Elsevier

Seminars in Immunology

Volume 25, Issue 1, February 2013, Pages 29-38
Seminars in Immunology

Review
Complement-triggered pathways orchestrate regenerative responses throughout phylogenesis

https://doi.org/10.1016/j.smim.2013.04.002Get rights and content

Highlights

  • Inflammation and regenerative capacity share interdependency across phylogenesis.

  • Complement affects fate-deciding stages in early development and embryogenesis.

  • Complement modulation of stem cells offers potential new regenerative therapeutics.

  • Complement drives amphibian regeneration morphogenesis and pattern formation.

  • Complement promotes mammalian regenerative responses in the liver, bone and muscle.

Abstract

Adult tissue plasticity, cell reprogramming, and organ regeneration are major challenges in the field of modern regenerative medicine. Devising strategies to increase the regenerative capacity of tissues holds great promise for dealing with donor organ shortages and low transplantation outcomes and also provides essential impetus to tissue bioengineering approaches for organ repair and replacement. The inherent ability of cells to reprogram their fate by switching into an embryonic-like, pluripotent progenitor state is an evolutionary vestige that in mammals has been retained mostly in fetal tissues and persists only in a few organs of the adult body. Tissue regeneration reflects the capacity of terminally differentiated cells to re-enter the cell cycle and proliferate in response to acute injury or environmental stress signals. In lower vertebrates, this regenerative capacity extends to several organs and remarkably culminates in precise tissue patterning, through cellular transdifferentiation and complex morphogenetic processes that can faithfully reconstruct entire body parts. Many lessons have been learned from robust regeneration models in amphibians such as the newt and axolotl. However, the dynamic interactions between the regenerating tissue, the surrounding stroma, and the host immune response, as it adapts to the actively proliferating tissue, remain ill-defined. The regenerating zone, through a sequence of distinct molecular events, adopts phenotypic plasticity and undergoes rigorous tissue remodeling that, in turn, evokes a significant inflammatory response. Complement is a primordial sentinel of the innate immune response that engages in multiple inflammatory cascades as it becomes activated during tissue injury and remodeling. In this respect, complement proteins have been implicated in tissue and organ regeneration in both urodeles and mammals. Distinct complement-triggered pathways have been shown to modulate critical responses that promote tissue reprogramming, pattern formation, and regeneration across phylogenesis. This article will discuss the mechanistic insights underlying the crosstalk of complement with cytokine and growth factor signaling pathways that drive tissue regeneration and will provide a unified conceptual framework for considering complement modulation as a novel target for regenerative therapeutics.

Section snippets

Current trends and challenges in regenerative medicine

Regenerative biology defines a rapidly expanding field of research that comes to terms with the very essence of organismic development; the inborn ability of cells and tissues to reprogram their fate, switch into an embryonic-like, pluripotent state, and repopulate damaged or malfunctioning organs through lineage-specific redifferentiation [1].

Regenerative responses culminate through finely orchestrated cellular processes and fate-deciding molecular circuits that are activated in response to

Tissue regeneration in lower vertebrates

Comparative phylogenetic studies have been instrumental in furthering our understanding of the molecular basis of organ regeneration [9], [48]. Regeneration appears to be a primordial attribute of metazoans that has gradually been lost or constrained during phylogeny, as organisms evolved to more complex and energy-demanding structures [8]. Along this trail of evolution, urodele amphibians hold a unique place in view of their capacity to regenerate entire body parts through precise tissue

Insights from liver regeneration models

The mammalian liver is among only a few organs of the adult body that have retained the inherent ability to regenerate in response to acute toxic injury, viral infection, or surgical resection (hepatectomy) [11]. Liver regeneration culminates in the coordinated activation of growth factor-regulated and cytokine-driven pathways that instruct quiescent hepatocytes and other non-parenchymal liver cells (Kupffer cells, endothelial cells) to re-enter the cell cycle and proliferate [11]. The

Concluding remarks and future perspectives

Complement, a primordial sentinel of innate immunity, has long been perceived as a mere “executioner” that directly neutralizes pathogens or tags them to promote their phagocytosis. However, over the past two decades, complement biology has undergone a drastic reorientation by recapitulating old developmental paradigms from a systems-wide perspective. Emerging evidence from various animal models points to a more subtle role of this innate immune system in basic development, vertebrate

Acknowledgments

We would like to thank Dr. Deborah McClellan for excellent editorial assistance, as well as current and past laboratory members for contributing to the research discussed in this article. This work was supported by NIH grants AI003040, AI068730, AI072106, AI097805, EY020633, GM097747, and DE021685 for JDL.

