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

Ermelinda Porpiglia; Thach Mai; Peggy Kraft; Colin A Holbrook; Antoine de Morree; Veronica D Gonzalez; Keren I Hilgendorf; Laure Frésard; Angelica Trejo; Sriram Bhimaraju; Peter K Jackson; Wendy J Fantl; Helen M Blau

doi:10.1016/j.stem.2022.10.009

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

Cell Stem Cell. 2022 Dec 1;29(12):1653-1668.e8. doi: 10.1016/j.stem.2022.10.009. Epub 2022 Nov 15.

Authors

Affiliations

¹ Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biomedicine, Aarhus University, Aarhus C 8000, Denmark. Electronic address: [email protected].
² Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Department of Biomedicine, Aarhus University, Aarhus C 8000, Denmark; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ Nolan Laboratory, Department of Pathology, Stanford University, Stanford, CA 94305, USA; Department of Urology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Jackson Laboratory, Baxter Laboratory for Stem Cell Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Department of Pathology, Stanford University, Stanford, CA 94305, USA.
⁷ Nolan Laboratory, Department of Pathology, Stanford University, Stanford, CA 94305, USA.
⁸ Department of Urology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].

Abstract

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 (CD47^hi) with impaired regenerative capacity that predominate with aging. The prevalent CD47^hi MuSC subset suppresses the residual functional CD47^lo 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.

Keywords: CyTOF; U1 snRNA; aging; alternative polyadenylation; antisense morpholino oligonucleotide; in vivo antibody blockade; muscle stem cells; paracrine signaling; regeneration; thrombospondin-1/CD47 signaling.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Aging
Animals
CD47 Antigen*
Disease Progression
Mice
Muscle, Skeletal
Myoblasts*

Substances

CD47 Antigen

Abstract

Publication types

MeSH terms

Substances

Grants and funding