Format

Send to

Choose Destination
Dev Cell. 2017 Mar 27;40(6):608-617.e6. doi: 10.1016/j.devcel.2017.03.002.

Serum Proteases Potentiate BMP-Induced Cell Cycle Re-entry of Dedifferentiating Muscle Cells during Newt Limb Regeneration.

Author information

1
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany; DFG Research Center for Regenerative Therapies, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
2
Department of Cell and Molecular Biology, Centre of Developmental Biology for Regenerative Medicine, Karolinska Institute, Berzelius väg 35, 17177 Stockholm, Sweden.
3
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
4
DFG Research Center for Regenerative Therapies, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany.
5
Department of Cell and Molecular Biology, Centre of Developmental Biology for Regenerative Medicine, Karolinska Institute, Berzelius väg 35, 17177 Stockholm, Sweden. Electronic address: andras.simon@ki.se.
6
Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany. Electronic address: david.drechsel@imp.ac.at.
7
DFG Research Center for Regenerative Therapies, Technische Universität Dresden, Fetscherstrasse 105, 01307 Dresden, Germany. Electronic address: elly.tanaka@imp.ac.at.

Abstract

Limb amputation in the newt induces myofibers to dedifferentiate and re-enter the cell cycle to generate proliferative myogenic precursors in the regeneration blastema. Here we show that bone morphogenetic proteins (BMPs) and mature BMPs that have been further cleaved by serum proteases induce cell cycle entry by dedifferentiating newt muscle cells. Protease-activated BMP4/7 heterodimers that are present in serum strongly induced myotube cell cycle re-entry with protease cleavage yielding a 30-fold potency increase of BMP4/7 compared with canonical BMP4/7. Inhibition of BMP signaling via muscle-specific dominant-negative receptor expression reduced cell cycle entry in vitro and in vivo. In vivo inhibition of serine protease activity depressed cell cycle re-entry, which in turn was rescued by cleaved-mimic BMP. This work identifies a mechanism of BMP activation that generates blastema cells from differentiated muscle.

KEYWORDS:

BMP (bone morphogenetic protein); cell cycle re-entry; dedifferentiation; limb regeneration; muscle; plasmin; salamander; thrombin

PMID:
28350991
DOI:
10.1016/j.devcel.2017.03.002
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center