Lagoa, Filipa Narciso
The role of the immune system in MuSC aging during regeneration [Dissertação de Mestrado] / Filipa Narciso Lagoa ; orient. Pedro Sousa-Victor, Joana Mendes Neves
The role of the immune system in MuSC aging during regeneration [Dissertação de Mestrado] / Filipa Narciso Lagoa ; orient. Pedro Sousa-Victor, Joana Mendes Neves . - Lisboa : NOVA Medical School, Universidade NOVA de Lisboa, 2023 . - 98 p. . -
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Abstract Age-related loss of regenerative capacity in the skeletal muscle is associated with a reduction in myeloid cells in the regenerating tissue, diminished muscle stem cell (MuSC) populations, and intrinsic defects within the remaining MuSCs. However, the consequences of the age-related immune alterations on MuSCs remain a subject of investigation. Preliminary investigations in both aged mice and mouse models of immune aging (that mimic age-related reductions in myeloid populations), have shown a dual phenomenon occurring during regeneration involving a reduction in MuSC numbers and the conversion of MuSCs into a distinct subpopulation characterized by the expression of Sca-1. Transcriptomic analysis of this new MuSC population showed a link with interferon (IFN) responses. This project aims to investigate the immune system's role in MuSC aging during regeneration and study the potential impact of IFN signaling on MuSC’s behavior during skeletal muscle regeneration in conditions of immune dysfunction. In this work, we showed that in the absence of macrophages during regeneration, MuSCs disappear from the skeletal muscle due to an increase in cell death and a cell fate switch mechanism from 7IntegrinposSca-1neg MuSCs to 7IntegrinposSca-1pos MuSC population, both happening at 3dpi. Interferon alpha, but also Poly IC (an inducer of IFN signaling, mimicking cellular debris), administration in vivo were sufficient to induce the cell fate switch observed after macrophage ablation. Using in vitro experiments, we found that IFN acts directly on MuSCs and the effects are mediated by the JAK-STAT pathway. Finally, we showed that the IFN administration is sufficient to impair myofiber formation following regeneration. With this work, we propose that the accumulation of cell debris after injury, in the absence of macrophages, activates an unknown cell to produce IFN that stimulates the MuSC to switch from a 7IntegrinposSca-1neg MuSC population into a 7IntposSca-1pos MuSC population, through the JAK-STAT pathway. We suggest a similar mechanism could mediate the cell fate switch of MuSCs in aging Muscle, Skeletal
Interferon-alpha
Academic Dissertation
The role of the immune system in MuSC aging during regeneration [Dissertação de Mestrado] / Filipa Narciso Lagoa ; orient. Pedro Sousa-Victor, Joana Mendes Neves . - Lisboa : NOVA Medical School, Universidade NOVA de Lisboa, 2023 . - 98 p. . -
. -
Abstract Age-related loss of regenerative capacity in the skeletal muscle is associated with a reduction in myeloid cells in the regenerating tissue, diminished muscle stem cell (MuSC) populations, and intrinsic defects within the remaining MuSCs. However, the consequences of the age-related immune alterations on MuSCs remain a subject of investigation. Preliminary investigations in both aged mice and mouse models of immune aging (that mimic age-related reductions in myeloid populations), have shown a dual phenomenon occurring during regeneration involving a reduction in MuSC numbers and the conversion of MuSCs into a distinct subpopulation characterized by the expression of Sca-1. Transcriptomic analysis of this new MuSC population showed a link with interferon (IFN) responses. This project aims to investigate the immune system's role in MuSC aging during regeneration and study the potential impact of IFN signaling on MuSC’s behavior during skeletal muscle regeneration in conditions of immune dysfunction. In this work, we showed that in the absence of macrophages during regeneration, MuSCs disappear from the skeletal muscle due to an increase in cell death and a cell fate switch mechanism from 7IntegrinposSca-1neg MuSCs to 7IntegrinposSca-1pos MuSC population, both happening at 3dpi. Interferon alpha, but also Poly IC (an inducer of IFN signaling, mimicking cellular debris), administration in vivo were sufficient to induce the cell fate switch observed after macrophage ablation. Using in vitro experiments, we found that IFN acts directly on MuSCs and the effects are mediated by the JAK-STAT pathway. Finally, we showed that the IFN administration is sufficient to impair myofiber formation following regeneration. With this work, we propose that the accumulation of cell debris after injury, in the absence of macrophages, activates an unknown cell to produce IFN that stimulates the MuSC to switch from a 7IntegrinposSca-1neg MuSC population into a 7IntposSca-1pos MuSC population, through the JAK-STAT pathway. We suggest a similar mechanism could mediate the cell fate switch of MuSCs in aging Muscle, Skeletal
Interferon-alpha
Academic Dissertation
