TABLE 1.

Cellular behaviors underlying regenerative capacity in emerging models.

Organism and Cell Behavior	Evidence of Regeneration-specific Control/Modulation	References
Hydra
Apoptosis	Apoptotic cells at amputation site secrete pro-proliferative Wnt3a	Chera et al. (2009)
ECM Remodeling	ECM remodeling required for head regeneration	Shimizu et al. (2002)
Proliferation	Maintenance of dedicated stem cells that proliferate in response to injury	Hobmayer et al. (2012), Buzgariu et al. (2018)
Migration	Stem cell migration towards injury	Boehm and Bosch (2012)
Differentiation	Re-establishment of axial polarity (Wnt signaling) controls head/foot identity during new tissue differentiation	[reviewed in Vogg et al. (2019)]
Planarians
Apoptosis/Survival	Differential control of neuronal survival in pre-existing and regenerating tissue	LoCascio et al. (2017), Karge et al. (2020)
Immunity/Inflammation	Disruption of innate immune signaling compromises regeneration	Arnold et al. (2016)
Proliferation	Maintenance of dedicated pluripotent stem cells (neoblasts) that proliferate in response to injury	Baguñà et al. (1989), Wenemoser and Reddien (2010)
Migration	Stem cell migration towards amputation site; remodeling/collective migration of pre-existing intestinal tissue in regenerating fragments	Forsthoefel et al. (2011), Guedelhoffer and Sánchez Alvarado (2012)
Differentiation	Re-establishment of axial polarity cue expression controls patterning and differentiation of regenerating tissue	[reviewed in Reddien (2018)]
Axolotls and Newts
Cell death	Programmed cell death induces de-differentiation of myofibers to proliferative progenitors	Wang et al. (2015)
Immunity/Inflammation	Macrophages are required for regeneration	Godwin et al. (2013)
ECM/Fibrosis	Scar-free skin, limb, and organ regeneration	[reviewed in Godwin et al. (2014), Erickson and Echeverri (2018)]
Proliferation	Pro-proliferative MARCKS-like protein secreted in axolotl (but not mammals) to drive blastema formation; Schwann cell-expressed newt Anterior Gradient protein promotes proliferation in the limb blastema	Kumar et al. (2007), Sugiura et al. (2016)
De-differentiation	Injury-induced cell cycle re-entry of newt skeletal muscle myotubes and cardiomyocytes	Oberpriller and Oberpriller (1974), Tanaka et al. (1997), Bettencourt-Dias et al. (2003)
Differentiation	Maintenance of positional identity and re-establishment of axial polarity controls patterning and differentiation during limb regeneration	[reviewed in Vieira and McCusker (2019)]
Transdifferentiation	Newt pigmented epithelial cells transdifferentiate to regenerate lens	[reviewed in Henry and Tsonis (2010)]
Spiny Mice
Immunity/Inflammation	Pro-regenerative M2 macrophages required for ear pinna regeneration; spatial restriction/reduction of pro-inflammatory macrophages during ear and skin regeneration	Brant et al. (2016), Simkin et al. (2017), Maden (2018), Brant et al. (2019)
ECM/Fibrosis	Fibrosis resolves in dorsal skin wounds and injured adult kidney; decreased collagen deposition during skin and spinal cord regeneration; upstream fibrosis-associated Wnt expression different between A. cahirinus and M. musculus	Seifert et al. (2012), Brant et al. (2016), Brant et al. (2019), Streeter et al. (2020), Okamura et al. (2021)
Proliferation	Elevated proliferation associated with skin and ear pinnae regeneration	Seifert et al. (2012), Maden (2018)
Differentiation	Repeated muscle differentiation after chronic injury	Maden et al. (2018)
Additional examples
Acoels: Proliferation	Maintenance of dedicated pluripotent stem cells (neoblasts) that proliferate in response to injury	Srivastava et al. (2014)
Annelids: Migration	Stem cell migration towards amputation site	Zattara et al. (2016)
Sea cucumber:  De-differentiation	Mesenterial muscle de-differentiation during digestive tract regeneration	Candelaria et al. (2006)
Lampreys: Migration	Axon regrowth, synapse regeneration, and full functional recovery after spinal cord transection	Rovainen (1976), Oliphint et al. (2010)
Xenopus  tadpole: Apoptosis	Apoptosis is required for regeneration	Tseng et al. (2007)
Lizard: Proliferation	Proliferation of multiple cell types occurs during tail regeneration; homologs of proliferation-associated miRNAs upregulated during tail regeneration	[reviewed in Lozito and Tuan (2017)], Hutchins et al. (2016)