DOI: 10.1111/exd.12611 www.wileyonlinelibrary.com/journal/EXD
Commentary: My Favourite Historical Paper
Kerr’s coining of ‘Apoptosis’ and its relevance in skin wound healing and fibrosis Nivedita Ravindran and Elena Garcıa-Gareta RAFT Institute of Plastic Surgery, Mount Vernon Hospital, Northwood, UK Correspondence: Dr Elena Garcıa-Gareta, RAFT Institute of Plastic Surgery, Leopold Muller Building, Mount Vernon Hospital, Northwood HA6 2RN, UK, Tel.: +44-1923-844555, Fax: +44-1923-84403, e-mail: [email protected] Key words: apoptosis – cell death – fibrosis – tissue homeostasis – wound healing
Accepted for publication 27 November 2014
‘Apoptosis’, a Greek word meaning ‘dropping off’ or ‘falling off’, was first used by Kerr and team to label a form of cell death (Table 1) by a controlled genetic process whose morphological features were described in their seminal paper Kerr et al. (1), commented in this article. (The full article is freely available in PubMed Central http://www.ncbi.nlm.nih.gov/pubmed/4561027). Although they were the first to coin the term, it had been observed by a handful of scientists since the mid-nineteenth century and described under names such as ‘necrobiosis’ and ‘chromatolysis’ (2). By mid-1900’s, spontaneous cell death was a concept known to developmental biologists, but the features involved were not elucidated, and it drew little interest from the wider scientific community (2). It was not until Kerr’s landmark paper that ‘apoptosis’ as we know it came to be recognized as a phenomenon distinctly different from ‘necrosis’. Kerr himself initially used the term ‘shrinkage necrosis’ to describe his observations of cell death. In his 1965 experiment, he ligated a branch of the hepatic portal vein resulting in liver atrophy. He observed classical necrosis and a different form of cell death in the surviving tissue as liver shrinkage occurred. Some hepatocytes rounded off into small bodies of cytoplasm which sometimes contained condensed chromatin, these were then engulfed by the neighbouring cells or by specialized histiocytes (3). Kerr observed that these cells were in reality dying off to probably achieve a balance between surviving cells and the remaining blood supply (4). In the following years, he began to study the morphological features of ‘shrinkage necrosis’ using the electron microscope. On a sabbatical leave to Aberdeen, he collaborated
with pathologists Alastair Currie and Andrew Wyllie who had themselves observed ‘shrinkage necrosis’ in rat adrenal cortices when adrenocorticotropic hormone was suppressed (3). It was here that they coined the term ‘apoptosis’ and described its morphological features. Decades later, this has evolved into the current understanding of the morphological hallmarks of apoptosis summarized in Fig. 1. Kerr et al. studied various instances of spontaneous cell loss such as in neoplasms, types of liver and adrenal injury, and in ontogenesis. They came to the fascinating conclusion that the morphological and ultra structural features exhibited by the phenomenon of cell death in each case were the same (1). We believe this was a remarkable achievement as nobody so far had realized that the features of this process in various tissues was similar enough to propose it as a concept of programmed cell death which as Kerr put it ‘plays a complementary but opposite role to mitosis’ in maintaining tissue homoeostasis. Interestingly, Kerr’s paper on apoptosis did not lead to an immediate flurry of research on the topic. However, the invention of novel techniques to detect apoptosis in cells, the discovery of genes regulating apoptosis in Caenorhabditis elegans and their mammalian homologues such as the BCL2 gene all played crucial roles in kindling scientific interest towards elucidating the biochemical mechanisms of apoptosis and the apoptotic machinery (5). It is now a well-known fact that altered tissue homoeostasis as a result of too much or too less apoptosis leads to a number of cutaneous pathologies such as toxic epidermal necrolysis, psoriasis, forms of skin cancer and fibrosis (6). Moreover, the molecular
Table 1. Forms of cell death Non-Inflammatory Apoptosis Anoikis Autophagic Cell Death Cornification Inflammatory Necrosis Necroptosis Oncosis Pyroptosis
