Cutting Edge

Through the lens of CyTOF: resolving signatures of muscle stem cell aging one cell at the time

Affiliation
Aarhus University, Department of Biomedicine, Aarhus, 8000, Denmark
Baxter Laboratory for Stem Cell Biology,
Stanford University School of Medicine; Stanford, USA

Abstract
Skeletal muscle mass, strength and regenerative capacity progressively decline with aging. This is partly due to functional impairment of muscle stem cells (MuSCs), the key players in muscle regeneration. However, the mechanisms responsible for ageassociated MuSC dysfunction remain elusive. A major barrier to gaining mechanistic insights into MuSC aging is the increased functional heterogeneity of the aged MuSC population, underscoring the need for single-cell studies. Here we capitalized on singlecell mass cytometry to resolve MuSC heterogeneity during aging and identified a dysfunctional MuSC subset, marked by high CD47 surface expression (CD47hi). Mechanistically, increased expression of U1 snRNA in aged MuSCs shifted the balance of CD47 mRNA isoforms, leading to increased levels of CD47 protein on the cell surface.Aged CD47hi MuSCs act via paracrine signaling, through secretion of thrombospondin-1,<a ligand for CD47, to suppress the regenerative capacity of CD47lo MuSCs. Strikingly, in vivo thrombospondin-1 blockade restored the proliferative potential of aged MuSCs and enhanced muscle regeneration and strength in aged mice. These findings uncover an unexpected role for thrombospondin-1/CD47 signaling in aged MuSCs and suggest a novel therapeutic approach to improve muscle regenerative function in the elderly.

Biosketch
Dr. Ermelinda Porpiglia is a tenure-track Assistant Professor at Aarhus University, Denmark, and an Associate Fellow at the Aarhus Institute of Advanced Studies (AIAS). Her research interest is to understand how aging impairs tissue regeneration. During her postdoctoral training at Stanford University, she pioneered the application of single-cell mass cytometry (CyTOF) to skeletal muscle, to identify rare stem cell populations that accumulate during aging and understand howthey affect muscle regeneration.Her laboratory at Aarhus University, employs novel single-cell technologies, such as single-cell masscytometry (CyTOF) and imaging mass cytometry, to map stem cell niche dynamics at single cell resolution and study the relationships between muscle stem cells and immune cells in skeletal muscle, in the context of aging and muscle diseases. Her long-term research goal is to develop therapeutic strategies to modulate the immune system in order to boost muscle tissue repair. Dr. Porpiglia’s research has been published in top scientific journals, including Nature Medicine, Nature Cell Biology and Cell Stem Cell. She holds a BS/MS degree in Medical Biotechnology from the University of Bologna Medical School, Italy, and a Ph.D. in Biomedical Sciences from the University of Massachusetts Medical School, USA. Dr. Porpiglia completed her postdoctoral training in the Blau lab at Stanford University, where she established a long-standing collaboration with the Nolan lab.