Primary cilia on muscle stem cells are critical to maintain regenerative capacity and are lost during aging

Adelaida R. Palla, Keren I. Hilgendorf, Ann V. Yang, Jaclyn P. Kerr, Aaron C. Hinken, Janos Demeter, Peggy Kraft, Nancie A. Mooney, Nora Yucel, David M. Burns, Yu Xin Wang, Peter K. Jackson () and Helen M. Blau ()
Additional contact information
Adelaida R. Palla: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine
Keren I. Hilgendorf: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine
Ann V. Yang: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine
Jaclyn P. Kerr: GlaxoSmithKline Research and Development, Muscle Metabolism Discovery Performance Unit
Aaron C. Hinken: GlaxoSmithKline Research and Development, Muscle Metabolism Discovery Performance Unit
Janos Demeter: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine
Peggy Kraft: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine
Nancie A. Mooney: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine
Nora Yucel: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine
David M. Burns: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine
Yu Xin Wang: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine
Peter K. Jackson: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine
Helen M. Blau: Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract During aging, the regenerative capacity of muscle stem cells (MuSCs) decreases, diminishing the ability of muscle to repair following injury. We found that the ability of MuSCs to regenerate is regulated by the primary cilium, a cellular protrusion that serves as a sensitive sensory organelle. Abolishing MuSC cilia inhibited MuSC proliferation in vitro and severely impaired injury-induced muscle regeneration in vivo. In aged muscle, a cell intrinsic defect in MuSC ciliation was associated with the decrease in regenerative capacity. Exogenous activation of Hedgehog signaling, known to be localized in the primary cilium, promoted MuSC expansion, both in vitro and in vivo. Delivery of the small molecule Smoothened agonist (SAG1.3) to muscles of aged mice restored regenerative capacity leading to increased strength post-injury. These findings provide fresh insights into the signaling dysfunction in aged MuSCs and identify the ciliary Hedgehog signaling pathway as a potential therapeutic target to counter the loss of muscle regenerative capacity which accompanies aging.

Date: 2022
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DOI: 10.1038/s41467-022-29150-6

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