Ionizing Particle Radiation as a Modulator of Endogenous Bone Marrow Cell Reprogramming: Implications for Hematological Cancers

Abstract

Exposure of individuals to ionizing radiation (IR), as in the case of astronauts exploring space or radiotherapy cancer patients, increases their risk of developing secondary cancers and other health-related problems. Bone marrow (BM), the site in the body where hematopoietic stem cell (HSC) self-renewal and differentiation to mature blood cells occurs, is extremely sensitive to low-dose IR, including irradiation by high-charge and high-energy particles. Low-dose IR induces DNA damage and persistent oxidative stress in the BM hematopoietic cells. Inefficient DNA repair processes in HSC and early hematopoietic progenitors can lead to an accumulation of mutations whereas long-lasting oxidative stress can impair hematopoiesis itself, thereby causing long-term damage to hematopoietic cells in the BM niche. We report here that low-dose 1H- and 56Fe-IR significantly decreased the hematopoietic early and late multipotent progenitor (E- and L-MPP, respectively) cell numbers in mouse BM over a period of up to 10 months after exposure. Both 1H- and 56Fe-IR increased the expression of pluripotent stem cell markers Sox2, Nanog, and Oct4 in L-MPPs and 10 months post-IR exposure. We postulate that low doses of 1H- and 56Fe-IR may induce endogenous cellular reprogramming of BM hematopoietic progenitor cells to assume a more primitive pluripotent phenotype and that IR-induced oxidative DNA damage may lead to mutations in these BM progenitors. This could then be propagated to successive cell lineages. Persistent impairment of BM progenitor cell populations can disrupt hematopoietic homeostasis and lead to hematologic disorders, and these findings warrant further mechanistic studies into the effects of low-dose IR on the functional capacity of BM-derived hematopoietic cells including their self-renewal and pluripotency.

Differences in responses to X-ray exposure between osteoclast and osteoblast cells

“…X-rays can cause the transient induction of hematopoietic stem cell (HSC) apoptosis due to their high sensitivity [ 31 ]. In addition, almost all the blood cells, including the lymphoid and myeloid lineages, are extremely sensitive to X-rays [ 32 ]. In this study, we found that osteoclasts, which originated from radiosensitive HSCs, also showed high sensitivity to X-rays, in both progenitors and differentiating cells.…”

The Influence of Radiation on Bone and Bone Cells—Differential Effects on Osteoclasts and Osteoblasts

“…For HSCs, the impact of IR reveals conflicting results. On the one hand, IR is reported to cause apoptosis in hematopoietic stem cells, when they are exposed to the low doses of high energy and high charge radiation that are relevant in space travel [ 125 ]. On the other hand, Li et al reported that very low doses of X-rays act as stimulants of hematopoietic progenitor cells, as their proliferation and mobilization was increased in an animal study [ 126 ].…”

Targeted Reduction of Senescent Cell Burden Alleviates Focal Radiotherapy-Related Bone Loss

“…Both low‐dose and high‐dose radiation treatment regimens result in bone loss, mainly due to increase in osteoclast function, and increases in DNA damage and cellular apoptosis of the bone lineage cells . Several studies suggest that bone marrow cells of the hematopoietic lineage are the most sensitive to radiation damage . Cells that are responsible for maintaining bone homeostasis, such as osteoblasts, osteocytes, and mesenchymal stem cells (MSCs), undergo varying degrees of DNA damage and apoptosis, with osteoblasts being more sensitive and MSCs more resistant.…”