Chapter Four - Control of Growth During Regeneration

https://doi.org/10.1016/B978-0-12-391498-9.00003-6Get rights and content

Abstract

Regeneration is a process by which organisms replace damaged or amputated organs to restore normal body parts. Regeneration of many tissues or organs requires proliferation of stem cells or stem cell-like blastema cells. This regenerative growth is often initiated by cell death pathways induced by damage. The executors of regenerative growth are a group of growth-promoting signaling pathways, including JAK/STAT, EGFR, Hippo/YAP, and Wnt/β-catenin. These pathways are also essential to developmental growth, but in regeneration, they are activated in distinct ways and often at higher strengths, under the regulation by certain stress-responsive signaling pathways, including JNK signaling. Growth suppressors are important in termination of regeneration to prevent unlimited growth and also contribute to the loss of regenerative capacity in nonregenerative organs. Here, we review cellular and molecular growth regulation mechanisms induced by organ damage in several models with different regenerative capacities.

Section snippets

Cells Participating in Regenerative Growth

A crucial question in epimorphic regeneration is the origin of the cells that participate in regenerative growth. In most cases, robust proliferation is local rather than systemic, and progenitor cells that concentrate around wound sites and are responsible for producing cells needed for regrowth form what is referred to as a blastema. In different systems, blastema cells can come from stem cells residing in injured tissues, differentiated cells that undergo dedifferentiation, or parenchymal

Recognizing Tissue Damage to Initiate Regeneration

When tissues are damaged, the injured cells often undergo apoptosis. Studies in many organisms, including Hydra, Drosophila, and mouse, have established that apoptosis is not only a way to remove damaged cells, but also an important trigger stimulating the proliferation of nearby healthy cells.

After mid-gastric bisection of Hydra, each half regenerates a complete Hydra body. Hydra regeneration is considered to be morphallactic (Park, Ortmeyer, & Blankenbaker, 1970). Nonetheless, proliferation

Regenerative Growth is Controlled by Signaling Networks

After damage is recognized, injury signals need to be translated to proliferating signals to guide the replacement of damaged parts with new tissue. One pathway involved in this link is c-Jun N-terminal kinase (JNK). JNK belongs to the mitogen-activated protein kinase (MAPK) family and is activated by diverse cellular stresses, including wounding, oxidative stress, loss of cell polarity, infection, and apoptosis. It regulates many biological processes including apoptosis, proliferation,

Control of Regenerative Growth by Organ Patterning

The regulation of cell proliferation induced during epimorphic regeneration must be precisely controlled such that neither too little nor too much new tissue is produced. Studies of intercalary regeneration within insect limbs were particularly influential in promoting the hypothesis that growth is influenced by a gradient of positional information (Day and Lawrence, 2000, French et al., 1976, Haynie and Bryant, 1976). According to this hypothesis, during developmental or regenerative growth,

Suppression of Regenerative Growth

As in developmental growth, growth inhibitors also exist in regenerative growth to prevent overgrowth. As regeneration proceeds, the proliferation rate decreases and redifferentiation occurs. This involves the downregulation of progrowth signals and upregulation of antigrowth signals. Growth inhibitors need to be downregulated during the initiation of regeneration, and then activated at the correct time to prevent tissue overgrowth and to allow differentiation to occur. Many studies on

Conclusion

Tissues under homeostasis balance progrowth signals with antigrowth signals. When injury occurs, this balance is rapidly disrupted, and through stress-response mechanisms, the progrowth signals become predominant. The duration and level of elevation of progrowth signals help determine the extent of regenerative growth. In regeneration-competent organs, progrowth signals are prolonged and augmented through collaboration of multiple pathways, including Wnt, BMP, EGFR, JAK-STAT, and Hippo, which

Acknowledgments

Research on regeneration in KDI's lab is supported by Human Frontiers Science Program Grant RGP0016/2010 and the Howard Hughes Medical Institute.

References (117)

  • J.R. Huh et al.

    Compensatory proliferation induced by cell death in the Drosophila wing disc requires activity of the apical cell death caspase Dronc in a nonapoptotic role

    Current Biology

    (2004)
  • H. Jiang et al.

    Intestinal stem cells in the adult Drosophila midgut

    Experimental Cell Research

    (2011)
  • H. Jiang et al.

    EGFR/Ras/MAPK signaling mediates adult midgut epithelial homeostasis and regeneration in Drosophila

    Cell Stem Cell

    (2011)
  • H. Jiang et al.

    Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut

    Cell

    (2009)
  • S. Kiso et al.

    Liver regeneration in heparin-binding EGF-like growth factor transgenic mice after partial hepatectomy

    Gastroenterology

    (2003)
  • W. Li et al.

    STAT3 contributes to the mitogenic response of hepatocytes during liver regeneration

    The Journal of Biological Chemistry

    (2002)
  • Y. Liu et al.

    Structural and functional characterization of the mouse hepatocyte growth factor gene promoter

    The Journal of Biological Chemistry

    (1994)
  • B. Liu et al.

    Investigation of the role of glypican 3 in liver regeneration and hepatocyte proliferation

    The American Journal of Pathology

    (2009)
  • C. Mitchell et al.

    Heparin-binding epidermal growth factor-like growth factor links hepatocyte priming with cell cycle progression during liver regeneration

    The Journal of Biological Chemistry

    (2005)
  • E. Moreno et al.

    Evolution of TNF signaling mechanisms: JNK-dependent apoptosis triggered by Eiger, the Drosophila homolog of the TNF superfamily

    Current Biology

    (2002)
  • A. Page-McCaw

    Remodeling the model organism: Matrix metalloproteinase functions in invertebrates

    Seminars in Cell & Developmental Biology

    (2008)
  • P.S. Pahlavan et al.

