Aging reduces robustness in regulating muscle stem cell fate decision and transition

Cells can be viewed as dynamical systems whose behavior emerges from underlying complex gene regulatory networks and intrinsic heterogeneity. These networks enable robust cellular decision-making, regulating diverse cellular programs in response to various internal and external signals, such as environmental changes, mutations, and tissue damage. Understanding how these regulatory networks coordinate multiple cellular programs while maintaining system stability remains a central question in systems biology.

Tissue homeostasis exemplifies this principle: a small pool of adult stem cells remains largely quiescent, upon injury becomes activated to proliferate, differentiate, and restore tissue integrity while preserving the stem cell reservoir. In the skeletal muscle, muscle stem cells (MuSCs) maintain this balance. However, this regenerative process declines with age, indicating the loss of robustness of the systems.

Here, we combine a bottom-up dynamical systems modeling with whole-cell models built upon genome-wide single-cell transcriptomics to dissect the regulatory mechanisms controlling the MuSC proliferation and differentiation. Mechanistic modeling of the core molecular regulators reveals the reasons for age-related dysregulations in MuSCs, while genome-wide analysis offers an unbiased view of global state transitions. Our integrated approach reveals two commitment pathways: (1) a canonical pathway involving activation, proliferation, and subsequent differentiation, and (2) a direct pathway towards differentiation from either a quiescent or activated state. The direct path becomes increasingly prominent in aged conditions, leading to the loss of robustness in cell fate choice. Our findings also highlight the design principles that guide the regulatory network in coordinating self-renewal, differentiation, and the selection of transition paths. Furthermore, the combined approach offers quantitative strategies to influence fate commitment and restore regenerative balance during the aging process.