Salamander limb regeneration involves the activation of a multipotent skeletal muscle satellite cell population

TLDR

Salamanders regenerate complex structures such as limbs by forming a blastema after dedifferentiation of stump tissues like skeletal muscle, though it was unclear whether this dedifferentiation activates stem cells. The study investigates whether limb regeneration and mammalian tissue repair share mechanisms by identifying a multipotent Pax7⁺ satellite cell population in salamander skeletal muscle that activates during dedifferentiation to contribute to new limb tissues. The authors demonstrate that dedifferentiation of salamander skeletal muscle activates satellite cells, which then contribute to the formation of new limb tissues. Activation of salamander satellite cells parallels mammalian myofiber stem‑cell mobilization, revealing shared cellular and molecular programs and positioning satellite cells as potential targets for promoting mammalian blastema formation.

Abstract

In contrast to mammals, salamanders can regenerate complex structures after injury, including entire limbs. A central question is whether the generation of progenitor cells during limb regeneration and mammalian tissue repair occur via separate or overlapping mechanisms. Limb regeneration depends on the formation of a blastema, from which the new appendage develops. Dedifferentiation of stump tissues, such as skeletal muscle, precedes blastema formation, but it was not known whether dedifferentiation involves stem cell activation. We describe a multipotent Pax7+ satellite cell population located within the skeletal muscle of the salamander limb. We demonstrate that skeletal muscle dedifferentiation involves satellite cell activation and that these cells can contribute to new limb tissues. Activation of salamander satellite cells occurs in an analogous manner to how the mammalian myofiber mobilizes stem cells during skeletal muscle tissue repair. Thus, limb regeneration and mammalian tissue repair share common cellular and molecular programs. Our findings also identify satellite cells as potential targets in promoting mammalian blastema formation.