    Prometheus' challenge: Molecular, cellular and systemic aspects of liver regeneration

    The Journal of Surgical Research

    (2006)
  • S. Paranjpe et al.

    RNA interference against hepatic epidermal growth factor receptor has suppressive effects on liver regeneration in rats

    The American Journal of Pathology

    (2010)
  • D. Rogulja et al.

    Morphogen control of wing growth through the Fat signaling pathway

    Developmental Cell

    (2008)
  • H.D. Ryoo et al.

    Apoptotic cells can induce compensatory cell proliferation through the JNK and the Wingless signaling pathways

    Developmental Cell

    (2004)
  • K. Sabapathy et al.

    Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation

    Molecular Cell

    (2004)
  • A. Satoh et al.

    Nerve-induced ectopic limb blastemas in the Axolotl are equivalent to amputation-induced blastemas

    Developmental Biology

    (2007)
  • R.F. Schwabe et al.

    c-Jun-N-terminal kinase drives cyclin D1 expression and proliferation during liver regeneration

    Hepatology

    (2003)
  • M. Shah et al.

    Control of scarring in adult wounds by neutralising antibody to transforming growth factor beta

    Lancet

    (1992)
  • R.K. Smith-Bolton et al.

    Regenerative growth in Drosophila imaginal discs is regulated by Wingless and Myc

    Developmental Cell

    (2009)
  • B.K. Staley et al.

    Warts and Yorkie mediate intestinal regeneration by influencing stem cell proliferation

    Current Biology

    (2010)
  • G. Sun et al.

    Regulation of Hippo signaling by Jun kinase signaling during compensatory cell proliferation and regeneration, and in neoplastic tumors

    Developmental Biology

    (2011)
  • E.M. Tanaka et al.

    The cellular basis for animal regeneration

    Developmental Cell

    (2011)
  • V. Vinarsky et al.

    Normal newt limb regeneration requires matrix metalloproteinase function

    Developmental Biology

    (2005)
  • P. Akerman et al.

    Antibodies to tumor necrosis factor-alpha inhibit liver regeneration after partial hepatectomy

    The American Journal of Physiology

    (1992)
  • U. Apte et al.

    Enhanced liver regeneration following changes induced by hepatocyte-specific genetic ablation of integrin-linked kinase

    Hepatology

    (2009)
  • T. Bando et al.

    Regulation of leg size and shape by the Dachsous/Fat signalling pathway during regeneration

    Development

    (2009)
  • A. Behrens et al.

    Impaired postnatal hepatocyte proliferation and liver regeneration in mice lacking c-jun in the liver

    The EMBO Journal

    (2002)
  • C. Bergantinos et al.

    Cell death-induced regeneration in wing imaginal discs requires JNK signalling

    Development

    (2010)
  • C. Bergantinos et al.

    Imaginal discs: Renaissance of a model for regenerative biology

    BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology

    (2010)
  • G.D. Block et al.

    Population expansion, clonal growth, and specific differentiation patterns in primary cultures of hepatocytes induced by HGF/SF, EGF and TGF alpha in a chemically defined (HGM) medium

    The Journal of Cell Biology

    (1996)
  • F. Bohm et al.

    Regulation of liver regeneration by growth factors and cytokines

    EMBO Molecular Medicine

    (2010)
  • M. Bosch et al.

    Origin and proliferation of blastema cells during regeneration of Drosophila wing imaginal discs

    The International Journal of Developmental Biology

    (2008)
  • J.P. Brockes et al.

    Comparative aspects of animal regeneration

    Annual Review of Cell and Developmental Biology

    (2008)
  • L.J. Campbell et al.

    Wound epidermis formation and function in urodele amphibian limb regeneration

    Cellular and Molecular Life Sciences

    (2008)
  • M.E. Carinato et al.

    Xenopus laevis gelatinase B (Xmmp-9): Development, regeneration, and wound healing

    Developmental Dynamics : An Official Publication of the American Association of Anatomists

    (2000)
  • B.M. Carlson

    Some principles of regeneration in mammalian systems

    Anatomical Record. Part B: New Anatomist

    (2005)
  • F. Chen

    JNK-induced apoptosis, compensatory growth, and cancer stem cells

    Cancer Research

    (2012)
  • S. Chera et al.

    Injury-induced activation of the MAPK/CREB pathway triggers apoptosis-induced compensatory proliferation in hydra head regeneration

    Development, Growth & Differentiation

    (2011)
  • R.N. Christensen et al.

    Expression of fibroblast growth factors 4, 8, and 10 in limbs, flanks, and blastemas of Ambystoma

    Developmental Dynamics: An Official Publication of the American Association of Anatomists

    (2002)
  • Cited by (59)

    • Chromatin dynamics in regeneration epithelia: Lessons from Drosophila imaginal discs

      2020, Seminars in Cell and Developmental Biology
      Citation Excerpt :

      These immune cells release cytokines that are also sensed as pro-regenerative signals [32–37]. Altogether, these signals ultimately regulate the activation of signaling pathways such as, JNK and p38, WNT, Jak-STAT, EGFR/Ras/MAPK or Hippo [29,31,38–45]. Upon receiving such input, cells undergo extensive changes in chromatin activity and switch their transcriptional programs to rebuild the tissue that has been lost or injured (Fig. 1).

    • From the raw bar to the bench: Bivalves as models for human health

      2019, Developmental and Comparative Immunology
    View all citing articles on Scopus
    View full text