Author: Eleanor Sheekey
Institution: Cambridge University
From William Hartnell to David Tennant through to Peter Capaldi, the legendary Doctor Who has always had the ability to completely regenerate. The term regeneration is used more generally in Biology to include renewal of cells, tissues and limbs. It is not surprising, therefore, that an exciting new discovery published in Nature by Nacu et al. has shed light on a crucial part of the process involved in limb regeneration(1). Scientists hope that this new insight can be extrapolated for use in mammals, in particular for organ regeneration.
Although all mammals have the capacity to regenerate tissue cells, for example in the liver, the ability to re-create more complex structures like limbs has been restricted to only certain species of animals. Many of these animals are amphibians such as the Salamanders, most notably including the Mexican Salamander otherwise known as the Axolotls(2).
Axolotls are famous amongst the scientific community for their adorable infant-like appearance. Axolotls remain in a larval state known as neoteny throughout their life span. This may allow the Axolotls to retain more flexibility over their limb development. Whilst this is still just speculation, it has been known since the 18th century that Axolotls have the ability to regenerate their limbs. However, only in the past forty years have significant advances been made in understanding the signaling molecules involved in Axolotls limb regeneration (4).
An outline of the limb regeneration process had already been established by the scientific community before Nacu’s research group published their study. After wounding, regeneration is triggered by tissue repair responses which cause innervation – the supply of nerves—to a lump of progenitor cells. Progenitor cells have the ability to differentiate into numerous cell types, and these progenitor cells form a structure known as a blastema after innervation. The blastema then outgrows and differentiates to form the new limb. It was found, however, that this growth requires two types of cells: cells from the anterior-most and posterior-most positions of the limb stump. Nacu et al. sought to explore the role of these two different types of cells in the regeneration process by testing molecular pathways in Axlotls.
In order to understand why both anterior and posterior tissue types are required in regeneration, researchers started experimenting with blastemas composed solely of either anterior or posterior tissue. Anterior tissue alone was not sufficient to initiate regeneration. Only when some posterior tissue was grafted to the anterior tissue did new growth begin. When analyzing the posterior-associated molecules, researchers found that a specific signaling molecule named Sonic Hedgehog (Shh) is sufficient to elicit full regeneration of the limb, including development of bone. This occurs because in the blastema, Shh can diffuse through the tissue from the posterior to the anterior tissue. On binding to the cell surface receptors of anterior tissue cells, Shh triggers internal reactions inside the cell that then stimulate growth. Nacu and his fellow researchers found that Shh then activates another diffusible protein in anterior cells: the fibroblast growth factor 8 (FGF8). Once FGF8 is activated, limb production can begin (1).
Since anterior tissue contains FGF8 but not Shh, Nacu et al. could therefore conclude that in order for limb production to start, FGF8-containing anterior cells must acquire Shh from elsewhere. Because the posterior tissue contains Shh, it makes sense that Shh originates in the posterior tissue and migrates to the anterior tissue. This transfer of signals between cell types is known as cross-inductive signaling. Cross-inductive signaling is the first real insight into the regeneration mechanism; it explains the necessity of both tissue types in initiation of limb production (1).
What is still unclear is why this mechanism evolved so that new limb production can only occur if both tissue types are present. Understanding this duality may help us answer further questions such as why only certain animals like the Axolotls have the ability to regenerate their limbs. Why is the trait of regeneration not more widespread? This trait would be an adaptive trait for many animals that may get injured though predation or intra-species fights. Answering these question will be a good starting point for future research (1).
Limb regeneration remains an active area of research. Earlier this year a study published by Suguira et al. discovered another diffusible molecule called MARCKS-like protein (MLP) that is relevant to limb regeneration. MLP is responsible for blastema formation. Suguira’s discovery, in conjunction with the work done by Nacu et al., begins to unravel the steps involved in limb regeneration (2).
Across the animal kingdom, signaling pathways are highly conserved. This means that humans may have the potential to regenerate limbs through mechanism similar to Axolotls’s(3). Achieving human limb regeneration may still be in the distant future, but an understanding of the regeneration mechanism can still be applied today to other areas of research including aging and cancer development.