A chloroquine sensitivity gradient induces tissue regeneration and maintenance phenotypes in planarians

Failure to properly regenerate and maintain tissues is a root cause of disease and aging. One goal of regenerative biology is to unveil mechanisms by which simpler model organisms successfully regenerate so that we can better understand how to control the cellular and molecular switches in human tissues. Planarians have become a favored model system for these studies because of their amazing capacity to fully and rapidly regenerate following amputation, but also for their response to other stressors such as starvation. Planarians undergo proportional degrowth when starved, a unique process that balances stem cell proliferation and apoptotic cell death, autophagy-mediated cell turnover, and energy sensing. We chose a pharmacological approach to study autophagy in planarians by using chloroquine, an autophagy inhibitor. We found that head regression and tissue lysis were induced by chloroquine in whole planarians and that starved planarians were more sensitive than their fed counterparts. While chloroquine treatment did not prevent tissue regeneration following injury, it caused regeneration delays and disruptions in photoreceptor replacement. Finally, we show that an anterior-posterior gradient of chloroquine sensitivity exists in the planarian with prepharyngeal tissues exhibiting significantly low sensitivity. Together, our results extend our understanding of autophagic flux in planarian tissue regeneration and maintenance and establish a model by which an autophagic gradient exists in this highly regenerative system.