Charge, Sophie B. P., and Michael A. Rudnicki. Cellular and Molecular Regulation of Muscle Regeneration. Physiol Rev 84: 209–238, 2004; 10.1152/physrev.00019.2003.—Under normal circumstances, mamma...

Cellular and Molecular Regulation of Muscle Regeneration

Subsets of mammalian adult stem cells reside in the quiescent state for prolonged periods of time. This state, which is reversible, has long been viewed as dormant and with minimal basal activity. Recent advances in adult stem cell isolation have provided insights into the epigenetic, transcriptional and post-transcriptional control of quiescence and suggest that quiescence is an actively maintained state in which signalling pathways are involved in maintaining a poised state that allows rapid activation. Deciphering the molecular mechanisms regulating adult stem cell quiescence will increase our understanding of tissue regeneration mechanisms and how they are dysregulated in pathological conditions and in ageing.

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Molecular regulation of stem cell quiescence

The ability to regenerate complex structures is widespread in metazoan phylogeny, but among vertebrates the urodele amphibians are exceptional. Adult urodeles can regenerate their limbs by local formation of a mesenchymal growth zone or blastema. The generation of blastemal cells depends not only on the local extracellular environment after amputation or wounding but also on the ability to reenter the cell cycle from the differentiated state. The blastema replaces structures appropriate to its proximodistal position. Axial identity is probably encoded as a graded property that controls cellular growth and movement through local cell interactions. The molecular basis is not understood, but proximodistal identity in newt blastemal cells may be respecified by signaling through a retinoic acid receptor isoform. The possibility of inducing a blastema on a mammalian limb cannot be discounted, although the molecular constraints are becoming clearer as we understand more about the mechanisms of urodele regeneration.

https://science.sciencemag.org/content/sci/276/5309/81.full.pdf

Amphibian Limb Regeneration: Rebuilding a Complex Structure

Dedifferentiation of Mammalian Myotubes Induced by msx1

Why does regeneration occur? And why, when it manifests itself, does it do so in some but not all metazoan species? Hence, what are the permissive or inhibitory factors operating behind this phenomenon? When it comes to regeneration, many questions, such as these, remain unanswered. In fact, the problem of animal regeneration has withstood the probing of scientific inquiry for over 250 years and still awaits a satisfactory mechanistic explanation. In this essay, I will review the distribution and the modes of regeneration that are found in the different metazoan phyla. Also, I will re-examine ideas on its evolutionary origins, and discuss its possible relationship to both asexual reproduction and embryogenesis. This endeavor has two objectives. First, to bring forward an interpretation of regeneration which integrates evolutionary and developmental considerations into its discussion. And second, to suggest a comparative experimental approach to this problem that may bring us closer to understanding the molecular basis of this long-standing biological problem. BioEssays 22:578-590, 2000.

Regeneration in the metazoans: why does it happen?

An amputated limb of an adult urodele amphibian is capable of undergoing regeneration. The new structures form from an undifferentiated mass of cells called the regenerative blastema. The cells of the blastema are believed to derive from differentiated tissues of the adult limb. However, the exact source of these cells and the process by which they undergo dedifferentiation are poorly understood. In order to elucidate the molecular and cellular basis for dedifferentiation we isolated a number of genes which are potential regulators of the process. These include Msx-1, which is believed to support the undifferentiated and proliferative state of cells in the embryonic limb bud; and two members of the myogenic regulatory gene family, MRF-4 and Myf-5, which are expressed in differentiated muscle and regulate muscle-specific gene activity. As anticipated, we find that Msx-1 is strongly up-regulated during the initiation of regeneration. It remains expressed throughout regeneration but is not found in the fully regenerated limb. The myogenic gene MRF-4 has the reverse expression pattern. It is expressed in adult limb muscle, is rapidly shut off in early regenerative blastemas, and is only reexpressed at the completion of regeneration. These kinetics are paralleled by those of a muscle-specific Myosin gene. In contrast Myf-5, a second member of the myogenic gene family, continues to be expressed throughout the regenerative process. Thus, MRF-4 and Myf-5 are likely to play distinct roles during regeneration. MRF-4 may directly regulate muscle phenotype and as such its repression may be a key event in dedifferentiation.(ABSTRACT TRUNCATED AT 250 WORDS)

https://anatomypubs.onlinelibrary.wiley.com/doi/pdf/10.1002/aja.1002020102

Hans‐George ‐G Simon

Papers

Differential expression of myogenic regulatory genes and Msx‐1 during dedifferentiation and redifferentiation of regenerating amphibian limbs