A cross-species analysis of systemic mediators of repair and complex tissue regeneration

Abstract

Regeneration is an elegant and complex process informed by both local and long-range signals. Many current studies on regeneration are largely limited to investigations of local modulators within a canonical cohort of model organisms. Enhanced genetic tools increasingly enable precise temporal and spatial perturbations within these model regenerators, and these have primarily been applied to cells within the local injury site. Meanwhile, many aspects of broader spatial regulators of regeneration have not yet been examined with the same level of scrutiny. Recent studies have shed important insight into the significant effects of environmental cues and circulating factors on the regenerative process. These observations highlight that consideration of more systemic and possibly more broadly acting cues will also be critical to fully understand complex tissue regeneration. In this review, we explore the ways in which systemic cues and circulating factors affect the initiation of regeneration, the regenerative process, and its outcome. As this is a broad topic, we conceptually divide the factors based on their initial input as either external cues (for example, starvation and light/dark cycle) or internal cues (for example, hormones); however, all of these inputs ultimately lead to internal responses. We consider studies performed in a diverse set of organisms, including vertebrates and invertebrates. Through analysis of systemic mediators of regeneration, we argue that increased investigation of these “systemic factors” could reveal novel insights that may pave the way for a diverse set of therapeutic avenues.

Kinematic self-replication in reconfigurable organisms

“…The ability of genetically unmodified cells to be reconfigured into kinematic self-replicators, a behavior previously unobserved in plants or animals, and the fact that this unique replicative strategy arises spontaneously rather than evolving by specific selection, further exemplifies the developmental plasticity available in biological design (1)(2)(3)(4)(5)(6)(7)(8). Although kinematic selfreplication has not been observed in extant cellular life forms, it may have been essential in the origin of life.…”

“…Despite this lack, organisms do possess deep reservoirs of adaptive potential at all levels of organization, allowing for manual or automated interventions that deflect development toward biological forms and functions different from wild type ( 1 ), including the growth and maintenance of organs independent of their host organism ( 2 – 4 ), or unlocking regenerative capacity ( 5 – 7 ). Design, if framed as morphological reconfiguration, can reposition biological tissues or redirect self-organizing processes to new stable forms without recourse to genomic editing or transgenes ( 8 ).…”

Epimorphic regeneration of the mouse digit tip is finite

“…The most parsimonious explanation for these findings could be that, at least in the context of repeated amputations, there are as yet unidentified systemic components regulating mammalian digit tip regeneration. While local effectors of epimorphic regeneration have been the primary focus in the last decades, both cellular and humoral systemic mediators of epimorphic regeneration have been explored [ 43 , 44 ]. With the exception of deer antler regeneration [ 45 ], no such studies exist for mammalian epimorphic regeneration until now.…”

Reactivation of the Neurogenic Niche in the Adult Zebrafish Statoacoustic Ganglion Following a Mechanical Lesion

“…However, in addition to local cues, systemic cues must play an important role because we observe reactive proliferation and reactive neurogenesis in the unlesioned side following a unilateral lesion, in particular, following ouabain injections. In this aspect, various systemic effects, including steroids such as estrogen or thyroid hormone, as well as peptide hormones, such as insulin or leptin, have been shown to act as mediators of complex tissue regeneration ( Losner et al, 2021 ). With respect to leptin function, epigenetic profiling provided even evidence for regeneration-dependent enhancer elements in the regeneration-competent zebrafish that are also able to control expression in transgenic mice in a lesion-dependent context ( Kang et al, 2016 ).…”