Neuregulin-1 exerts molecular control over axolotl lung regeneration through ErbB family receptors

Background

While some human organs can undergo compensatory growth after amputation or damage, the process is extremely slow, and learning the fundamental aspects of this process in order to speed it up would have a strong impact on regenerative medicine. A priori, there are at least two conceivable mechanisms by which organs can recover their lost mass: 1) epimorphic regeneration, whereby some cells near the wound dedifferentiate and form a highly-proliferative blastema (e.g. regenerating limbs in amphibians and fins zebrafish); 2) compensatory growth of the organ as a whole, such that the mass is recovered but the original shape is not (e.g. liver in humans). Jensen and colleagues use the axolotl salamander to study lung regeneration, a process relatively unexplored outside mammalian models. Their molecular analysis focuses on the ErbB family of receptors and its activation of YAP signalling, both of which are important for pulmonary tissue proliferation. In particular, the ligand NRG1, the receptors ErbB2/4 and the YAP target HoxA1 are the usual suspects involved in the proliferative response [1-3].

Key findings

1. Amputation of one third of one of the lungs leads to a rapid wound closure, with inflammation receding 7 days post amputation (dpa).
2. There is a strong proliferative response as early as 7 dpa, but strikingly it is not restricted to the amputated region, but rather a whole-organ response, including the contralateral lung (Fig. 1A, B).
3. While lung length is not overly recovered, lung volume is, and therefore the overall shape of the lung is altered. After 8 weeks, the amputated lung catches up to the control one in volume.
4. Proliferative cells undergo only a few rounds of cell division, and tracking those cells suggests they give rise only to cells of their own cell type. If confirmed by marker expression studies, this would indicate that, as in rodent lungs [4], there is no a restricted population of multipotent stem cells that carries out the whole regenerative response. This is distinct from limb regeneration in the axolotl, which despite being quite lineage-restricted [5], works through the formation of a highly proliferative blastema where progenitor cells accumulate and proliferate actively.
5. NRG1, ErbB4 and HoxA1 are upregulated in the injured lungs, suggesting they are responsible for the proliferative response. In fact, systemic inhibition of ErbB2 (which binds NRG1 and heterodimerizes with ErbB4) abolishes the proliferative response in injured lungs (Fig. 1C). Moreover, injection of NRG1 in uninjured lungs activates proliferation and a similar molecular response as seen upon amputation, and these responses depend on ErbB2 signalling.

What I like about this preprint

The study of Jensen and colleagues (understandably foundational as it is the senior thesis work of the first author) reveals that not all organs regenerate through the same mechanism in axolotl, and opens up a new set of questions to be explored in the future. It is surprising and refreshing that new basic discoveries are still possible in such an long-established model.

Pending questions

1. Despite proliferation being activated in both the injured and contralateral lung, the injured one eventually catches up to the intact one in volume. Is this due to mechanical factors, such as there being more space available for the resected lung? And what happens to the extra cells in the uninjured lung?
2. The authors suggest that inflammation plays a role to maintain the proliferative cells undifferentiated through repression of EGFR (ErbB1). Have the authors considered using antagonists of IL1B signalling after amputation, or agonists in combination with NRG1 treatment?
3. The fact that NRG1 is able to induce proliferation of lung cells in the absence of amputation suggests that mass reduction is not required for the compensatory response to happen. If this is the case, I wonder how do lung cells ‘know’ when they have to stop proliferating –in other words, how do they know when the lung has been repaired?

 Related research

1. Liu et al. 2009. Exp. Lung Res.
2. Haskins et al. 2014. Sci. Signal.
3. Liu et al. 2015. Mol. Cell. Biol.
4. Kotton et al. 2014. Nature Medicine.
5. Kragl et al. 2009. Nature.

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