Unlocking a Super Power: Regeneration

By Thanya (Safi) Siamwalla

The fascinating ability of some animals to regenerate body parts has captured the imagination of scientists for decades (Echeverri,1969). Incredible regenerative talents are widespread in the animal kingdom. Invertebrates are capable of re-growing almost their entire body. A common example of this is the Planarian flatworm, which deploys adult pluripotent stem cells to regrow from just a tiny clipping (An Zeng et al., 2018). Vertebrates possessing this ability utilize tissue-specific stem cells and dedifferentiation. A notorious example of this being the axolotl, which can regenerate spinal cords, limbs, eyes and even portions of their brain (Roy, 2006). Unfortunately, human regenerative abilities remain limited to muscle and liver tissue. Using animals such as the planarian and axolotl, collective efforts by the regenerative community may be uncovering avenues to ‘scale up’ our capabilities.

One of the earliest breakthroughs in these efforts was made by Dr Elly Tanaka, who used molecular marker analysis to identify the cellular underpinnings of regeneration (Tanaka, 2012). Transgenic axolotl expressing GFP (Green Fluorescent Protein) transgene were used as donors in embryonic tissue grafts of prospective limb forming regions in order to specifically label one of the various tissues of the limb: epidermis, muscle, Schwann cells or connective tissues. Limbs of the resulting axolotl were amputated. GFP enabled the detection and tracking of the specific cell population through the process of regeneration. It was observed that each different tissue provides a distinct progenitor cells which migrate to the site of injury and begin the development of a mass of undifferentiated cells called the blastema. the mixture of cells differentiate to form the necessary limb tissues and coordinately regenerate a fully functioning limb.

This served as a basis for regenerative biologist Catherine McCusker to successfully force an axolotl to grow a new arm from a wound on its limb, giving it an additional arm (McCusker, 2015). McCusker uncovered the 3 principal requirements for successful limb regeneration. Firstly, a wound is needed with formation of wound epithelium. Secondly, either a nerve or growth factors BMP and FGF must be present to cause connective tissues to form a blastema. Thirdly, fibroblasts of the anterior and posterior sides of the wound must interact to correctly pattern the limb. In the experiment, small square pieces of skin on the arm were removed from 38 axolotl. When the wound epithelium formed, a small excision was made to insert a gelatin bead carrying FGF and BMP. Then, a week later, the axolotls were injected with retinoic acid, substitute for fibroblast. 25 out of 38 axolotls developed a blastema and 7 of those grew between one and three additional arms. Demonstrating that the cellular aspect of regeneration is relatively well understood.

Now, new generations of experiments are digging deeper by exploring the genetic mechanisms driving this phenomenon. A ground-breaking study led by scientist Wei Wang discovered a snippet of DNA in humans very similar to a genetic element determined as fundamental in regeneration (Wang, 2020). This genetic element was first identified by the team through comparative study of the zebrafish and the turquoise killifish. To begin the experiment, their tailfins were clipped to induce regeneration; comparative epigenomic profiling and single-cell sequencing were performed on the resultant blastemal cells.230 million years of evolutionary distance between the two species enabled the team to distinguish between species specific and evolutionary conserved regenerative genetic elements. Genetic elements found common in both species, conserved regenerative genetic elements, were established as a group of ancestral genetic element likely present in some form in all animals – including humans. A short sequence of DNA in Humans was found to closely match one of the ancestral genetic elements, K-IEN, which when deleted or blocked, halted regeneration in fish. The regenerative potential of the similar human DNA sequence was tested by cloning it into killifish. The sequence was found to turn on during latter stages of regeneration in the fins. This strongly suggests that in future, with further investigation and advancements in technology, it will be possible to reverse-engineer regenerative processes back into humans (Alvarado, 2020). 

  With the considerable progress in understanding the biology of regeneration, the idea of human regeneration has evolved from an “if” to a “when”. It led to the inception of the Regenerative Medical Research field – developing therapies to regenerate tissues and organs where they have been lost to disease. Aside from avoiding the complications that come with transplants, regeneration from the body itself will produce perfect replacements which neither prosthetics or transplants can do. As of current, advancements in cell therapy and bioengineering methodologies have facilitated stem cell-based regeneration (Tatullo, 2020). The stem cell capacity to self-replicate and differentiation potential serve as important features for the purposes of regeneration. However, the use of stem cells as such has yet to be deemed completely safe. Whether isolated from adult tissue or induced, they require tight control over their behavior to increase their safety profile. Ongoing studies work to address this and validate this exciting prospect. 

References:

Echeverri, K. and Zayas, R. (2018) “Regeneration: From cells to tissues to organisms”, Developmental Biology, 433(2), pp. 109-110. doi: 10.1016/j.ydbio.2017.12.005.

Zeng, A., Li, H., Guo, L., Gao, X., McKinney, S., Wang, Y., Yu, Z., Park, J., Semerad, C., Ross, E., Cheng, L., Davies, E., Lei, K., Wang, W., Perera, A., Hall, K., Peak, A., Box, A. and Sánchez Alvarado, A. (2018) “Prospectively Isolated Tetraspanin+ Neoblasts Are Adult Pluripotent Stem Cells Underlying Planaria Regeneration”, Cell, 173(7), pp. 1593-1608.e20. doi: 10.1016/j.cell.2018.05.006.

Wang, W., Hu, C., Zeng, A., Alegre, D., Hu, D., Gotting, K., Ortega Granillo, A., Wang, Y., Robb, S., Schnittker, R., Zhang, S., Alegre, D., Li, H., Ross, E., Zhang, N., Brunet, A. and Sánchez Alvarado, A. (2020) “Changes in regeneration-responsive enhancers shape regenerative capacities in vertebrates”, Science, 369(6508), p. eaaz3090. doi: 10.1126/science.aaz3090.

Roy, S. and Lévesque, M. (2006) “Limb Regeneration in Axolotl: Is It Superhealing?”, The Scientific World JOURNAL, 6, pp. 12-25. doi: 10.1100/tsw.2006.324.

Tanaka, E. and Reddien, P. (2011) “The Cellular Basis for Animal Regeneration”, Developmental Cell, 21(1), pp. 172-185. doi: 10.1016/j.devcel.2011.06.016.

McCusker, C., Bryant, S. and Gardiner, D. (2015) “The axolotl limb blastema: cellular and molecular mechanisms driving blastema formation and limb regeneration in tetrapods”, Regeneration, 2(2), pp. 54-71. doi: 10.1002/reg2.32.

Wang, W. et al. (2020) “Changes in regeneration-responsive enhancers shape regenerative capacities in vertebrates”, Science, 369(6508), p. eaaz3090. doi: 10.1126/science.aaz3090.

Sánchez Alvarado (2020) “Genetic Tool Kit Helps Some Animals Regrow Body Parts”, Available at: https://www.hhmi.org/news/genetic-tool-kit-helps-some-animals-regrow-body-parts (Accessed: 8 October 2020).

Tatullo, M. et al. (2020) “Stem cells and regenerative medicine”, Translational Systems Medicine and Oral Disease, pp. 387-407. doi: 10.1016/b978-0-12-813762-8.00017-7.

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