Regeneration of Vertebrate Tissues: Model Systems

David L Stocum, Indiana University‐Purdue University, Indianapolis, Indiana, USA

Published online: September 2009

DOI: 10.1002/9780470015902.a0001105.pub3

Vertebrate animals exhibit three mechanisms of tissue regeneration. The most common mechanism is the proliferation and differentiation of adult stem cells, used by epithelia, muscle, bone and blood. Urodele salamanders are able to regenerate complex structures such as limbs by the dedifferentiation of adult cells to mesenchymal stem cell-like cells at the site of amputation. Tissue lost from the vertebrate liver regenerates by compensatory hyperplasia. The mouse pancreas also regenerates by compensatory hyperplasia. The cellular activities in all these mechanisms are regulated by a wide variety of growth factors and hormones. Regenerative medicine aims to use three strategies based on 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 three mechanisms to regenerate: adult stem cells sequestered during tissue development (epithelia, bone, muscle, blood), creation of stem cells by the dedifferentiation of differentiated cells (salamander limb regeneration) and proliferation of cells in their differentiated state (liver, pancreas).
  • Growth factors are important regulators of regeneration.
  • Regenerative medicine uses three strategies to regenerate damaged tissue: 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) may solve many of the problems presented by adult and embryonic stem cells.

Keywords: regeneration; stem cells; growth factors and hormones; dedifferentiation; compensatory hyperplasia; biomaterials

Figure 1. Progenitor cells involved in the regeneration of bone and muscle. (a) Top: To regenerate a fractured bone, osteoprogenitor cells located in the layer of periosteum (p) next to the bone (b) and in the endosteum (e) lining the marrow cavity are activated. The periosteum provides the major fraction of osteoprogenitor cells for regeneration. Bottom: The boxed area of periosteum, showing that it consists of an outer layer of fibroblastic cells (fl) and an inner layer of osteoprogenitor cells (ol). (b) Top: Cross-section of a muscle showing myofibres (mf) and a satellite cell (sc) on the surface of one myofibre. Bottom: A single multinucleate myofibre with three satellite cells on its surface. The satellite cells lie between the myofibre plasma membrane and a basal lamina (bl) that encases the myofibre.
Figure 2. Spinal cord regeneration in a larval salamander. (a) Ependymal cells line the central spinal canal at the distal (Ds) and proximal (Pr) edges of the wound created by removing a segment of cord. Arrows indicate axons going to and from the brain. Many ependymal cells have ‘feet’ that touch the connective tissue covering the cord. d, dorsal and v, ventral. (b) After transection of the cord, the ependymal cells transform into mesenchymal (black) cells, which proliferate to bridge the lesion from distal and proximal edges of the lesion (arrows). (c) The mesenchymal cells transform back into ependymal cells, restoring the ependyma across the lesion. At the same time, severed axons regenerate across the lesion to restore continuity.
Figure 3. Longitudinal sections of a larval salamander limb. Left: 3–4 days after amputation. The extracellular matrix of the dermis (d) and cartilage (c) has broken down, releasing individual cells, and the ends of the cut muscle fibres (m) have broken up into mononucleate cells. The liberated cells dedifferentiate, enter the cell cycle and divide, forming a small blastema at the tip of the amputated limb. In addition, satellite cells of muscle contribute to the blastema; e, epidermis. Right: By 6–7 days after amputation, the blastema has grown to a conical shape by mitosis and further histolysis and dedifferentiation at the junction between blastema and differentiated tissues.
Figure 4. Compensatory hyperplasia in regenerating liver. Left: hepatocytes (h) of intact liver are surrounded by a scant extracellular matrix (stipple). Right: after removal of a portion of the liver, the extracellular matrix dissolves. The cells enter the cell cycle and proliferate while maintaining all phenotypic-specific functions.
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 Further Reading
    book Atala A, Lanza R, Thomson J and Nerem R (eds) (2008) Principles of Regenerative Medicine, 1148 pp. San Diego: Elsevier/Academic Press.
    book Carlson BM (2007) Principles of Regenerative Biology, 379 pp. San Diego: Elsevier/Academic Press.
    Chernoff EAG, Stocum DL, Nye HLD and Cameron JA (2003) Urodele spinal cord regeneration and related processes. Developmental Dynamics 226: 280–294.
    Dor Y, Brown J, Martinez OI and Melton DA (2004) Adult pancreatic -cells are formed by self-duplication rather than stem-cell dedifferentiation. Nature 429: 41–46.
    Geraudie J and Ferretti P (1998) Gene expression during amphibian limb regeneration. International Journal of Cytology 180: 1–50.
    Jaenisch R and Young R (2008) Stem cells, the molecular circuitry of pluripotency and nuclear reprogramming. Cell 132: 567–582.
    Kumar A, Godwin JW, Gates PB, Garza-Garcia A and Brockes JP (2007) Molecular basis for the nerve dependence of limb regeneration in an adult vertebrate. Science 318: 772–777.
    Michalopoulos GK and De Frances MC (1997) Liver regeneration. Science 276: 60–66.
    book Stocum DL (2006) Regenerative Biology and Medicine, 465 pp. San Diego: Elsevier/Academic Press.
    Stocum DL and Zupanc GKH (2008) Stretching the limits: Stem cells in regeneration science. Developmental Dynamics 237: 3648–3671.
    book Stocum DL (2008) "Developmental mechanisms of regeneration". In: Atala A, Lanza R, Thomson J and Nerem R (eds) Principles of Regenerative Medicine, pp. 100–125. San Diego: Elsevier/Academic Press.
    Straube WL and Tanaka EM (2006) Reversibility of the differentiated state: regeneration in amphibians. Artif Organs 30: 743–755.
    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.
    book Yannas IV (2001) Tissue and Organ Regeneration in Adults. New York: Springer.
    Young H and Black AC Jr (2004) Adult stem cells. Anatomical Record 276A: 75–102.
    Yu J, Vodyanik MA, Smuga-Otto K et al. (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318: 1917–1920.

Related Sub-Topics:

Developmental Models | Regeneration: Vertebrates
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Article Title: Regeneration of Vertebrate Tissues: Model Systems
 
How to Cite close
Stocum, David L(Sep 2009) Regeneration of Vertebrate Tissues: Model Systems. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001105.pub3]