Project description
Studying immune signals and muscle ageing
Ageing leads to the decline of tissue renewal and repair, partly due to impaired stem cell (SC) function. Changes in the immune environment are emerging as key contributors to this decline, yet their impact on SC dysfunction remains unclear. With this in mind, the ERC-funded immSC-AgingFate project is exploring how immune alterations contribute to age-related muscle stem cell (MuSC) dysfunction. By studying the immune signals affecting MuSC plasticity and lineage commitment, the team aims to uncover how these changes lead to impaired muscle regeneration. This research will also investigate the underlying epigenetic changes and potential transcriptional regulators of MuSC fate, with the ultimate goal of improving MuSC-based therapies for age-related muscle disorders.
Objective
Adult stem cells (SCs) sustain tissue renewal and repair throughout life. The SC niche is fundamental in the regulation of SC function and an important contributor to SC decline in aging. While alterations in the tissue’s immune environment are emerging as important contributors to impairments found in aged organs, their contribution to SC dysfunction in aging is unknown.
The skeletal muscle (SkM) is a paradigmatic model to study age-related loss of repair capacity. Muscle stem cell (MuSC) function during regeneration requires plasticity in transit between states of quiescence, activation and differentiation. MuSC functional impairments in aging result from changes in the extrinsic cues that govern their behavior, but also cell intrinsic alterations, including senescence and defects in lineage commitment. However, we still have a limited understanding of how changes in the environment manifest as SC intrinsic defects.
Our previous work indicates that changes in immune signaling are important drivers of MuSC dysfunction and regenerative decline in aging. Here, we propose to identify the contribution of specific immune populations and signals to changes in regenerative capacity and MuSC activity in aging (Aim 1). We hypothesize that the immune environment is an essential regulator of MuSC plasticity and lineage commitment under regenerative pressure, and immune alterations underlie defects in MuSC lineage fidelity in aging. We propose to map the trajectories of MuSCs diverging from the myogenic lineage and uncover the changes in epigenetic landscape that underlie the loss of lineage fidelity associated with immune aging, identifying transcriptional regulators of MuSC fate (Aim 2). The knowledge generated on the mechanisms linking immune aging and MuSC dysfunction will be tested for the conservation in human SkM and will be applied to improve the success of MuSC-based therapies in aging (Aim 3).
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC - HORIZON ERC GrantsHost institution
1649-035 LISBOA
Portugal