SCIENCE STORYTELLING Breaking the regeneration barrier

Breaking the

regeneration Barrier

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

by Jianyi lee

INƒŽƒ›•‹ƒǡ–Š‡•‹‰Š–‘ˆ–Š‡…‘‘Š‘—•‡Ž‹œƒ”†‹’‘•‹‰ƒ—™‡Ž…‘‡†•–ƒ›‹›‘—”Š‘‡ƒ›•‡‡ 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 1ȌǤŠ‹• 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 thought 1 ǤŠ‡”‡ˆ‘”‡ǡ—”ƒ˜‡Ž‹‰ the mystery behind how some of these model organisms regenerate is at the forefront of „‹‘‡†‹…ƒŽ”‡•‡ƒ”…ŠǤŠ‹•‘™Ž‡†‰‡™‹ŽŽ’ƒ˜‡ –Š‡™ƒ›ˆ‘”‘˜‡Žƒ†•’‡…‹ϐ‹…ƒŽŽ›†‡•‹‰‡† Photo: Deseret News ‡†‹…ƒŽ–Š‡”ƒ’‹‡•ˆ‘”–Š‘•‡ƒˆϐŽ‹…–‡†™‹–Š Figure 1: Limb regeneration in newts. 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 tissues 2 Ǥ‹–Š‹–Š‡ϐ‹‡Ž†‘ˆ”‡‰‡‡”ƒ–‹˜‡‡†‹…‹‡ǡ•…‹‡–‹•–••–”‹˜‡ to answer four main questions. First, what determines the regenerative potential of an organism? Second, ™Šƒ–ƒ”‡–Š‡…‡ŽŽ—Žƒ”•‘—”…‡•‘ˆ”‡‰‡‡”ƒ–‹˜‡–‹••—‡ǫŠ‹”†ǡŠ‘™†‘‡•‹Œ—”›‹‹–‹ƒ–‡”‡‰‡‡”ƒ–‹‘ǫ ‹ƒŽŽ›ǡ how does the organism control and terminate the regenerative program appropriately? Here, I present a minimalist view of common themes in regeneration.

‘’Ž‡š„‹‘Ž‘‰‹…ƒŽ’”‘…‡••‡••—…Šƒ•”‡‰‡‡”ƒ–‹‘ƒ”‡‹ϐŽ—‡…‡† “...mammals by multiple factors. In highly regenerative species, certain genetic pathways or conserved genes are selectively activated during actually have a regeneration. Incremental changes in the expression of these genes ƒ”‡•—ˆϐ‹…‹‡––‘–”‹‰‰‡””‡‰‡‡”ƒ–‹˜‡…ƒ’ƒ…‹–›ǤŠ‡”‡ˆ‘”‡ǡ‹†‡–‹ˆ›‹‰ higher capacity to –Š‡•’‡…‹ϐ‹…‘Ž‡…—Ž‡•–Šƒ–”‡‰—Žƒ–‡–Š‡•‡‰‡‡•…ƒ„‡–”ƒ•Žƒ–‡† into potential targets for therapy. In mammals, it is apparent that regenerate than ”‡‰‡‡”ƒ–‹˜‡‡ˆϐ‹…‹‡…›†‡…Ž‹‡•™‹–Šƒ‰‡Ǥ ‘”‹•–ƒ…‡ǡ›‘—‰…Š‹Ž†”‡ ƒ”‡ƒ„Ž‡–‘”‡‰”‘™Ž‘•–ϐ‹‰‡”–‹’•™Š‡”‡ƒ•ƒ†—Ž–•Žƒ…–Š‹•ƒ„‹Ž‹–›ǤŠ‹• previously thought.” 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 tissues 2 .

One can address the regeneration problem by understanding the origins of the new cells that reconstitute –Š‡”‡’Žƒ…‡‡––‹••—‡ǤŠ‡•‡…‡ŽŽ•ƒ”‡‡‹–Š‡”‰‡‡”ƒŽŽ›†‡”‹˜‡†ˆ”‘–Š‡”‡•‹†‡–•–‡…‡ŽŽ’‘’—Žƒ–‹‘‘” require the de-differentiation or trans-differentiation of existing cells 3 (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.

