Lung injury in axolotl salamanders induces an organ‐wide proliferation response

Abstract

Background: Ambystoma mexicanum, the axolotl salamander, is a classic model organism used to study vertebrate regeneration. It is assumed that axolotls regenerate most tissues, but the exploration of lung regeneration has not been performed until now. Results: Unlike the blastema-based response used during appendage regeneration, lung amputation led to organ-wide proliferation. Pneumocytes and mesenchymal cells responded to injury by increased proliferation throughout the injured lung, which led to a recovery in lung mass and morphology by 56 days post-amputation. Receptors associated with the Neuregulin signaling pathway were upregulated at one and 3 weeks post lung amputation. We show expression of the ligand, neuregulin, in the I/X cranial nerve that innervates the lung and cells within the lung. Supplemental administration of Neuregulin peptide induced widespread proliferation in the lung similar to an injury response, suggesting that neuregulin signaling may play a significant role during lung regeneration. Conclusion:Our study characterizes axolotl lung regeneration. We show that the lung responds to injury by an organ-wide proliferative response of multiple cell types, including pneumocytes, to recover lung mass.

Regenerating axolotl retinas regrow diverse cell types with modulation by Notch signaling and reconnect to the brain

“…Limb amputation triggers cell-cycle activation in the contralateral, uninjured limbs, but also in other organs (Johnson et al, 2018). After a lung injury, a variety of cell types proliferate in the contralateral, uninjured lung (Jensen et al, 2021). In a regenerating tail, proliferating cells can be detected in the spinal cord as far as 5 mm away from the amputation site (Duerr et al, 2021).…”

“…Probes were also generated for Vimentin, Notch1, Jag1, Hes1 , and Hes5 . Probes were designed as described previously (Jensen et al, 2021), using Oligominer (Beliveau et al, 2018) and Bowtie2 (Langmead & Salzberg, 2012) against the 6.0-DD axolotl genome (Nowoshilow et al, 2018; Smith et al, 2019) (http://probegenerator.herokuapp.com/).…”

“…This salamander is a popular model of complex tissue regeneration, most notably of limbs and the spinal cord (Simon & Tanaka, 2013; Tazaki et al, 2017). It can also regenerate portions of ovaries, lungs, the liver, and the brain even in adulthood (Erler et al, 2017; Jensen et al, 2021; Maden et al, 2013; Ohashi et al, 2021). However, the regenerative abilities of axolotl eye tissues at different life stages are either limited or understudied.…”

Comparing nerve‐mediated FGF signalling in the early initiation phase of organ regeneration across mutliple amphibian species

“…Additionally, the involvement of nerves in regulating this process remains unknown, and the molecular mechanism is also widely unknown. There are some classic reports about regeneration (or lack of regeneration) in other internal organs, such as in the intestine (Grubb, 1975; O'Steen, 1958), pronephric duct (Howland, 1926), lung (Jensen et al, 2021), and kidney (Scadding & Liversage, 1974). For regeneration in these organs, the molecular mechanisms are widely unknown.…”

Salamander models for elucidating mechanisms of developmental biology, evolution, and regeneration: Part one

“…In an effort to understand the regeneration capacity of internal organs, Jensen et al, studied the regenerative capacity of the axolotl lung. 4 By characterizing cell proliferation in a number of cell types following injury at the distal tip of the lung, the authors found that increased proliferation was equal throughout the injured lung suggesting an organ-wide response to injury. In limb regeneration, while proliferation has also been documented to occur at more distant sites, 5 it is more focused at the site of injury compared to in lung regeneration.…”