Breaking The Regeneration Barrier

Could we someday be able to regenerate organs or tissues like house lizards?

by Jianyi Lee

Figure2_JL
Figure 1: Limb regeneration in newts.

In Malaysia, the sight of the common house lizard imposing an unwelcomed stay in your home may seem like a nuisance. If you pay closer attention, you will notice that lizards can voluntarily shed their tails and grow a replacement tail soon after. Lizards are among the many species within the animal kingdom that possess the ability to regenerate lost or damaged appendages (Figure 1). This naturally occurring prowess is part of an evolutionarily acquired trait that enables the animal to escape threatening encounters with predators. One may wonder then, why do humans have limited capabilities to regenerate damaged organs or tissues after an injury? Recently, evidence from skin shedding African spiny mice suggests that mammals actually have a higher capacity to regenerate than previously thought1. Therefore, unraveling the mystery behind how some of these model organisms regenerate is at the forefront of biomedical research. This knowledge will pave the way for novel and specifically designed medical therapies for those afflicted with injury and diseases.

Quite simply put, regeneration is the ability of an adult organism to fully replace damaged tissues and organs by growing or remodeling existing tissues2. Within the field of regenerative medicine, scientists strive to answer four main questions. First, what determines the regenerative potential of an organism? Second, what are the cellular sources of regenerative tissue? Third, how does injury initiate regeneration? Finally, how does the organism control and terminate the regenerative program appropriately? Here, I present a minimalist view of common themes in regeneration.

Complex biological processes such as regeneration are influenced by multiple factors. In highly regenerative species, certain genetic pathways or conserved genes are selectively activated during regeneration. Incremental changes in the expression of these genes are sufficient to trigger regenerative capacity. Therefore, identifying the specific molecules that regulate these genes can be translated into potential targets for therapy. In mammals, it is apparent that regenerative efficiency declines with age. For instance, young children are able to regrow lost fingertips whereas adults lack this ability. This may be attributed to the fact that young tissues have more access to embryonic developmental programs that are required for regeneration as opposed to adults whose tissues have kept these programs dormant for long periods of time. Age-related drop in regenerative capacity is particularly evident in the brain, pancreas and skeletal muscle, therefore explaining why many aging diseases are associated with these tissues2.

One can address the regeneration problem by understanding the origins of the new cells that reconstitute the replacement tissue. These cells are either generally derived from the resident stem cell population or require the de-differentiation or trans-differentiation of existing cells3 (Figure 2). New cell production from de-differentiation involves mature cells reverting back to a state where they are competent to become multiple cell types. During trans-differentiation, cells directly convert from one mature cell type to another.

Remarkably, flatworms severed into five individual pieces can utilise stem cells to rebuild five separate and complete animals within a week. Stem cell based strategies for regeneration require that these cells be maintained and activated appropriately. In view of that, identification of stem cell markers and stem cell niches has helped us develop feasible methods for mass production of stem cells in laboratories. These choices vary between species and also differ from one tissue to another within the same organism. Furthermore, the nature of the injury can influence which cellular sources are used to build he regenerating tissue.

In order for injured tissues to regenerate, they must initiate responses that alter their cellular behaviours at the wound site. Mechanisms operate either locally or from a distance to stimulate regeneration. At the local level, programmed cell death (called “apoptosis”) releases signals in the wound site that promote surrounding cells to divide and proliferate4. This serves as a highly robust way for maintaining tissues with high turnover rates, such as in the intestine or during injury or infection. Regeneration can also be triggered by organ- and organism-

Figure2_scientificmalaysian
Figure 2 Three routes to regeneration. Illustrated model of
(A) stem cells self-renewing and giving rise to one or more
differentiated cells, (B) dedifferentiation where cells revert to
a precursor cell that can divide to produce more differentiated
cells and (C) transdifferentiation where cells change from one
cell type to another.

wide events. For instance, circulating factors drive skeletal muscle regeneration, and exercise has been demonstrated to stimulate the growth of new neurons in mice2.

Finally and most importantly, caution must be taken to exercise control over the proliferation and patterning of the new tissue so that only appropriate structures are replaced and regeneration is terminated. These processes require the cooperative efforts of molecules triggering cell division (mitogens), signals patterning the tissue precisely, together with the active process of sensing the scale and shape of the repaired tissue. We are also beginning to appreciate the role of the nervous system in the secretion of molecules encoding positional information for the actively renewing tissue4.

The sky is the limit, though it will be a matter of time before advances in the experimental tools at our disposal can bridge the gaps in our knowledge of regenerative biology. Ultimately, learning about regeneration will have a profound impact on the way we overcome debilitating medical conditions that result in amputation, cancer and degenerative diseases. With the help of various model organisms, we will break down the barriers to our regeneration.

ABOUT THE AUTHOR:

Jianyi Lee graduated with a Bachelor of Science in Biology from the University of Virginia (UVa) in 2008. She is currently a PhD candidate at the Department of Cell Biology at UVa. Her thesis work is focused on identifying the mechanisms that regulate sensory hair cell planar polarity in the inner ear. She can be reached at [email protected]. Find out more about Jianyi by visiting her Scientific Malaysian profile: http://www.scientificmalaysian.com/members/jianyi

References

[1] Seifert AW, Kiama SG, Seifert MG, Goheen JR, Palmer TM, Maden M. (2012) Skin shedding and tissue regeneration in African spiny mice (Acomys). Nature 489, 561–565.

[2] Poss KD. (2010) Advances in understanding tissue regenerative capacity and mechanisms in animals. Nature Reviews Genetics, 11, pp. 710–722.

[3] Jopling C, Boue S and Belmonte JCI. (2011) Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. Nature Reviews Molecular Cell Biology 12, 79-89.

[4] King RS and Newmark PA. (2012) The cell biology of regeneration. Journal of Cell Biology, 196(5):553-62



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