (BMC) to regenerate and functionally restore irradiated salivary glands used as a model for normal tissue damage. Experimental Design: Male-eGFP+ bone marrow chimeric female C57BL/6 mice were treated with G-CSF, 10 to 60 days after local salivary gland irradiation. Four months after irradiation, salivary gland morphology and flow rate were assessed. Results: G-CSF treatment induced homing of large number of labeled BMCs to the submandibular glands after irradiation. These animals showed significant increased gland weight, number of acinar cells, and salivary flow rates. Donor cells expressed surface markers specific for hematopoietic or endothelial/mesenchymal cells. However, salivary gland acinar cells neither express the G-CSF receptor nor contained the GFP/Y chromosome donor cell label. Conclusions: The results show that BMCs home to damaged salivary glands after mobilization and induce repair processes, which improve function and morphology. This process does not involve transdifferentiation of BMCs to salivary gland cells. Mobilization of BMCs could become a promising modality to ameliorate radiation-induced complications after radiotherapy.

Neurotrophic factor GDNF promotes survival of salivary stem cells

“…There is an increasing interest in SC therapy to restore salivary gland function after radiation. SCs from tissues other than salivary gland, including bone marrow (7,(44)(45)(46)(47)(48)(49)(50), pancreas (51), and lacrimal gland (52), have been shown to differentiate into salivary acinar-like structures in vitro, but whether these cells can have acini function in vivo remains to be further investigated.…”

Decreasing the Adverse Effects of Cancer Therapy: National Cancer Institute Guidance for the Clinical Development of Radiation Injury Mitigators

“…The efficacy of these agents at clinically relevant drug doses, combined with their widespread clinical use for other indications, makes them attractive for the mitigation of radiation injuries. The third group of agents, perhaps best applied weeks or months after irradiation, includes regenerative agents, such as stem cells (30).…”

Cytokine Treatment Improves Parenchymal and Vascular Damage of Salivary Glands after Irradiation

“…We recently showed that treatment with granulocyte colonystimulating factor (G-CSF), inducing mobilization of bone marrow-derived cells (BMC) to the bloodstream, resulted in the abundant presence of BMCs in irradiated salivary glands and improved morphology and function (8). Similar observations have been made in tissues like skin (9), lung (10), kidney (11,12), liver (13), brain (14), and myocardium (15).…”