Complement-triggered pathways orchestrate regenerative responses throughout phylogenesis

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.

Keywords: ASP; Anaphylatoxins; C3a receptor; C3aR; C5a receptor; C5aR; CCl(4); Complement; DAMPs; ECM; EMT; HSCs; HSPCs; IPE; Inflammation; Innate immunity; MAC; MSCs; PHx; RPE; Tissue plasticity; Vertebrate regeneration; acylation-stimulating protein; carbon tetrachloride; danger-associated molecular patterns; epithelial-to-mesenchymal transition; extracellular matrix; hematopoietic stem cells; hematopoietic stem-like progenitor cells; iris pigmented epithelial; membrane attack complex; mesenchymal stem cells; partial hepatectomy; retinal pigmented epithelium.

Figure 1. Complement-associated regenerative processes in evolutionarily distinct organisms

Taxinomic order ranks are shown as an evolutionary “ladder” from lower species such as zebrafish up to humans. As one ascends the ladder, there is a maturation of acquired immunity. Conversely, the regenerative potential of organisms is low in higher-order animals and increases as one goes down the ladder. The specific regenerative processes for each taxonomic order in which complement is known to play a role, as discussed in the text, are shown. *, Zebrafish and frog neural crest migration is listed due to the multipotent embryonic-like nature of the neural crest cells, though complement has been shown to regulate this process during development, not tissue regeneration.