_Dear Editor,_ During the EMBO Programmed Cell Death in Model Organisms meeting that was held in Israel (February 2012), the topic of compensatory proliferation (CP) took an important place

in conference presentations and animated discussions. Several scientists felt the need for a term clarification at a time when the importance of the findings made in _Drosophila_ have

greatly impacted the understanding of tumor repopulation during cancer irradiation and also the process of regeneration in vertebrates. The scientists agreed that the terms of CP have been

used sometimes inappropriately to describe the process by which apoptotic cells mediate mitogenic signaling thus promoting proliferation of the surrounding cells. The phenomenon of CP was

stimulated to undergo apoptosis were able to promote proliferation of neighboring cells.1, 2, 3, 4 This suggested that apoptotic cells can release mitogenic signals to promote tissue repair

and regeneration (Supplementary Figure S1B). Candidates for mitogens produced by apoptotic cells included the products of the signaling genes _wingless_ (_wg_) and _decapentaplegic_ (_dpp_),

which are activated under these conditions.4, 5 However, it is important to mention that in those experiments the authors used ‘undead’ cells: in these, apoptosis is induced by stress

treatments or by ectopic induction of pro-apoptotic genes, but the cells are kept alive by the caspase inhibitor P35. Under these conditions, there is no ‘compensation’ for cell loss because

the cells do not die, and hence it is problematic to refer to this paradigm as ‘compensatory proliferation’. On the other hand, the persistent secretion of the Dpp and Wg mitogens results

in excessive cell proliferation and the generation of hyperplastic overgrowths in the discs.2, 4, 5 One important finding was that the secretion of Wg and Dpp is not limited to undead cells,

but also occurs in ‘genuine’ apoptotic cells.1, 3, 4, 6 These observations suggested that the proliferation mediated by apoptotic cells might have an important role in CP,1, 3, 4 as it

would be instrumental in the restoration of normal size after massive cell death. However, flies carrying mutations in both _wg_ and _dpp_ are still capable of CP after high levels of X-rays

induced apoptosis.5 Therefore either additional signals from apoptotic cells or more complex mechanisms must contribute to CP. In contrast, the hyperplastic overgrowths triggered by

‘undead’ cells are dependent on _wg_ and _dpp_, as cells mutant for either wg or dpp cannot produce them. The ability of apoptotic cells to secrete mitogenic signals may be of major

significance in regeneration processes and in the development of tumors. The formation of a new head of Hydra after amputation requires Wnt3-mediated induction of proliferation by apoptotic

cells close to the cut site.7 More recently, it was shown that PGE2 emanating from apoptotic cells stimulates the growth of surviving tumor cells after irradiation and thereby promotes the

repopulation of the tumor.8 Thus, the understanding of apoptosis-induced proliferation may open a new avenue to improve cancer radiotherapy. In conclusion, we recommend a precise and

distinct use of the terms of CP and apoptosis-induced proliferation or mitogenic signaling. CP is the process by which an injured tissue recovers its original size and in which the role of

apoptosis remains to be elucidated. Apoptosis-induced proliferation is a cellular process by which apoptotic cells secrete mitogens, which in turn promote proliferation of surrounding living

cells. REFERENCES * Fan Y, Bergmann A . _Dev Cell_ 2008; 14: 399–410. * Kondo S _et al_ _Mol Cell Biol_ 2006; 26: 7258–7268. * Perez-Garijo A, Martin FA, Morata G . _Development_ 2004; 131:

5591–5598. * Ryoo HD, Gorenc T, Steller H . _Dev Cell_ 2004; 7: 491–501. * Perez-Garijo A, Shlevkov E, Morata G . _Development_ 2009; 136: 1169–1177. * Smith-Bolton RK _et al_ _Dev Cell_

2009; 16: 797–809. * Chera S _et al_ _Dev Cell_ 2009; 17: 279–289. * Huang Q _et al_ _Nat Med_ 2011; 17: 860–866. Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Group

Apoptosis and Neurogenetics, Laboratory of Molecular Biology of the Cell, CNRS UMR5239, Ecole Normale Supérieure de Lyon, UMS3444 Biosciences Lyon Gerland, Université de Lyon, Lyon, 69007,

France B Mollereau * Howard Hughes Medical Institute, Laboratory of Apoptosis and Cancer Biology, The Rockefeller University, New York, NY, USA A Perez-Garijo & H Steller * Department of

Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA A Bergmann * Department of Genetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, CREST,

JST 7-3-1 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan M Miura * Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah

Medical School, Jerusalem, 91120, Israel O Gerlitz * Department of Cell Biology, New York University School of Medicine, New York, NY, USA H D Ryoo * Centro de Biología Molecular, CSIC-UAM,

Madrid, Spain G Morata Authors * B Mollereau View author publications You can also search for this author inPubMed Google Scholar * A Perez-Garijo View author publications You can also

search for this author inPubMed Google Scholar * A Bergmann View author publications You can also search for this author inPubMed Google Scholar * M Miura View author publications You can

also search for this author inPubMed Google Scholar * O Gerlitz View author publications You can also search for this author inPubMed Google Scholar * H D Ryoo View author publications You

can also search for this author inPubMed Google Scholar * H Steller View author publications You can also search for this author inPubMed Google Scholar * G Morata View author publications

You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to B Mollereau, H Steller or G Morata. ETHICS DECLARATIONS COMPETING INTERESTS The authors

declare no conflict of interest. ADDITIONAL INFORMATION Supplementary Information accompanies the paper on Cell Death and Differentiation website SUPPLEMENTARY INFORMATION SUPPLEMENTARY

FIGURE SUPPLEMENTARY FIGURE LEGEND RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Mollereau, B., Perez-Garijo, A., Bergmann, A. _et al._ Compensatory

proliferation and apoptosis-induced proliferation: a need for clarification. _Cell Death Differ_ 20, 181 (2013). https://doi.org/10.1038/cdd.2012.82 Download citation * Published: 22 June

2012 * Issue Date: January 2013 * DOI: https://doi.org/10.1038/cdd.2012.82 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link

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