Publicação
Testing miRNA-cell based strategies to obtain therapeutic secretomes for spinal ALS
| Resumo: | Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs) and glia dysfunction, which con-tribute to disease onset and progression. miRNA dysregulation and neuroinflammation have been pointed to contribute for MN degeneration in ALS. Lately, our group demon-strated that miR-124 was increased in SOD1G93A (mSOD1) NSC-34 MNs and in their de-rived sEVs, causing an early microglia activation followed by cell repairing mechanisms. Increased expression of miR-124 was also identified in the spinal cord (SC) of mSOD1 mice during the symptomatic stage, indicating a potential pathological role of this miRNA in ALS. Interestingly, the secretome from mSOD1 MNs transfected with anti-miR-124 was promising in reverting the damage-associated mechanisms since it prevents neurodegeneration, microglia activation and the pathology associated to neuro-immune homeostatic imbalance in spinal cord organotypic cultures (SCOCs) from mSOD1 mice. Moreover, unpublished studies from our group have shown increased levels of miR-125b in micro-glia isolated from the SC of mSOD1 mouse pups and cultured for 16 days in vitro (aged cells). miR-125b was also found increased in mSOD1 NSC-34 MNs, while it was shown to be upregulated in the SC of symptomatic/end-stage mSOD1 mice and to drive microglia activation and MN death in ALS. Here, our major goal was to explore the potential therapeutic effects of secretomes from MNs and microglia after reparative strategies with anti-miR-124 and anti-miR-125b towards translation into clinics. Our results highlight that secretome from mSOD1 MNs with normalized levels of miR-124 and miR-125b counter-acted some abnormalities found in the mSOD1 SCOCs such as axonal transport, phagocytic ability and oligodendrocytes maturation. Our data also suggest that the combined usage of anti-miR-124 and anti-miR-125b modulatory strategies may provide a better therapeutic approach to be adopted. Further, although both secretomes from either modulated mSOD1 MNs or mSOD1 microglia are able to restore cellular homeostasis in mSOD1 SCOCs, our findings suggest that modulated mSOD1 MNs secretome produces more benefits in comparison with those from modulated mSOD1 microglia in ALS, for early stages of disease progression. |
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| Autores principais: | Martins, Nísia Borralho |
| Assunto: | ALS Models Neuroinflammation Microglia miRNA targeting Motor Neuron Organotypic cultures |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade Nova de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório Institucional da UNL |
| Resumo: | Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs) and glia dysfunction, which con-tribute to disease onset and progression. miRNA dysregulation and neuroinflammation have been pointed to contribute for MN degeneration in ALS. Lately, our group demon-strated that miR-124 was increased in SOD1G93A (mSOD1) NSC-34 MNs and in their de-rived sEVs, causing an early microglia activation followed by cell repairing mechanisms. Increased expression of miR-124 was also identified in the spinal cord (SC) of mSOD1 mice during the symptomatic stage, indicating a potential pathological role of this miRNA in ALS. Interestingly, the secretome from mSOD1 MNs transfected with anti-miR-124 was promising in reverting the damage-associated mechanisms since it prevents neurodegeneration, microglia activation and the pathology associated to neuro-immune homeostatic imbalance in spinal cord organotypic cultures (SCOCs) from mSOD1 mice. Moreover, unpublished studies from our group have shown increased levels of miR-125b in micro-glia isolated from the SC of mSOD1 mouse pups and cultured for 16 days in vitro (aged cells). miR-125b was also found increased in mSOD1 NSC-34 MNs, while it was shown to be upregulated in the SC of symptomatic/end-stage mSOD1 mice and to drive microglia activation and MN death in ALS. Here, our major goal was to explore the potential therapeutic effects of secretomes from MNs and microglia after reparative strategies with anti-miR-124 and anti-miR-125b towards translation into clinics. Our results highlight that secretome from mSOD1 MNs with normalized levels of miR-124 and miR-125b counter-acted some abnormalities found in the mSOD1 SCOCs such as axonal transport, phagocytic ability and oligodendrocytes maturation. Our data also suggest that the combined usage of anti-miR-124 and anti-miR-125b modulatory strategies may provide a better therapeutic approach to be adopted. Further, although both secretomes from either modulated mSOD1 MNs or mSOD1 microglia are able to restore cellular homeostasis in mSOD1 SCOCs, our findings suggest that modulated mSOD1 MNs secretome produces more benefits in comparison with those from modulated mSOD1 microglia in ALS, for early stages of disease progression. |
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