Stem Cell Niche-Radiobiological Response

Abstract

Ionizing radiation (IR) in the context of radiotherapy or unplanned exposure events results in a myriad of biological events with clinical outcomes that range in severity from DNA damage, local tissue damage, and even death. Radiation is widely utilized in medicine for imaging diagnostics, total body irradiation (TBI) in bone marrow (BM) transplantation and cancer therapy, and for the management of non-cancerous syndromes, including Dupuyten and Ledderhose disease (Halperin in Lancet Oncol 7(8):676–85, 2006; Seegenschmiedt and Attassi in Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft [et al] 179(12):847–853, 2003; Heyd et al. in Organ der Deutschen Rontgengesellschaft [et al] 186(1):24–29, 2010). To eradicate tumors, x-rays, gamma rays, or high-energy charged particle beams are emitted at malignant cells to induce DNA damage and death. The disadvantages associated with radiation therapy include damage to proximal healthy tissues and cell death. The blood forming system is highly sensitive to radiation with increasing risk of morbidity and mortality resulting from loss of white blood cells and platelets with the sequela of opportunistic infection and hemorrhage with increasing duration and intensity of exposure. Radiation therapy increases the risk of infertility, can cause joint and mouth (stoma) complications, and can result in lymphedema and cancer. Irradiation impairs osteogenesis causing cell cycle arrest, reduction of osteoblast proliferation and differentiation (although not initially), collagen and vascular suppression, increased sensitivity to apoptotic agents, osteoradionecrosis, bone demineralization, loss of trabecular connections, sclerosis, and destruction of a stem cell niche that contributes to maintenance of hematopoiesis [Hopewell in Med Pediatr Oncol 41(3):208–211, 2003]. In this chapter, we will review what is known regarding the impact of radiation exposure on BM stromal cells that constitute microenvironments/niches that support blood cell production and an overview of hematopoietic stem cell (HSC) radioprotection and regeneration of the stem cell niche. We will outline the acute and late effects of irradiation on hematopoietic stem and progenitor cells leading to hematopoietic acute radiation syndrome (H-ARS) and residual bone marrow damage (RBMD), respectively. The interactive components of the stem cell niche respond to radiation distinctively by cell type and even by state of maturation, and influence the fate of one another. The reader will appreciate a greater understanding of the HSC niche, the radiobiological response as an interconnected symphony, and the therapeutic approach of HSC niche protection and regeneration.