Given the prevalence of superheros in the modern cinematic zeitgeist, one may be familiar with the fictional biologist Dr. Curt Connors, a human turned lizard chimera as a botched attempt towards regenerating his amputated arm.
While amphibious rather than reptilian in nature, salamander species such as the axolotl and newt have been a primary focus of previous tissue regeneration studies due to the species' ability to fully regrow lost limbs, appendages (tail), jaws, and even spinal cords following amputation or traumatic injury (Lévesque et al., 2007). This is defined as "true regeneration", where through epigenetic regulators and inflammatory mediators, differentiated cells (cells with a specific phenotypic specialization) migrate to the site of injury and revert into a less differentiated state. The unspecialized cells, now referred to as the "blastema" in axolotl, then serve as a precursor to regeneration as they re-differentiate and proliferate into specialized cell types (Stocum, 2012).
Interestingly, these cells retain information from lost parent cells regarding their organization in three-dimensional space (positional memory). As an integral ligand for signal transduction and regulation during embryonic development, retinoic acid was a substance of interest in early research regarding true regeneration and positional memory. Ludolph et al. (1990) demonstrated that, with respect to the dorsoventral axis of development, application of exogenous retinoic acid to blastema ventralized positional memory: inducing regeneration in the dorsal half of the amputated limb but inhibiting regeneration in the ventral half. Presumably, the cell-to-cell signalling involved with positional memory is a complex mechanism that extends beyond retinoic acid, and is free-standing subject for later review; however, modern research is interested in evaluating the importance of other molecular markers such as Shh and Lmx1b in axis development (Iwata et al., 2019).
Transitioning from the axolotl model, limb regeneration study is a subject of interest for treatment in humans following traumatic injury or disease. While most human organs are incapable of regeneration, the liver is often classically cited for its ability to regrow following partial resections, most notably in liver transplant donors. However, this is not "true regeneration", but rather compensatory hyperplasia (Stocum), where existing hepatocytes replicate and proliferate without transitioning through an undifferentiated phase. This becomes problematic because while the hepatic tissue regrows, it generally lacks the original structure and vascular organization that exists with true regeneration and positional memory.
While totipotent embryonic stem cells is a subject of ethical debate (non-maleficence), understanding the relationship between epigenetic regulators and inflammatory mediators in true regeneration and positional memory serves as a ethically viable alternative treatment for regeneration of tissues that are difficult to repair/regrow, including cartilage.
Hsueh et al. (2019) found an increased rate of protein turnover in ankle cartilage tissue when compared to cartilage tissue in the hip, which correlated with a comparatively higher incidence of hip osteoarthritis. Additionally, regenerative blastema microRNA (miRNA) in axolotls has been associated with increased protein turnover. These findings suggest a potential role of regenerative miRNA in cartilage homeostasis, and thus a direction of future research to identify a potential treatment for osteoarthritis and cartilage degeneration, and potentially regeneration of more complex tissues in organs or appendages.
References:
Hsueh, M.F., Onnerfjord, P., Bolognesi, M.P., Easley, M.E., Kraus, V.B. (2019). Analysis of "old" proteins unmasks dynamic gradient of cartilage turnover in human limbs. Science Advances, 5(10). DOI: 10.1126/sciadv.aax3203
Iwata, R., Makanae, A., Satoh, A. (2019). Stability and Plasticity of Positional Memory During Limb Regeneration in Ambystoma mexicanum. Developmental Dynamics. https://doi.org/10.1002/dvdy.96
Lévesque, M., Gatien, S., Finnson, K., Desmeules, S., Villiard, E., Pilote, M., Philip, A., Roy, S. (2007). Transforming Growth Factor: β Signaling is Essential for Limb Regeneration in Axolotls. PLoS ONE 2(11): e1227. https://doi.org/10.1371/journal.pone.0001227
Ludolph, D.C., Cameron, J.A., Stocum, D.L. (1990). The Effect of Retinoic Acid on Positional Memory in the Dorsoventral Axis of Regenerating Axolotl Limbs. Developmental Biology, 140, 41-52.
Stocum, D. (2012). Regenerative Biology and Medicine (2nd ed.). Academic Press.
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