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Advances in understanding tissue regenerative capacity and mechanisms in animals

Key Points

  • There is much to learn regarding how and why tissue regeneration occurs. A synthesis of efforts using different model systems and maturing tools will unite strengths and perspectives towards this goal.

  • Regenerative capacity is a complex trait dependent on the ability to access high-fidelity morphogenetic programmes after injury. It is distributed unequally among species and, within individuals, among their tissues.

  • Mammalian regenerative capacity is influenced by developmental stage, and is usually greater prenatally than postnatally. Ageing adult mammals display reduced regenerative capacity in tissues like liver, blood, pancreas and skeletal muscle compared with younger cohorts.

  • Source tissue for regeneration is commonly derived from the activity of undifferentiated stem or progenitor cells, or by dedifferentiation or transdifferentiation from differentiated cells. Regenerative sources and mechanisms differ by tissue type and injury type.

  • Mechanisms acting locally often initiate growth from regenerative sources. For example, the epithelial cover of an injury can mature into a paracrine stimulator of regenerative growth, or stressed or dying cells can release signals that stimulate their replacement by the activity of progenitor cells.

  • Signals operating from areas away from an injury or systemically as circulating factors can also influence the initiation and targeting of tissue regeneration.

  • Positional memory is the process by which adult cells spared from injury maintain information necessary to replace structures of the correct size and shape. It is likely that this property is contributed to by the maintenance of developmental patterning factors in adult tissues.

Abstract

Questions about how and why tissue regeneration occurs have captured the attention of countless biologists, biomedical engineers and clinicians. Regenerative capacity differs greatly across organs and organisms, and a range of model systems that use different regenerative strategies and that offer different technical advantages have been studied to understand regeneration. Making use of this range of systems and approaches, recent advances have allowed progress to be made in understanding several key issues that are common to natural regenerative events. These issues include: the determination of regenerative capacity; the importance of stem cells, dedifferentiation and transdifferentiation; how regenerative signals are initiated and targeted; and the mechanisms that control regenerative proliferation and patterning.

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Figure 1: Injured tissues retain lineages during axolotl limb regeneration.
Figure 2: Signals initiating regeneration.
Figure 3: Models of positional memory in invertebrates and vertebrates.

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Acknowledgements

I thank the Howard Hughes Medical Institute, National Institute of General Medical Sciences, National Heart, Lung and Blood Institute, American Heart Association, American Federation for Aging Research, Pew Charitable Trusts and Whitehead Foundation for funding my laboratory's research on regeneration. I apologize to colleagues in the field if discussion or depth was omitted due to space constraints.

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Glossary

Regeneration

The replacement of lost body parts, restoring mass and function. Homeostatic regeneration refers to the natural replacement of cells lost in day-to-day minor damage, cell death, and ageing. Injury-induced or facultative regeneration refers to tissue replacement after substantial trauma like amputation or ablation.

Blastema

A mass of proliferative mesenchymal cells that accumulates in certain tissues after severe trauma, ultimately morphing into the lost structures.

Lineage tracing

Methods used to tag cells and their progeny with irreversible markers, allowing a retrospective or real-time view of cell decisions. One popular method is based on experimentally induced recombination events that cause expression of an inert enzyme or fluorescent protein through the localized expression of a recombinase to a specific cell type.

Progenitor cell

Broadly defined as a precursor to a mature cell type that is present in functioning tissue. Progenitors often express a programme indicative of partial or full commitment to a cell lineage, but lack a molecular profile representative of fully differentiated cells.

Dedifferentiation

Broadly defined as a developmental event involving reduction in the molecular and/or functional properties of a differentiated cell type; for example, changes in gene programmes that convert a normally non-proliferative cell to a proliferative cell. Experimental reprogramming of fibroblasts or liver cells to generate induced pluripotent stem cells is a form of dedifferentiation.

Positional memory

In regeneration, this refers to the molecular programmes that maintain cell type-specific information, region-specific information and developmental competency to respond to injury signals by appropriate proliferation and integration of cells into new structures.

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Poss, K. Advances in understanding tissue regenerative capacity and mechanisms in animals. Nat Rev Genet 11, 710–722 (2010). https://doi.org/10.1038/nrg2879

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