Wild-type bone marrow cells ameliorate the phenotype of SOD1-G93A ALS mice and contribute to CNS, heart and skeletal muscle tissues

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neurodegenerative disease without any effective therapy. To evaluate the potential of wild-type bone marrow (BM)-derived stem cells to modify the ALS phenotype, we generated BM chimeric Cu/Zn superoxide dismutase (SOD1) mice by transplantation of BM cells derived from mice expressing green fluorescent protein (GFP) in all tissues and from Thy1-YFP mice that express a spectral variant of GFP (yellow fluorescent protein) in neurons only. In the recipient cerebral cortex, we observed rare GFP+ and YFP+ neurons, which were probably generated by cell fusion, as demonstrated by fluorescence in situ hybridization (FISH) analysis, suggesting that this phenomenon is not limited to Purkinje cells. GFP-positive microglial cells were extensively present in both the brain and spinal cord of the affected animals. Completely differentiated and immature GFP+ myofibres were also present in the heart and skeletal muscles of SOD1 mice, confirming that BM cells can participate in striated muscle tissue regeneration. Moreover, wild-type BM chimeric SOD1 mice showed a significantly delayed disease onset and an increased life span, probably due to a positive 'non-neuronal environmental' effect rather than to neuronogenesis. This improvement in SOD1-G93A mouse survival is comparable with that previously obtained using some safer pharmacological agents. BM transplantation-related complications in humans preclude its clinical application for ALS treatment. However, our data suggest that further studies aimed at improving the degree of tissue chimerism by BM-derived cells may provide valuable insights into strategies to slow ALS progression.

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

“…Interestingly, diminution of mSOD1 restricted to microglia leads to slower disease progression and extends survival considerably 47. In a similar manner, wild type bone marrow transfer in either lethally irradiated mSOD1 or mSOD1; PU.1 − / − mice leads to slower progression and increased survival 48, 49. These changes were suggested to be conferred by wild type microglial cells 48, 49.…”

“…In a similar manner, wild type bone marrow transfer in either lethally irradiated mSOD1 or mSOD1; PU.1 − / − mice leads to slower progression and increased survival 48, 49. These changes were suggested to be conferred by wild type microglial cells 48, 49. However, these reports did not take into account that donor wild type lymphoid cells, like T‐cells, may also contribute to the beneficial effect 48, 49.…”

“…These changes were suggested to be conferred by wild type microglial cells 48, 49. However, these reports did not take into account that donor wild type lymphoid cells, like T‐cells, may also contribute to the beneficial effect 48, 49. In vitro, mSOD1 microglia release more pro‐inflammatory cytokines like IL‐1β and TNFα, superoxide, but less neuroprotective IGF1 49, 50, 51.…”

Donor Y chromosome in renal carcinoma cells of a female BMT recipient: visualization of putative BMT–tumor hybrids by FISH

“…This is due, at least in part, to cell fusion, in some cases with macrophages. [1][2][3][4][5][6] There are more than 25 reports of tumor hybridization in animals, 7 and myeloid cell-tumor hybrids have been observed in melanoma, 8 lymphoma, 9 sarcoma, 10,11 and insulinoma models. 12 In some cases, tumor hybridization was associated with metastasis.…”

Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis

“…Direct implantation of nondiseased bone marrow into bone marrow of SOD1-G93A mice improved survival, an effect linked to the presence of non-neuronal cells derived from the transplanted tissue in the spinal cord [20]. Likewise, intraperitoneal transplantation of wild-type bone marrow into SOD1-G93A mice resulted in extensive incorporation of transplanted cells as microglia with improved animal survival [18]. Enriching the population of transplanted cells for c-kit+ stem cells allowed the infusion of cells peripherally into SOD1-G93A mice, with again improved function and survival associated with nonneuronal cells that migrated to the spinal cord [23].…”