Apoptotic Cells Activate the “Phoenix Rising” Pathway to Promote Wound Healing and Tissue Regeneration

Abstract

The ability to regenerate damaged tissues is a common characteristic of multicellular organisms. We report a role for apoptotic cell death in promoting wound healing and tissue regeneration in mice. Apoptotic cells released growth signals that stimulated the proliferation of progenitor or stem cells. Key players in this process were caspases 3 and 7, proteases activated during the execution phase of apoptosis that contribute to cell death. Mice lacking either of these caspases were deficient in skin wound healing and in liver regeneration. Prostaglandin E 2 , a promoter of stem or progenitor cell proliferation and tissue regeneration, acted downstream of the caspases. We propose to call the pathway by which executioner caspases in apoptotic cells promote wound healing and tissue regeneration in multicellular organisms the "Phoenix Rising" pathway.

Injury-induced asymmetric cell death as a driving force for head regeneration in Hydra

“…Here we viewed apoptosis as an additional signaling tool to launch head regeneration, the dying cells providing signals to modulate the behavior of their neighbors. This is an "inductive or active" view of injury-induced apoptosis, similar to that described in Drosophila or in mice (Ryoo et al 2004;Bergmann and Steller 2010;Li et al 2010). However injury-induced apoptosis can also be viewed as "suppressive or passive", as a way to transiently interrupt the cross-talk between two or several cell types, here the interstitial cells that die upon injury and the epithelial cells that survive.…”

“…Since the 70s it was known that dying cells can trigger the proliferation of their neighbors, a process firstly identified by developmental biologists who had noticed in Drosophila larvae that irradiation of their imaginal discs can induce regeneration through compensatory proliferation (Haynie and Bryant 1977;Bergmann and Steller 2010) and secondly by radiologists who had understood that irradiated tumoral tissues also lead to compensatory proliferation, proposing the name of "altruistic cell death" to describe this phenomenon (Kondo 1988;Li et al 2010 …”

Instructive reconstruction: A new role for apoptosis in pattern formation

“…This is likely to be the case as apoptosis-induced compensatory proliferation and regeneration is certainly conserved across numerous species [14][15][16][17]. Therefore, the link between apoptosis and developmental patterning should now be examined more closely in multiple phyla.…”

“…If the former is the case, the widespread mechanism of 'apoptosisinduced compensatory proliferation and regeneration' [14][15][16][17] can be incorporated into a broader developmental mechanism of 'instructive apoptotic patterning'.…”

Entre homéostasie et développement, quelles stratégies pour régénérer ?

“…Récemment, nous avons proposé que la prolifération compensatrice induite par l'apoptose agisse comme un mécanisme conservé capable de déclencher une réponse de type régénératif à une blessure. Ce mécanisme semble en effet être à l'oeuvre chez la larve de mouche qui régénère ses disques imaginaux (Fan & Bergmann, 2008a;Bergantinos et al, 2010;Morata et al, 2011), chez le têtard de Xénope qui régénère sa queue (Tseng et al, 2007), chez l'Hydre qui régénère sa tête après bissection mi-gastrique , ou chez la souris qui régénère sa peau ou son foie (Li et al, 2010). Par ailleurs l'apoptose a été détectée dans de nombreux contextes régénératifs tels que la planaire régénérant son corps (Hwang et al, 2004;Pellettieri et al, 2009).…”