Heart regeneration in the salamander relies on macrophage-mediated control of fibroblast activation and the extracellular landscape

Abstract

In dramatic contrast to the poor repair outcomes for humans and rodent models such as mice, salamanders and some fish species are able to completely regenerate heart tissue following tissue injury, at any life stage. This capacity for complete cardiac repair provides a template for understanding the process of regeneration and for developing strategies to improve human cardiac repair outcomes. Using a cardiac cryo-injury model we show that heart regeneration is dependent on the innate immune system, as macrophage depletion during early time points post-injury results in regeneration failure. In contrast to the transient extracellular matrix that normally accompanies regeneration, this intervention resulted in a permanent, highly cross-linked extracellular matrix scar derived from alternative fibroblast activation and lysyl-oxidase enzyme synthesis. The activation of cardiomyocyte proliferation was not affected by macrophage depletion, indicating that cardiomyocyte replacement is an independent feature of the regenerative process, and is not sufficient to prevent fibrotic progression. These findings highlight the interplay between macrophages and fibroblasts as an important component of cardiac regeneration, and the prevention of fibrosis as a key therapeutic target in the promotion of cardiac repair in mammals.

Unified nexus of macrophages and maresins in cardiac reparative mechanisms

“…These findings indicate the importance of macrophages in the regeneration of the neonatal heart and suggest that newborn (d 1) mice are rich in M2 macrophages, with high regenerative angiogenic potential, distinctive from the profibrotic and scar-forming activities of adult monocytes/ macrophages (54). These fundamental insights have been gained from cardiac regeneration in fish, salamander, and neonatal mouse; are translatable; and have paved the way to study cardiac repair in humans (54,63). As in newborn mice, newborn humans with signs of ischemic injury or heart attack heal faster than adult humans; the mechanism that facilitates this healing is unclear (64).…”

Advancements to the Axolotl Model for Regeneration and Aging

“…Despite anecdotal evi-dence suggesting a suppressed immune response during regeneration, the presence of immune cells is also a requirement. For example, macrophages are essential for regeneration in both the axolotl heart and limb [38,39]. Macrophages could play multiple roles in the regenerate, potentially clearing out tissue and cell debris in the injured tissue and removing senescent cells from the regenerated tissue.…”

Reversion to developmental pathways underlies rapid arm regeneration in juvenile European cuttlefish, Sepia officinalis (Linnaeus 1758)

“…Previous studies have identified many genes implicated in cephalopod limb morphogenesis; future experimentation would especially benefit from timepoint‐ and treatment‐specific profiles, with particular emphasis on genes associated with nervous precursor distribution and development of complex sensory and neurological structures (Baratte & Bonnaud, ; Bassaglia et al, ; Buresi, Baratte, Da Silva, & Bonnaud, ; Buresi, Canali, Bonnaud, & Baratte, ; Buresi, Croll, Tiozzo, Bonnaud, & Baratte, ; Focareta, Sesso, & Cole, ; Zhang & Tublitz, ), as well as muscle (Bassaglia et al, ; Fossati et al, ; Navet et al, ; Zullo et al, ) and endothelium (Focareta & Cole, ). Additional genes of interest should be garnered from the available studies in models across taxa (Fei et al, ; Godwin et al, ; Kawakami et al, ; Uygur & Lee, ; Wischin et al, ); ideally strategies utilizing transcriptomic or single‐cell RNA sequencing could be compared on both amputated and regenerated limb tips to provide greater clarity on intraindividual variation in expression based on injury‐naïve and regenerating conditions. Finally, the probing of different common patterning and speciation pathways (e.g., sonic hedgehog, Wnt/β‐catenin, Hippo/YAP/TAZ, etc.)…”

“…Finally, there is significant evidence that nerve damage is necessary in stimulating a regenerative response (Imperadore, Shah, Makarenkova, & Fiorito, 2017;Uygur & Lee, 2016), and that an initial immune response is required to stimulate cell proliferation and proper fibroblastic activity conducive to a scarless repair (Godwin, Debuque, Salimova, & Rosenthal, 2017;Imperadore et al, 2017;Uygur & Lee, 2016). Little is known about cephalopod immunity in general (Castillo, Salazar, & Joffe, 2015), including the existence of a polarization capability (such as a proinflammatory process that may impair healing) or if the immune response is general and unilateral.…”