A form of programmed cell death that involves a controlled sequence of steps characterized by distinct morphological features. At the end, apoptosis produces cell fragments or apoptotic bodies quickly removed by phagocytic cells (14) A form of programmed cell death in response to inappropriate cell/extracellular matrix interactions (15) Non-apoptotic or necrotic programmed cell death in which autophagy acts as a cell death mechanism. The same proteins are involved in both autophagy (survival) and autophagic cell death but their regulation is substantially different during each process. Its physiological relevance is mainly observed in lower eukaryotes and invertebrates (16) Very specific form of programmed cell death occurring in the epidermis. Also referred to as ‘keratinization’ or ‘cornified envelope formation’, it leads to the formation of corneocytes (dead keratinocytes) (17) Accidental cell death that results in autolysis and release of intracellular content causing inflammation (18) Also called ‘programmed necrosis’, necroptosis is a non-apoptotic backup, necrosis-like cell death mechanism that is initiated when apoptosis is blocked. Necroptosis is a RIP1/RIP3-dependent programmed cell death (19) Also known as ischaemic cell death, oncosis is a form of accidental cell death characterized by cell swelling and coagulation of the cytoplasm (20) Caspase-1-dependent programmed cell death stimulated by a range of microbial infections as well as non-infectious stimuli such as host factors during myocardial infarction (21)
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2015, 24, 99–100
99
Commentary: my favourite historical paper
Figure 1. Current understanding of the morphological hallmarks of apoptosis in the footsteps of Kerr et al. 1972.
details of apoptosis regulation are becoming ever better defined, including by most recent studies published in this journal (7–9). An excellent example is the role of apoptosis in skin wound healing, a highly organized process in which specific cells arrive, proliferate and are downregulated before the next wave of cells appear (5). In the inflammatory stage apoptosis is believed to be the most energy efficient way of removing the inflammatory cells (5). A currently researched topic is the elucidation of the molecular signals and growth factors involved in initiating apoptosis of neutrophils and other immune cells (5). In the next phase of formation of granulation tissue, fibroblasts need to be downregulated after a point, achieved by apoptosis, also involved in stimulating collagenase activity (5). Formation of blood vessels by endothelial cells and wound contraction by myofibroblasts are also believed to be regulated by apoptosis (5). After the final maturation phase, the end result is a healed wound with reduced cellularity, vascularity and scar thickness.
In contrast, in fibrotic outcomes such as hypertrophic scars and keloids, the healing process results in an inflamed wound where the number of cells, blood vessels and extracellular matrix content differ from a normal wound. Recent studies point at apoptosis as a key role player in regulating cell numbers in fibrosis (5). The persistence of inflammatory cells and an imbalance in fibroblast cell turnover mainly contribute to pathologic conditions (10,11). Increased endothelial cell apoptotic load with a correlation to angiogenesis has been implicated in fibrotic outcomes (10). The upregulation and downregulation of apoptotic proteins such as Bcl2 and p53 are being studied as indicators of apoptotic levels in abnormal wounds (5). Studies have shown that under stress, apoptotic cells can release mitotic signals affecting the neighbouring cells which can have implications in wound healing (12). Further research into the molecular signals involved in initiating or preventing apoptosis in cutaneous fibrotic conditions will benefit treatment options. In conclusion, research in apoptosis has come a long way since the coining of this term and formal recognition of the underlying process. The tremendous explosion of apoptosis research has led to the discovery of a number of molecular regulators of this process. A very exciting frontier is the development of anti-apoptotic drugs to target these regulators. Anti-apoptotic drugs which were just a prospect a few years back are currently being used in human phase trials along with other treatment strategies (13). Any signs of success would only further the realms of apoptosis research and keep this an intriguing field for decades to come.
Acknowledgement This work was supported by the Restoration of Appearance and Function Trust (UK, registered charity number 299811) charitable funds.
Author contribution NR performed the research and wrote the paper. EG designed the commentary, wrote the paper and critically revised it. Both authors approved the submitted and final version.
Conflict of interest The authors have declared no conflicting interests.
