Regeneration of Vertebrate Tissues: Model Systems


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.


Conboy IM, Conboy MJ, Wagers AJ, et al. (2005) Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433: 760–764.

Diep CQ, Ma D, Deo RC, et al. (2011) Identification of adult nephron progenitors capable of kidney regeneration in zebrafish. Nature 470: 95–100.

Dor Y, Brown J, Martinez OI and Melton DA (2004) Adult pancreatic β‐cells are formed by self‐duplication rather than stem‐cell dedifferentiation. Nature 429: 41–46.

Drenckhan JD, Schwarz QP, Gray S, et al. (2008) Compensatory growth of healthy cardiac cells in the presence of diseased cells restores tissue homeostasis during heart development. Developmental Cell 15: 521–533.

Eguchi G, Eguchi Y, Nakamura K, et al. (2011) Regenerative capacity in newts is not altered by repeated regeneration and aging. Nature Communications 384. DOI: 10.1038/ncomms1389.

Godwin JW, Liem KF Jr and Brockes JP (2010) Tissue factor expression in newt iris coincides with thrombin activation and lens regeneration. Mechanisms of Development 127: 321–328.

Gonzalez‐Rosa JM, Martin V, Torres M and Mercader N (2011) Extensive scar formation and regression during heart regeneration after cryoinjury in zebrafish. Development 138: 1663–1674.

Hall SS (2014) Young blood. Science 345: 1234–1237.

Hayashi T, Mizuno N, Takada R, et al. (2008) Determinative roles of FGF and Wnt signals in iris‐derived lens regeneration in newt eye. Mechanisms of Development 123: 793–800.

Jarraya B, Boulet S, Ralph GS, et al. (2009) Dopamine gene therapy for Parkinson's disease in a nonhuman primate without associated dyskinesia. Science Translational Medicine 1: 2ra4.

Jopling C, Sleeo E, Raya M, et al. (2010) Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464: 606–609.

Kikuchi K, Holdway JE, Werdich AA, et al. (2010) Primary contribution to zebrafish heart regeneration by gata4 cardiomyocytes. Nature 464: 601–605.

LeWitt PA, Rezai AR, Leehy MA, et al. (2011) AAV2‐GAD gene therapy for advanced Parkinson's disease: a double‐blind, sham‐surgery controlled, randomized trial. Lancet Neurology 10: 309–319.

Macchiarini P, Jungebluth P, Go T, et al. (2008) Clinical transplantation of a tissue engineered airway. Lancet 372: 2023–2030.

Michalopoulos GK and De Frances MC (1997) Liver regeneration. Science 276: 60–66.

Pagliuca FW, Millman JR, Gurtier M, et al. (2014) Generation of functional human pancreatic b cells in vitro. Cell 159: 428–439.

Porrello ER, Mahmoud AL, Simpson E, et al. (2011) Transient regenerative potential of the neonatal mouse heart. Science 331: 1078–1080.

Sagriniti C, Netti GS, Mazzinghi B, et al. (2006) Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys. Journal of the American Society of Nephrology 17: 2443–2456.

Sambasivan R, Yao R, Kissenpfennig A, et al. (2011) Pax‐7 expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development 138: 3647–3656.

Takahashi K, Tanabe K, Ohnuki M, et al. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131: 861–872.

Villeda SA, Luo J, Mosher KI, et al. (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477: 90–94.

Yu J, Vodyanik MA, Smuga‐Otto K, et al. (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 1917–1920.

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.

Carlson BM (2007) Principles of Regenerative Biology, 379 pp. San Diego, CA: Elsevier/Academic Press.

Fu SY and Gordon T (1997) The cellular and molecular basis of peripheral nerve regeneration. Molecular Neurobiology 14: 67–116.

Jaenisch R and Young R (2008) Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132: 567–582.

Lanza R and Atala A (eds) (2013) Handbook of Stem Cells, 2nd edn, Vols I and II. San Diego, CA: Elsevier/Academic Press.

Morrison SJ and Spradling AC (2008) Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132: 598–611.

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.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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