Single-Cell Analysis of Muscle Stem Cell Heterogeneity in Tissue Regeneration

Abstract

Skeletal muscle is an essential organ that supports many vital functions. Within skeletal muscle, a resident population of stem cells called Muscle Stem Cells (MuSCs) is responsible to coordinate muscle repair after injuries. Muscle tissue regeneration by MuSCs is temporally regulated at the cellular and tissue levels by stem cell differentiation and cell-communication programs. In this thesis, I use single-cell RNA-sequencing technology to map the transcriptome of the cell populations that compose muscle tissue and provide a new description of MuSC differentiation programs in homeostasis and in regeneration. By generating so-called “transcriptomic atlases”, I explore the cellular heterogeneity within myogenic differentiation and formulate new hypotheses on cell-interactions that direct muscle repair. Specifically, I first present a single-cell analysis of the mouse regenerating muscle tissue where, by ligand-receptor bioinformatic modeling, I identify new heterotypic communication channels signals involved in muscle repair. Second, I present a single-cell transcriptomic atlas of human donor muscle tissue where I describe the effect of ageing and disease on MuSCs. These studies also highlight differences between mouse and human muscle. Although mouse and human MuSCs share similar transcriptomic profiles, there are notable differences in surface proteins that are commonly used to mark those cells. Human MuSCs also appear more heterogenous and exist in two distinct subpopulations. Together, these two single-cell transcriptomic atlases provide reference resources to examine the role of muscle-tissue cellular diversity and communication in regeneration, aging, disease, and across species.