Regenerative capacity in newts is not altered by repeated regeneration and ageing

mages of regenerated lenses after the seventeenth lentectomy.

Following along a theme of what some would have called ‘Mad Science’ (the prior article being about a double leg transplant from a cadaver) we have a researcher who removed the lens from an eye of newts 18 times. Fictional Witches should never run out of the ingredient eye of newt.

Nature Communications – Regenerative capacity in newts is not altered by repeated regeneration and ageing

The extent to which adult newts retain regenerative capability remains one of the greatest unanswered questions in the regeneration field. Here we report a long-term lens regeneration project spanning 16 years that was undertaken to address this question. Over that time, the lens was removed 18 times from the same animals, and by the time of the last tissue collection, specimens were at least 30 years old. Regenerated lens tissues number 18 and number 17, from the last and the second to the last extraction, respectively, were analysed structurally and in terms of gene expression. Both exhibited structural properties identical to lenses from younger animals that had never experienced lens regeneration. Expression of mRNAs encoding key lens structural proteins or transcription factors was very similar to that of controls. Thus, contrary to the belief that regeneration becomes less efficient with time or repetition, repeated regeneration, even at old age, does not alter newt regenerative capacity.

Over a 16-year period, Panagiotis Tsonis at the University of Dayton, Ohio, and colleagues removed the lenses of six Japanese newts 18 times. After each excision, the lenses regenerated. They did so not from remaining lens tissue, but from pigment epithelial cells in the upper part of the iris.

By the end of the study the newts were 30 years old, five years older than their average lifespan in the wild. Even so, the regenerated lenses from the last two excisions were indistinguishable from lenses of 14-year-old adults that had never regenerated a lens.

Tsonis says the regenerative abilities may be down to efficient DNA repair. “The knowledge that newts can regenerate even in old age presents an opportunity to uncover mechanisms of regeneration resistant to ageing,” says James Godwin of the Australian Regenerative Medicine Institute in Clayton, Victoria. This, he adds, could one day help develop therapies to extend tissue regeneration in humans.

Our observation that regenerative ability in newts does not decline with repetition or over time suggests that mechanisms that underlie these activities are not altered by the debilitating effects of injury and ageing. It is also possible that the newt might use novel mechanisms to protect its cells from harmful mutations that might be introduced over long periods of time. It is important that no cataract (a common disease of the lens related to ageing) was ever observed. Moreover, our observations have significant consequences on the role of ‘precursor’ cells for lens transdifferentiation. If the source of the regenerating lens is cells of the iris that do not replenish themselves, then, by the 18th time there would be hardly any iris left. To alleviate such a problem two possibilities can be considered. First, that loss of iris PECs results in regeneration of iris from precursor cells and thus there is source of cells all the time. Second, that as the PECs divide, both daughter cells do not contribute to transdifferentiation, as one of them should be maintained as a PEC. The latter possibility seems most probable as the same occurs during retina regeneration from the retina pigment epithelium. In this sense, somatic PECs behave as progenitor cells. Such patterns of proliferation have not been studied well in this system, and our present data provide the impetus to identify them. Also, based on the fact that carcinogens induce lens regeneration even from the ventral iris (but no cancer) it is possible that signalling related to oncogenesis inhibits the action of replicative senescence during regeneration. In addition, despite beliefs that aged animals regenerate less efficiently than young ones (also discussed by Darwin), our experiments show that this is not the case in the newt. As regenerative medicine has entered a new era, the knowledge that aged tissues possess robust regenerative capabilities should provide the impetus to identify mechanisms underlying this capacity in the newt and compare them with strategies being employed to promote mammalian regeneration, such as the creation of iPS cells. Our findings, thus, are of paramount importance to the field of regeneration and ageing.

Panagiotis Tsonis webpage

Research: Mechanisms and induction of tissue regeneration

Tissue repair and regeneration of body parts are quite amazing biological and physiological processes that occur in all animals to one degree or another. Many animals, including humans, contain stem cells or progenitor cells that are capable of differentiating to several cell types at injury sites and contribute to repair. On the other hand some urodele amphibians have the incredible capacity of regenerating whole body parts, such as limbs, tails, spinal cord, eyes, brain, ear, jaw and heart. In these animals regeneration is achieved through the dedifferentiation of the existing terminally differentiated cells at the injury site. In other words these animals possess the unique capacity of returning their adult somatic cells back to an embryonic state or a progenitor state. To address these very important questions we use as a system regeneration of eye and limb tissues in amphibians. During the past few years we have learned much about the induction mechanisms and we are attempting to extend our studies in mammals as well. We have also heavily invested in establishing technology for gain and loss of function in adult newts as well as in creating resources, such as ESTs and whole transcriptome.

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