‡ƒ”ƒ„Ž›ǡϐŽƒ–™‘”••‡˜‡”‡†‹–‘ϐ‹˜‡‹†‹˜‹†—ƒŽ ’‹‡…‡•…ƒ—–‹Ž‹•‡•–‡…‡ŽŽ•–‘”‡„—‹Ž†ϐ‹˜‡•‡’ƒ”ƒ–‡ and complete animals within a week. Stem cell based strategies for regeneration require that these cells be maintained and activated appropriately. In view ‘ˆ–Šƒ–ǡ‹†‡–‹ϐ‹…ƒ–‹‘‘ˆ•–‡…‡ŽŽƒ”‡”•ƒ†•–‡ cell niches has helped us develop feasible methods for mass production of stem cells in laboratories. Š‡•‡…Š‘‹…‡•˜ƒ”›„‡–™‡‡•’‡…‹‡•ƒ†ƒŽ•‘ differ from one tissue to another within the same organism. Furthermore, the nature of the injury can ‹ϐŽ—‡…‡™Š‹…Š…‡ŽŽ—Žƒ”•‘—”…‡•ƒ”‡—•‡†–‘„—‹Ž†–Š‡ regenerating tissue.

In order for injured tissues to regenerate, they must initiate responses that alter their cellular behaviours ƒ––Š‡™‘—†•‹–‡Ǥ‡…Šƒ‹••‘’‡”ƒ–‡‡‹–Š‡” 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 proliferate Ͷ . Š‹••‡”˜‡•ƒ•ƒŠ‹‰ŠŽ›”‘„—•–™ƒ›ˆ‘”ƒ‹–ƒ‹‹‰ tissues with high turnover rates, such as in the intestine or during injury or infection. Regeneration can also be triggered by organ- and organism

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 mice 2 . taken to exercise control over the proliferation and patterning of the new tissue so that only appropriate structures are replaced and regeneration is –‡”‹ƒ–‡†ǤŠ‡•‡’”‘…‡••‡•”‡“—‹”‡–Š‡…‘‘’‡”ƒ–‹˜‡ efforts of molecules triggering cell division (mitogens), signals patterning the “...learning about tissue precisely, together with regeneration will the active process of have a profound sensing the scale and shape impact on the of the repaired tissue. We are way we overcome also beginning to appreciate debilitating medical the role of the nervous system conditions...” in the secretion of molecules encoding positional information for the actively renewing tissue Ͷ .

Š‡•›‹•–Š‡Ž‹‹–ǡ–Š‘—‰Š‹–™‹ŽŽ„‡ƒƒ––‡”‘ˆ time before advances in the experimental tools at our disposal can bridge the gaps in our knowledge ‘ˆ”‡‰‡‡”ƒ–‹˜‡„‹‘Ž‘‰›ǤŽ–‹ƒ–‡Ž›ǡŽ‡ƒ”‹‰ƒ„‘—– 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 ‹‘Ž‘‰›ˆ”‘–Š‡‹˜‡”•‹–›‘ˆ‹”‰‹‹ƒȋƒȌ‹ʹͲͲͺǤ She is currently a PhD candidate at the Department ‘ˆ‡ŽŽ‹‘Ž‘‰›ƒ–ƒǤ‡”–Š‡•‹•™‘”‹•ˆ‘…—•‡†‘ identifying the mechanisms that regulate sensory hair cell planar polarity in the inner ear. She can be reached at jl5zc@virginia.edu. Find out more about ‹ƒ›‹„›˜‹•‹–‹‰Š‡”…‹‡–‹ϐ‹…ƒŽƒ›•‹ƒ’”‘ϐ‹Ž‡ǣ Š––’ǣȀȀ™™™Ǥ•…‹‡–‹ϐ‹…ƒŽƒ›•‹ƒǤ…‘Ȁ‡„‡”•Ȁ jianyi/

REFERENCES: ȏͳȐ‡‹ˆ‡”–ǡ‹ƒƒ ǡ‡‹ˆ‡”– ǡ ‘Š‡‡ ǡƒŽ‡”ǡ ƒ†‡ǤȋʹͲͳʹȌ‹•Š‡††‹‰ƒ†–‹••—‡”‡‰‡‡”ƒ–‹‘‹ African spiny mice (Acomys). NatureͶͺͻǡͷ͸ͳȂͷ͸ͷǤ

[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.