Integrin-alpha-6+ Candidate stem cells are responsible for whole body regeneration in the invertebrate chordate Botrylloides diegensis

Abstract

Colonial ascidians are the only chordates able to undergo whole body regeneration (WBR), during which entire new bodies can be regenerated from small fragments of blood vessels. Here, we show that during the early stages of WBR in Botrylloides diegensis, proliferation occurs only in small, blood-borne cells that express integrin-alpha-6 (IA6), pou3 and vasa. WBR cannot proceed when proliferating IA6+ cells are ablated with Mitomycin C, and injection of a single IA6+ Candidate stem cell can rescue WBR after ablation. Lineage tracing using EdU-labeling demonstrates that donor-derived IA6+ Candidate stem cells directly give rise to regenerating tissues. Inhibitors of either Notch or canonical Wnt signaling block WBR and reduce proliferation of IA6+ Candidate stem cells, indicating that these two pathways regulate their activation. In conclusion, we show that IA6+ Candidate stem cells are responsible for whole body regeneration and give rise to regenerating tissues.

And Then There Were Three…: Extreme Regeneration Ability of the Solitary Chordate Polycarpa mytiligera

“…Ascidians are unique among the chordates as they present robust regeneration abilities, including whole body regeneration, following an injury ( Voskoboynik et al, 2007 ; Blanchoud et al, 2018 ; Kassmer et al, 2020 ). The current study has uncovered exceptional regeneration abilities in a solitary ascidian, a group of animals considered to be regeneratively deficient compared to their colonial relatives ( Kassmer et al, 2019 ).…”

“…Undifferentiated circulatory cells were shown to be involved in tissue regeneration in solitary and colonial ascidians ( Rinkevich et al, 2006 ; Auger et al, 2010 ; Jeffery, 2014 , 2015 , 2019 ). In colonial Styelidae species, a population of pluripotent or multipotent undifferentiated circulatory cells contributes to the formation of somatic tissues during budding and whole body regeneration ( Laird et al, 2005 ; Voskoboynik et al, 2007 ; Brown and Swalla, 2012 ; Kassmer et al, 2020 ). In the solitary ascidian C. intestinalis , injury-induced regeneration resulted in the proliferation of circulatory cells located in the branchial basket.…”

“…Ascidians are sessile invertebrates found in all marine habitats, from shallow waters to the deep sea ( Monniot et al, 1991 ; Shenkar and Swalla, 2011 ). Their phylogenetic position as a sister group of the vertebrates, simple body plan, and exceptional regenerative abilities ( Voskoboynik et al, 2007 ; Brown et al, 2009 ; Kassmer et al, 2020 ), have established them as a valuable model system for developmental and evolutionary studies ( Satoh and Jeffery, 1995 ; Corbo et al, 2001 ; Passamaneck and Di Gregorio, 2005 ; Delsuc et al, 2006 ; Voskoboynik and Weissman, 2015 ; Kowarsky et al, 2019 ; Manni et al, 2019 ).…”

“…In addition to these developmental processes, which are part of their life cycle, both solitary and colonial ascidians share another mode of development in the form of tissue and whole-body regeneration ( Gordon et al, 2019 ; Kassmer et al, 2019 ; Alié et al, 2020 ). Colonial species possess high regenerative abilities, being able to regenerate their entire body from small tissue fragments or blood cells ( Voskoboynik et al, 2007 ; Brown et al, 2009 ; Blanchoud et al, 2017 ; Kassmer et al, 2020 ). In contrast, the few solitary species studied to date have demonstrated a more limited ability, as most can only regenerate anterior organs following their removal, such as the siphons and neural complex ( Jeffery, 2015 ; Medina et al, 2015 ; Gordon et al, 2019 ).…”

“…Recent studies have demonstrated that regeneration in both colonial and solitary ascidians involves the proliferation of pluripotent or multipotent cells that eventually give rise to a blastema (Jeffery, 2014(Jeffery, , 2019Kassmer et al, 2016). Kassmer et al (2020) showed the presence of blood-borne multipotent cells in the colonial Botrylloides leachii (order Stolidobranchia) and demonstrated their functional role in whole-body regeneration. Similarly, in the solitary ascidian Ciona intestinalis (order Phlebobranchia), branchial sac piwi-positive hemocytes were shown to migrate and proliferate in response to injury (Jeffery, 2014).…”