References 1 Kerr J F, Wyllie A H, Currie A R. Br J Cancer 1972: 26: 239. 2 Majno G, Joris I. Am J Pathol 1995: 146: 1. 3 Kerr J F. Toxicology 2002: 181–182: 471–474. 4 Kerr J F. J Pathol 1971: 105: 13–20. 5 Huang N F, Varghese S Z, Luke S. Wounds 2003: 15: 7. 6 Scharadin T M, Eckert R L. J Invest Dermatol 2014: 134: 1811–1816. 7 Liu H, Jian Q, Xue K et al. Exp Dermatol 2014: 23: 896–901. 8 Plotz M, Eberle J. Exp Dermatol 2014: 23: 375– 378. 9 Miyazaki T, Kadono N, Konishi Y et al. Exp Dermatol 2013: 22: 845–847.
100
10 Johnson A, DiPietro L A. FASEB J 2013: 27: 3893–3901. 11 Shih B, Garside E, McGrouther D A et al. Wound Repair Regen 2010: 18: 139–153. 12 Suzanne M, Stellar H. Cell Death Differ 2013: 20: 669–675. 13 Nikolaou V, Stratigos A, Bafaloukos D, Katsambas A. Clin Dermatol 2013: 31: 257–263. 14 Wlodkowic D, Telford W, Skommer J, Darzynkiewicz Z. Methods Cell Biol 2011: 103: 55–98. 15 Gilmore A P. Cell Death Differ 2005: 12: 1473–1477. 16 Shen H M, Codogno P. Autophagy 2011: 7: 457–465. 17 Kroemer G, Galluzzi L, Vandenabeele P et al. Cell Death Differ 2009: 16: 3–11.
18 Vanden Berghe T, Linkermann A, JouanLanhouet S et al. Nat Rev Mol Cell Biol 2014: 15 : 135–147. 19 Saeed W K, Jun D W. World J Gastroenterol 2014: 20: 12526–12532. 20 Weerasinghe P, Buja L M. Exp Mol Pathol 2012: 93: 302–308. 21 Bergsbaken T, Fink SL, Cookson BT. Nat Rev Microbiol 2009: 7: 99–109.
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2015, 24, 99–100
Commentary: My Favourite Historical Paper
Kerr’s coining of ‘Apoptosis’ and its relevance in skin wound healing and fibrosis Nivedita Ravindran and Elena Garcıa-Gareta RAFT Institute of Plastic Surgery, Mount Vernon Hospital, Northwood, UK Correspondence: Dr Elena Garcıa-Gareta, RAFT Institute of Plastic Surgery, Leopold Muller Building, Mount Vernon Hospital, Northwood HA6 2RN, UK, Tel.: +44-1923-844555, Fax: +44-1923-84403, e-mail: [email protected] Key words: apoptosis – cell death – fibrosis – tissue homeostasis – wound healing
Accepted for publication 27 November 2014
‘Apoptosis’, a Greek word meaning ‘dropping off’ or ‘falling off’, was first used by Kerr and team to label a form of cell death (Table 1) by a controlled genetic process whose morphological features were described in their seminal paper Kerr et al. (1), commented in this article. (The full article is freely available in PubMed Central http://www.ncbi.nlm.nih.gov/pubmed/4561027). Although they were the first to coin the term, it had been observed by a handful of scientists since the mid-nineteenth century and described under names such as ‘necrobiosis’ and ‘chromatolysis’ (2). By mid-1900’s, spontaneous cell death was a concept known to developmental biologists, but the features involved were not elucidated, and it drew little interest from the wider scientific community (2). It was not until Kerr’s landmark paper that ‘apoptosis’ as we know it came to be recognized as a phenomenon distinctly different from ‘necrosis’. Kerr himself initially used the term ‘shrinkage necrosis’ to describe his observations of cell death. In his 1965 experiment, he ligated a branch of the hepatic portal vein resulting in liver atrophy. He observed classical necrosis and a different form of cell death in the surviving tissue as liver shrinkage occurred. Some hepatocytes rounded off into small bodies of cytoplasm which sometimes contained condensed chromatin, these were then engulfed by the neighbouring cells or by specialized histiocytes (3). Kerr observed that these cells were in reality dying off to probably achieve a balance between surviving cells and the remaining blood supply (4). In the following years, he began to study the morphological features of ‘shrinkage necrosis’ using the electron microscope. On a sabbatical leave to Aberdeen, he collaborated
