Senescence-unrelated impediment of osteogenesis from Flk1+ bone marrow mesenchymal stem cells induced by total body irradiation and its contribution to long-term bone and hematopoietic injury

Abstract

Ionizing irradiation is a common treatment for cancer patients and can result in adverse side effects affecting the bone and hematopoietic systems. Although some studies have demonstrated that ionizing radiation can induce apoptosis and senescence in hematopoietic stem cells, little is known about the effects of total body irradiation (TBI) on bone marrow (BM) mesenchymal stem cells (MSC). The objectives of this study were to determine the response of BM MSC to irradiation stress, such as cellular senescence and differentiation potential in BM MSC, and the clinical significance of these changes caused by TBI. At different time points after TBI, Flk1+ MSC were isolated from BM of male C57BL/6 mice and analyzed for colony forming units-fibroblast (CFU-F), cellular senescence-related indices and osteogenic potential. Bone histomorphometric analysis, immunohistochemical staining and bone mineral density (BMD) tests were performed to detect the effects of TBI on bone and the hematopoietic system. TBI reduced the pool of BM mesenchymal stem/progenitor cells, and altered osteoblast differentiation ability of BM MSC evidenced by changes in TAZ expression. These alterations, sustained up to 28 days post-irradiation, were independent of cellular senescence in BM MSC. Irradiated mice showed obvious bone loss and destruction of the hematopoietic osteoblastic niche, which is normally comprised of spindle-shaped N-cadherin-expressing osteoblasts. TBI treatment results in impairment in BM MSC, which might be responsible for bone loss and, at least partially, for impaired hematopoiesis.