References (86)

  • S. Filoni

    Retina and lens regeneration in anuran amphibians

    Seminars in Cell and Developmental Biology

    (2009)
  • W.M. Kulyk et al.

    Hyaluronic acid production and hyaluronidase activity in the newt iris during lens regeneration

    Experimental Cell Research

    (1987)
  • E. Makarev et al.

    Gene expression signatures in the newt irises during lens regeneration

    FEBS Letters

    (2007)
  • S. Akira et al.

    Pathogen recognition and innate immunity

    Cell

    (2006)
  • S.M. da Silva et al.

    The newt ortholog of CD59 is implicated in proximodistal identity during amphibian limb regeneration

    Developmental Cell

    (2002)
  • J. Stein-Streilein

    Immune regulation and the eye

    Trends in Immunology

    (2008)
  • A. Clark et al.

    Evidence for non-traditional activation of complement factor C3 during murine liver regeneration

    Molecular Immunology

    (2008)
  • A.T. Naito et al.

    Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes

    Cell

    (2012)
  • H. Clevers

    Wnt/beta-catenin signaling in development and disease

    Cell

    (2006)
  • P. Schoengraf et al.

    Does complement play a role in bone development and regeneration

    Immunobiology

    (2013)
  • Z. Tu et al.

    Efficient osteoclast differentiation requires local complement activation

    Blood

    (2010)
  • J.P. Brockes et al.

    Plasticity and reprogramming of differentiated cells in amphibian regeneration

    Nature Reviews Molecular Cell Biology

    (2002)
  • S.B. Carroll

    Chance and necessity: the evolution of morphological complexity and diversity

    Nature

    (2001)
  • K. Hochedlinger et al.

    Nuclear reprogramming and pluripotency

    Nature

    (2006)
  • T.A. Rando

    Stem cells, ageing and the quest for immortality

    Nature

    (2006)
  • J.B. Gurdon et al.

    Injected nuclei in frog oocytes provide a living cell system for the study of transcriptional control

    Nature

    (1976)
  • D.E. Cohen et al.

    Turning straw into gold: directing cell fate for regenerative medicine

    Nature Reviews Genetics

    (2011)
  • A.S. Alvarado

    Regeneration in the metazoans: why does it happen

    Bioessays

    (2000)
  • J.P. Brockes et al.

    Comparative aspects of animal regeneration

    Annual Review of Cell and Developmental Biology

    (2008)
  • J.P. Brockes

    Amphibian limb regeneration: rebuilding a complex structure

    Science

    (1997)
  • R. Taub

    Liver regeneration: from myth to mechanism

    Nature Reviews Molecular Cell Biology

    (2004)
  • P. Bianco et al.

    Stem cells in tissue engineering

    Nature

    (2001)
  • R.E. Schwartz et al.

    Hepatic stem cells

    Methods in Molecular Biology

    (2010)
  • K. Kikuchi et al.

    Cardiac regenerative capacity and mechanisms

    Annual Review of Cell and Developmental Biology

    (2012)
  • P. Sreejit et al.

    Natural ECM as biomaterial for scaffold based cardiac regeneration using adult bone marrow derived stem cells

    Stem Cell Reviews

    (2013)
  • R.A. DeAngelis et al.

    Liver regeneration: a link to inflammation through complement

    Advances in Experimental Medicine and Biology

    (2006)
  • J.W. Godwin et al.

    Regeneration, tissue injury and the immune response

    Journal of Anatomy

    (2006)
  • J.O. Sunyer et al.

    Complement diversity: a mechanism for generating immune diversity

    Immunology Today

    (1998)
  • A.L. Mescher et al.

    Regenerative capacity and the developing immune system

    Advances in Biochemical Engineering/Biotechnology

    (2005)
  • M. Harty et al.

    Regeneration or scarring: an immunologic perspective

    Developmental Dynamics

    (2003)
  • L.B. Tolle et al.

    Danger-associated molecular patterns (DAMPs) in acute lung injury

    Journal of Pathology

    (2013)
  • C. Nathan

    Neutrophils and immunity: challenges and opportunities

    Nature Reviews Immunology

    (2006)
  • S. Gordon

    Alternative activation of macrophages

    Nature Reviews Immunology

    (2003)
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