Abstract
The ability to repeatedly regenerate limbs during the entire lifespan of an animal is restricted to certain salamander species among vertebrates. This ability involves dedifferentiation of post-mitotic cells into progenitors that in turn form new structures. A long-term enigma has been how injury leads to dedifferentiation. Here we show that skeletal muscle dedifferentiation during newt limb regeneration depends on a programmed cell death response by myofibres. We find that programmed cell death-induced muscle fragmentation produces a population of ‘undead' intermediate cells, which have the capacity to resume proliferation and contribute to muscle regeneration. We demonstrate the derivation of proliferating progeny from differentiated, multinucleated muscle cells by first inducing and subsequently intercepting a programmed cell death response. We conclude that cell survival may be manifested by the production of a dedifferentiated cell with broader potential and that the diversion of a programmed cell death response is an instrument to achieve dedifferentiation.
Highlights
The ability to repeatedly regenerate limbs during the entire lifespan of an animal is restricted to certain salamander species among vertebrates
We find that the multinucleateto-mononucleate fragmentation is dependent on caspase activity, but the mononucleate cells formed re-enter the cell cycle only if the complete execution of programmed cell death (PCD) is prevented
The small molecule, myoseverin, has been shown to cause the reversion of the mononucleate-to-multinucleate transition leading to myotube fragmentation[7]; rigorous live imaging studies showed that the mononucleate cells derived from myotubes never resumed proliferation[8]
Summary
The ability to repeatedly regenerate limbs during the entire lifespan of an animal is restricted to certain salamander species among vertebrates This ability involves dedifferentiation of post-mitotic cells into progenitors that in turn form new structures. We show that skeletal muscle dedifferentiation during newt limb regeneration depends on a programmed cell death response by myofibres. We demonstrate the derivation of proliferating progeny from differentiated, multinucleated muscle cells by first inducing and subsequently intercepting a programmed cell death response. Blastema formation in newts involves dedifferentiation of myofibres, by which process the multinucleated myofibres fragment into mononucleate cells that in turn downregulate muscle differentiation markers, re-enter the cell cycle and subsequently redifferentiate into myofibres[3]. Muscle differentiation can be achieved in tissue culture from proliferating, mononucleate myogenic precursor cells by withdrawal of serum growth factors. Other studies indicated that experimentally induced fragmentation of myotubes might lead to proliferating mononucleate cells; these studies were typically lacking appropriate lineage-tracing strategies, leaving open the possibility that proliferating cells were derived from pre-existing mononucleate cells in the culture dish[9,10,11,12]
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