Year-end Sale % OFF 
Abstract
Myeloablative preconditioning using irradiation is the most commonly used technique to generate rodents having chimeric bone marrow, employed for the study of bone marrow-derived cell accumulation in the healthy and diseased central nervous system. However, irradiation has been shown to alter the blood-brain barrier, potentially creating confounding artefacts. To better study the potential of bone marrow-derived cells to function as treatment vehicles for neurodegenerative diseases alternative preconditioning regimens must be developed. We treated transgenic mice that over-express human mutant superoxide dismutase 1, a model of amyotrophic lateral sclerosis, with busulfan to determine whether this commonly used chemotherapeutic leads to stable chimerism and promotes the entry of bone marrow-derived cells into spinal cord. Intraperitoneal treatment with busulfan at 60 mg/kg or 80 mg/kg followed by intravenous injection of green fluorescent protein-expressing bone marrow resulted in sustained levels of chimerism (∼80%). Bone marrow-derived cells accumulated in the lumbar spinal cord of diseased mice at advanced stages of pathology at both doses, with limited numbers of bone marrow derived cells observed in the spinal cords of similarly treated, age-matched controls; the majority of bone marrow-derived cells in spinal cord immunolabelled for macrophage antigens. Comparatively, significantly greater numbers of bone marrow-derived cells were observed in lumbar spinal cord following irradiative myeloablation. These results demonstrate bone marrow-derived cell accumulation in diseased spinal cord is possible without irradiative preconditioning.
Highlights
Clinical and experimental observations indicate that under certain conditions, bone marrow (BM)-derived cells (BMDCs) can transmigrate across the BBB and take up residence within the CNS
To investigate the short-term level of peripheral blood cell (PBC) chimerism and BMDC engraftment within the healthy spinal cord following BUinduced myeloablation and BM transplantation, 8 week-old Bl.6 mice were treated with 60, 80 (n = 4 per group) or 100 mg/kg (n = 3) BU administered as fractionated doses of 20 mg/kg per day via intraperitoneal injection
Comparative levels of chimerism in circulating myeloid cells were 79.762.8%, 91.863.3%, and 89.667.2% for mice treated with 60, 80, and 100 mg/kg BU, respectively. This disparity between the total PBC and circulating myeloid cell chimerism can be attributed to the lack of immunosuppression elicited by BU, as the majority of circulating leukocytes are lymphoid cells, which are spared the cytotoxic effects of BU and have a relatively long half-life in the circulation [15]
Summary
Clinical and experimental observations indicate that under certain conditions, bone marrow (BM)-derived cells (BMDCs) can transmigrate across the BBB and take up residence within the CNS. Studies employing BM chimeric rodents created using a myeloablative irradiation/BM transplantation paradigm have demonstrated that BMDCs migrate to and populate the CNS, and BMDC accumulation is significantly increased in affected areas of the CNS in murine models of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) [1,2,3,4] and Alzheimer’s disease [5,6], suggesting that BMDCs home to and/ or expand at sites of neurodegeneration In both the healthy and diseased murine CNS, the majority of BMDCs exhibit an immunophenotype consistent with CNS-associated macrophages, such as perivascular cells and other cell types, with a small proportion acquiring residence within the CNS parenchyma [4,7]. Studies employing parabiosis, a technique that surgically joins the circulations of two genetically distinct mice resulting in peripheral blood cell (PBC) chimerism, have demonstrated that in the absence of irradiation and/or the nonphysiological presence of circulating BM progenitors, very few BMDCs are observed within the healthy or diseased CNS [9,10]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
