Differences in Regenerative Capacity Between Organisms: an Evaluation of the Underlying Mechanisms
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University of Groningen Bachelor’s Thesis Molecular and Genetic Age Research ERIBA Differences in regenerative capacity between organisms: an evaluation of the underlying mechanisms Author: Supervisor: E.A. Nagel (S3158241) dr. S.M. Mouton July 1, 2019 Abstract The capacity to regenerate varies greatly within the animal kingdom. Invertebrates like planarian flatworms and Hydra are very good regenerators, while mammals are only able to regenerate a limited amount of tissue and show a lot of scar formation. How the regenerative capacity can differ so profoundly between organisms has fascinated the scientific community for many years. In this review, several mechanisms and processes that might underly the differences in regenerative capacity amongst organisms will be discussed. It focusses on the cellular basis of regeneration, immune responses, expression of tumor suppressor genes, telomerase activity and cellular senescence. A better understanding of the role of these processes in regeneration could be useful for the development of new therapies to stimulate regeneration in mammals. Graphical abstract 2 Contents Introduction ............................................................................................................................................. 4 Cellular sources for regeneration ............................................................................................................ 5 Cellular sources for regeneration in invertebrates .................................................................................. 5 Cellular sources for regeneration in vertebrates ..................................................................................... 5 More advanced immune response causes a decrease in regenerative capacity .................................... 8 Alterations in tumor suppressor pathways during evolution ................................................................. 9 Telomere length is maintained in highly regenerative organisms ........................................................ 11 Effective clearance of senescent cells is crucial during tissue repair .................................................... 12 Conclusion ............................................................................................................................................. 13 Bibliography ........................................................................................................................................... 14 3 Introduction Regeneration is the regrowth of damaged or missing body parts. The capacity to regenerate varies greatly within the animal kingdom, and in particular between invertebrates and vertebrates (Tanaka & Reddien, 2011). Invertebrates such as planarian flatworms and Hydra have a very high regenerative capacity. They are capable of regenerating a new head, tail or even their entire body from only small body fragments (Tanaka & Reddien, 2011). Primitive vertebrates such as the zebrafish and salamander cannot regrow a whole organism, but have the capacity to regenerate complex structures. For example, the zebrafish is able to regrow the heart, brain, fin or even its retina (Gemberling, Bailey, Hyde, & Poss, 2013) and salamanders can also regenerate complete appendages, such as the limb, after injury (Kragl et al., 2009). Mammals have a rather limited regenerative capacity. Although mice and young children are capable of digit tip regeneration (Han, Yang, Jangwoo, Allan, & Muneoka, 2008; Illingworth, 1974), regeneration in adult humans is mainly limited to skin and liver cells and often goes together with scar formation (Iismaa et al., 2018). Why some organisms have a better capacity to regenerate than others, especially humans, is of great interest to scientists. Although people have been doing research into regeneration for a long time, the rise of regenerative medicine caused an increasing interest in understanding the mechanisms and elements underlying regeneration, for these might be crucial for developing new therapies and promote regeneration in humans. One important underlying mechanism is the generation of new cells for the formation of new tissue. Depending on whether an organism is able to do this and to what extent, determines how quickly and how well it can regenerate. Also the immune response appears to have an effect on the regenerative capacity of organisms (Godwin & Rosenthal, 2014). With evolution, the adaptive immune response arose and the capacity to regenerate decreased. This suggests a correlation that might explain differences in regeneration ability. Tumor suppressor genes are present in both invertebrates and vertebrates and are known to be involved in cellular processes like cell proliferation (Pomerantz & Blau, 2013). Differences in expression of these genes could be one of the reasons why invertebrates regenerate but higher vertebrates don’t. Another process which is involved in cell division and proliferation is telomere shortening (Shay & Wright, 2005). Telomere shortening leads to cell cycle arrest and inhibits cell proliferation, which is crucial for regeneration. The expression of telomerase prevents this from happening, and could underlie regeneration capability. A permanent cell cycle arrest leads to the formation of senescent cells. Senescence is known to be involved in ageing, but recent work also shows an important role of senescent cells during tissue repair, as their secretory phenotype induces proliferation of surrounding cells (Demaria et al., 2014). This review of contemporary knowledge concerning biological regeneration aims to uncover the workings of the aforementioned mechanisms, and shed light on what causes the difference in regenerative capacity between organisms. First, the cellular basis of regeneration in both highly- and poorly regenerative animals will be described, making use of well-known regeneration models. Subsequently, the effect of the immune response, tumor suppressors, telomerase activity and cellular senescence on regenerative capacity will be examined. 4 Cellular sources for regeneration New cells have to be generated in order to form new tissues. The generation of new cells can be achieved by activation of stem cells or progenitor cells, dedifferentiation of specialized cells to undifferentiated progenitor cells, or even the direct conversions of one differentiated cell into another, called transdifferentiation (Eguizabal, Montserrat, Veiga, & Belmonte, 2013). Which one of these mechanisms is used to yield new cells during regeneration is dependent on the organism and the tissue of origin. Cellular sources for regeneration in invertebrates One of the best studied regeneration models is the planarian flatworm. Planarians are found in both saltwater and freshwater ponds and have the capacity to regenerate a whole new organism out of small body fragments (Morgan, 1898). The source for this regeneration is a population of somatic dividing cells, called neoblasts, that exist throughout the whole planarian body. This population is composed of a heterogeneous pool of cells which are either lineage-restricted or pluripotent (Van Wolfswinkel, Wagner, & Reddien, 2014). The pluripotent neoblasts are called clonogenic neoblasts (cNeoblasts) and can give rise to any cell type within the body. Even after lethal irradiation, a single cNeoblast is capable of restoring regeneration (Wagner, Wang, & Reddien, 2011). After wounding, neoblasts proliferate and accumulate at the site of injury to form a blastema, out of which the new tissue will grow (Figure 1a)(Reddien, 2018). Like planarians, Hydra also have a highly regenerative capacity and are able to form an entire organism out of small body fragments (Bosch, 2007). Hydra are freshwater hydrozoans that belong to the phylum Cnidaria. They have a polarized, primary body axis with a head and tentacles on one side and a foot on the other side. Hydra are composed of two cell layers: an ectodermal and an endodermal layer, separated by an extracellular matrix (Bosch, 2007). They possess three different cell types: ectodermal epithelial cells, endothermal epithelial cells and interstitial cells which are located in the interstitial space between the epithelial cells (Bosch, 2007). Interstitial cells are proliferative multipotent stem cells and generate neurons, gametes and secretory cells (Bosch & David, 1987). The epithelial cells in the body column continuously self-renew and therefore can be considered as stem cells which contribute to the regeneration of the ectodermal and endodermal layers (Figure 1b)(Wittlieb, Khalturin, Lohmann, Anton-Erxleben, & Bosch, 2006). Although Hydra have three types of cells, only the epithelial cells are needed for tissue regeneration (Marcum & Campbell, 1978). During regeneration, epithelial cells are activated and mobilised towards the damaged tissue (Wittlieb et al., 2006). In contrast to planarians and many other organisms, blastema formation does not take place, but the pre-existing epithelial cells are rearranged and form newly organized structures (Bosch, 2007). Cellular sources for regeneration in vertebrates Although vertebrates are not capable of full-body regeneration, primitive vertebrates such as the zebrafish are widely used for studying vertebrate tissue regeneration. Zebrafish live in freshwater and have the potential to regenerate complex tissues like their heart or brain (Gemberling et al., 2013). Especially their remarkable ability to perform appendage regeneration, such as the tail or fin, is a phenomenon that has