Inter-organ communication during tissue regeneration

Abstract

Tissue regeneration is not simply a local repair event occurring in isolation from the distant, uninjured parts of the body. Rather, evidence indicates that regeneration is a whole-animal process involving coordinated interactions between different organ systems. Here, we review recent studies that reveal how remote uninjured tissues and organ systems respond to and engage in regeneration. We also discuss the need for toolkits and technological advancements to uncover and dissect organ communication during regeneration.

Keywords: Circulating factors; Enhancers; Growth factors; Hormones; Organ communication; Tissue regeneration.

Fig. 1.

Injury induces cell cycle entry in distant tissues. (A) Resection of the planarian head induces two phases of mitosis. The first systemic mitotic event is a general response to injury. The second local mitotic event is a response specific to tissue loss. (B) Limb amputation in axolotls induces cycling events in organs far from the regenerating stump, including the contralateral intact limb, liver, heart and spinal cord. This occurs concomitantly with increased cell proliferation at the amputation site. In A and B, red circles represent cycling cells. (C) Muscle injury in mice catalyzes circulating, inactive pro-HGFA (green hexagons) into active HGFA (purple circles). HGFA then activates pro-HGF residing in the tissue distant from the injury site into active HGF to induce the conversion of quiescent (G₀) stem cells into an alert state (G_alert), accelerating their responses to future injuries.

Fig. 2.

Imaginal tissue injury in third instar Drosophila larvae delays pupariation. Schematic on the left indicates the locations of the ring gland, brain and wing discs in a third instar Drosophila larva. Schematic on the right shows interactions between the injured imaginal disc and the brain. Injury induces the production and secretion of Dilp8 (pink hexagons) from the injured imaginal tissue (pink) into the hemolymph. A pair of bilateral Lgr3 neurons (green) in the brain responds to Dilp8, suppressing the activity of PTTH neurons (purple). Reduced PTTH decreases secretion of ecdysone (pale purple circles) from the ring gland and slows developmental progression. Lgr3 neurons also suppress the secretion of insulin-like peptides from insulin-producing neurons (brown), which reduces ecdysone synthesis and prevents the overgrowth of uninjured imaginal tissues during regeneration. Dilp8-Lgr3 signaling in neurons or ring gland can each activate NOS in the ring gland. This activated NOS is required to retard growth of uninjured imaginal tissues. Refer to the main text for more details on these studies.

Fig. 3.

Examples of contralateral effects during tissue regeneration. (A) Extirpating the pedicle and the attached frontal bone of the growing deer antler induces the growth of two exostoses centimeters away from the antler. These exostoses form during the first growing period. In the second growing period, the exostose on the contralateral, uninjured side grows faster than the one on the injured side, forming a spiked secondary antler. (B) Limb amputation of Xenopus at regenerative stages not only leads to depolarization of the regenerating limb stump, but also induces depolarization in the contralateral uninjured limb. The depolarization zone reflects the position of the amputation plane of the injured limb.