Elevated CD47 is a hallmark of dysfunctional aged muscle stem cells that can be targeted to augment regeneration

• Published in: Cell stem cell 2022-12, Vol.29 (12), p.1653-1668.e8
• Main Authors: Porpiglia, Ermelinda, Mai, Thach, Kraft, Peggy, Holbrook, Colin A., de Morree, Antoine, Gonzalez, Veronica D., Hilgendorf, Keren I., Frésard, Laure, Trejo, Angelica, Bhimaraju, Sriram, Jackson, Peter K., Fantl, Wendy J., Blau, Helen M.
• Format: Article
• Language: English
• Subjects: Aging; alternative polyadenylation; Animals; antisense morpholino oligonucleotide; CD47 Antigen; CyTOF; Disease Progression; in vivo antibody blockade; Mice; muscle stem cells; Muscle, Skeletal; Myoblasts; paracrine signaling; regeneration; thrombospondin-1/CD47 signaling; U1 snRNA
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2022.10.009

In aging, skeletal muscle strength and regenerative capacity decline, due in part to functional impairment of muscle stem cells (MuSCs), yet the underlying mechanisms remain elusive. Here, we capitalize on mass cytometry to identify high CD47 expression as a hallmark of dysfunctional MuSCs (CD47hi) with impaired regenerative capacity that predominate with aging. The prevalent CD47hi MuSC subset suppresses the residual functional CD47lo MuSC subset through a paracrine signaling loop, leading to impaired proliferation. We uncover that elevated CD47 levels on aged MuSCs result from increased U1 snRNA expression, which disrupts alternative polyadenylation. The deficit in aged MuSC function in regeneration can be overcome either by morpholino-mediated blockade of CD47 alternative polyadenylation or antibody blockade of thrombospondin-1/CD47 signaling, leading to improved regeneration in aged mice, with therapeutic implications. Our findings highlight a previously unrecognized age-dependent alteration in CD47 levels and function in MuSCs, which underlies reduced muscle repair in aging. [Display omitted] •Elevated CD47 levels define a dysfunctional aged muscle stem cell (MuSC) subset•U1 snRNA upregulation drives CD47 alternative polyadenylation in aged MuSCs•Thrombospondin-1/CD47 paracrine signaling suppresses aged MuSC proliferation•In vivo thrombospondin-1 blockade restores regeneration and strength in aged muscle Porpiglia and colleagues identify a dysfunctional CD47hi muscle stem cell (MuSC) subset in aged mice, which arises from increased U1 snRNA-driven CD47 alternative polyadenylation. CD47hi MuSCs trigger deleterious thrombospondin-1/CD47 signaling. A thrombospondin-1 antibody or a morpholino to the U1 site on CD47 restores aged MuSC function and muscle regeneration in vivo.