Mesenchymal Stem Cells under Irradiation
Mesenchymal Stem Cells of Mammalian Bone Marrow under Conditions of Irradiation at Ultralow Doses: Mechanisms of Action
Tech Area / Field
3 Approved without Funding
Kolt'sov Institute of Developmental Biology, Russia, Moscow
- Institute of Immunological Engineering, Russia, Moscow reg., Lyubuchany
- University of Toronto / Institute of Biomaterials & Biomedical Engineering, Canada, ON, Toronto\nUS Department of Health & Human Services / National Institutes of Health, USA, MD, Bethesda\nCNRS / Institut National de la Recherche Agronomique / Centre de Tours, France, Tours\nCold Spring Harbor Laboratory, USA, NY, Cold Spring Harbor
Project summaryThe aim of the Project: To investigate the effect of chronic gamma-irradiation at an extremely low dose rate (about 0.15 cGy/day) on the content of MSCs in the bone marrow and their proliferative activity (based on analysis of colonies (clones) formed in vitro), regeneration potential upon ectopic transplantation to syngeneic recipients, and in vitro differentiation in permissive media.
MSCs are the component of transitory and definitive hematopoietic organs, such as the embryonic liver and adult bone marrow, which is responsible for the so-called hematopoietic microenvironment providing for the normal functioning of hematopoietic stem cells and their descendants. MSCs are multipotent and, under corresponding conditions, can differentiate into osteoblasts, chondrocytes, adipose cells, and myoblasts (Prockop, 1997; Pittenger et al., 1999; Caterson et al., 2002; Sekiya et al., 2001).
Moreover, recent investigations have shown that MSCs exhibit plasticity and can differentiate in the directions atypical of the embryonic mesenchyme, in particular, into the neural tissue (Woodbury et al., 2000). MSCs are characterized by a high degree of functional lability and responsiveness to the effects of various chemical and physical factors. This makes them an informative test system for the assessment of tolerance for external influences at the organismal level.
Radiation is a universal factor permanently affecting living organisms. Extensive data accumulated to date discredit the no-threshold model of its action. Irradiation at high doses (beginning from about 1 Gy) is deleterious and, in particular, disturbs the hematopoietic function of the bone marrow. Radiation doses regarded as low (below 0.1 Gy) have a stimulating effect on many processes. For example, they activate protective systems and repair process, which is manifested in an enhanced immune response, inhibition of apoptosis, and intensification of DNA, RNA, and protein synthesis in lymphocytes and thymocytes. Thus, the phenomena observed in the ranges of high and low radiation doses are basically different, and the difference between the effects of these doses are qualitative rather than quantitative.
The influence of low radiation doses on stem elements of the bone marrow, MSCs in particular, is a problem of major importance, taking into account the key role of these cells in histogenesis of supporting connective-tissue structures and their capacity for switching to alternative developmental pathways. To date, however, neither experimental approaches to this problem nor its theoretical and applied aspects have received due attention.
Our preliminary experiments have shown that continuous gamma-irradiation at a low dose rate for ten days entails a significant increase in the number of MSCs in the bone marrow and stimulates their reparative potential (Domaratskaya et al., 2002, 2003; Domaratskaya, 2004).
The project deals with the basic problem of developmental biology concerning the mechanisms of cell proliferation and differentiation, and one of its purposes is the development of cell technologies expediting tissue and organ repair after injury. In particular, it is planned to study the effect of chronic gamma-irradiation at an extremely low dose rate (0.15 cGy/day) on the content of MSCs in the bone marrow, their proliferative activity (based on analysis of colonies (clones) in vitro), regeneration potential upon ectopic transplantation to syngeneic recipients, and in vitro differentiation in permissive media.