Regeneration of Vertebrate Tissues: Model Systems

Abstract

Vertebrate animals exhibit four mechanisms of tissue regeneration: re‐growth of cellular parts, such as nerve axons; lineage‐specific proliferation of differentiated cells with or without dedifferentiation; transdifferentiation and activation of adult stem cells. The most common mechanism is the proliferation and differentiation of adult stem cells, used by epithelia, muscle, bone and blood. In some cases, such as the liver and pancreas, regeneration is accomplished by either lineage‐specific proliferation of differentiated cells or a stem cell population, depending on the nature of the damage. All four mechanisms are used by urodele salamanders in the regeneration of limbs. The cellular activities in all these mechanisms are regulated by a wide variety of growth factor signalling pathways and transcription factors. Regenerative medicine uses three major strategies based on knowledge of regenerative mechanisms: transplants of stem cells or their derivatives, construction of bioartificial tissues composed of natural or synthetic biomaterials seeded with cells and the pharmaceutical induction of regeneration at the site of injury by natural or synthetic regeneration‐promoting molecules.

Key Concepts

  • Regeneration restores the original structure and function of damaged or missing tissues.
  • Tissues use four mechanisms to regenerate: re‐growth of cell parts, lineage‐specific reproduction of parent cells, transdifferentiation and activation of adult stem cells.
  • Some tissues use more than one mechanism of regeneration.
  • Growth factor signals and transcription factors are important regulators of regeneration.
  • Regenerative medicine uses three strategies to regenerate damaged tissues: cell transplants, bioartificial tissue implants and pharmaceutical induction of regeneration directly at the site of damage by scaffolds or soluble molecules.
  • The source of cells for transplants and bioartificial tissues is a crucial issue for regenerative medicine.
  • Induced pluripotent stem cells (iPSCs) and/or transdifferentiation may solve many of the problems presented by adult and embryonic stem cells.

Keywords: regeneration; regenerative medicine; stem cells; growth factors; dedifferentiation; compensatory hyperplasia; transdifferentiation; biomaterials

Figure 1. The four mechanisms of regeneration. (a) Cellular re‐growth. MN = motor neuron; AX = axon; M = muscle. The vertical green line indicates the level of transection and the arrow indicates regeneration of the axon to its target muscle. (b) Lineage‐specific regeneration from differentiated parent cells by compensatory hyperplasia (CH) or dedifferentiation/redifferentiation (D/R). Compensatory hyperplasia is the proliferation of cells while maintaining their differentiated structure and function. Dedifferentiation/redifferentiation involves dedifferentiation (D) of the cell to a progenitor state, followed by proliferation (P) and redifferentiation (R) into the parent cell type. (c) Transdifferentiation is the conversion of one cell type to another. Direct transdifferentiation (T, upper arrow) involves a switch in gene activity without going through an intermediate state. Indirect transdifferentiation (lower part of diagram) involves dedifferentiation (D) of the cell to a plastic intermediate state, followed by transdifferentiation (T). (d) Adult stem cell activation. Adult stem cells (ASCs) divide asymmetrically to self‐renew (SR) and produce a lineage‐committed progenitor (LC). The progenitor proliferates (P) and then differentiates (D).
Figure 2. Transdifferentiation of pigmented dorsal iris cells into lens cells after lentectomy in the newt. Tissue factor is selectively produced by non‐endothelial cells by injured vessels of the dorsal iris, leading to thrombin activation and clot formation (red). Macrophages attracted to the clot release PDGF and TGF‐β3 that induce the dorsal pigmented iris cells to produce FGF‐2 and its receptor at higher levels dorsally (+3 vs +1), which in turn leads to a higher level of Wnt signalling through its receptor. The result is the dedifferentiation and proliferation of these cells to form a lens vesicle (green circle).
Figure 3. Strategies of regenerative medicine. (a) Cell transplantation. The example is bone marrow cells (yellow) injected into a region of myocardial infarct of the heart. (b) Bioartificial tissue construction. A matrix (blue) is seeded with cells (yellow). (c) Pharmaceutical induction of regeneration. Growth factors or transcription factors, or their genes (black dots), are injected into a damaged organ such as the heart. The growth factors act as anti‐scarring and cell survival agents. Transcription factors could be used to transdifferentiate cardiac fibroblasts to cardiomyocytes.
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Further Reading

Atala A, Lanza R, Thomson J and Nerem R (eds) (2011) Principles of Regenerative Medicine, 2nd, 1148 pp edn. San Diego, CA: Elsevier/Academic Press.

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Sell S (ed) (2013) Stem Cells Handbook. New York, NY: Humana Press/Springer.

Stocum DL (2012) Regenerative Biology and Medicine, 2nd, 465 pp edn. San Diego, CA: Elsevier/Academic Press.

Stocum DL and Zupanc GKH (2008) Stretching the limits: stem cells in regeneration science. Developmental Dynamics 237: 3648–3671.

Yannas IV (2001) Tissue and Organ Regeneration in Adults. New York, NY: Springer.

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Stocum, David L(Mar 2015) Regeneration of Vertebrate Tissues: Model Systems. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001105.pub4]