with pathologists Alastair Currie and Andrew Wyllie who had themselves observed ‘shrinkage necrosis’ in rat adrenal cortices when adrenocorticotropic hormone was suppressed (3). It was here that they coined the term ‘apoptosis’ and described its morphological features. Decades later, this has evolved into the current understanding of the morphological hallmarks of apoptosis summarized in Fig. 1. Kerr et al. studied various instances of spontaneous cell loss such as in neoplasms, types of liver and adrenal injury, and in ontogenesis. They came to the fascinating conclusion that the morphological and ultra structural features exhibited by the phenomenon of cell death in each case were the same (1). We believe this was a remarkable achievement as nobody so far had realized that the features of this process in various tissues was similar enough to propose it as a concept of programmed cell death which as Kerr put it ‘plays a complementary but opposite role to mitosis’ in maintaining tissue homoeostasis. Interestingly, Kerr’s paper on apoptosis did not lead to an immediate flurry of research on the topic. However, the invention of novel techniques to detect apoptosis in cells, the discovery of genes regulating apoptosis in Caenorhabditis elegans and their mammalian homologues such as the BCL2 gene all played crucial roles in kindling scientific interest towards elucidating the biochemical mechanisms of apoptosis and the apoptotic machinery (5). It is now a well-known fact that altered tissue homoeostasis as a result of too much or too less apoptosis leads to a number of cutaneous pathologies such as toxic epidermal necrolysis, psoriasis, forms of skin cancer and fibrosis (6). Moreover, the molecular
Table 1. Forms of cell death Non-Inflammatory Apoptosis Anoikis Autophagic Cell Death Cornification Inflammatory Necrosis Necroptosis Oncosis Pyroptosis
A form of programmed cell death that involves a controlled sequence of steps characterized by distinct morphological features. At the end, apoptosis produces cell fragments or apoptotic bodies quickly removed by phagocytic cells (14) A form of programmed cell death in response to inappropriate cell/extracellular matrix interactions (15) Non-apoptotic or necrotic programmed cell death in which autophagy acts as a cell death mechanism. The same proteins are involved in both autophagy (survival) and autophagic cell death but their regulation is substantially different during each process. Its physiological relevance is mainly observed in lower eukaryotes and invertebrates (16) Very specific form of programmed cell death occurring in the epidermis. Also referred to as ‘keratinization’ or ‘cornified envelope formation’, it leads to the formation of corneocytes (dead keratinocytes) (17) Accidental cell death that results in autolysis and release of intracellular content causing inflammation (18) Also called ‘programmed necrosis’, necroptosis is a non-apoptotic backup, necrosis-like cell death mechanism that is initiated when apoptosis is blocked. Necroptosis is a RIP1/RIP3-dependent programmed cell death (19) Also known as ischaemic cell death, oncosis is a form of accidental cell death characterized by cell swelling and coagulation of the cytoplasm (20) Caspase-1-dependent programmed cell death stimulated by a range of microbial infections as well as non-infectious stimuli such as host factors during myocardial infarction (21)
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2015, 24, 99–100
99
Commentary: my favourite historical paper
Figure 1. Current understanding of the morphological hallmarks of apoptosis in the footsteps of Kerr et al. 1972.
details of apoptosis regulation are becoming ever better defined, including by most recent studies published in this journal (7–9). An excellent example is the role of apoptosis in skin wound healing, a highly organized process in which specific cells arrive, proliferate and are downregulated before the next wave of cells appear (5). In the inflammatory stage apoptosis is believed to be the most energy efficient way of removing the inflammatory cells (5). A currently researched topic is the elucidation of the molecular signals and growth factors involved in initiating apoptosis of neutrophils and other immune cells (5). In the next phase of formation of granulation tissue, fibroblasts need to be downregulated after a point, achieved by apoptosis, also involved in stimulating collagenase activity (5). Formation of blood vessels by endothelial cells and wound contraction by myofibroblasts are also believed to be regulated by apoptosis (5). After the final maturation phase, the end result is a healed wound with reduced cellularity, vascularity and scar thickness.
In contrast, in fibrotic outcomes such as hypertrophic scars and keloids, the healing process results in an inflamed wound where the number of cells, blood vessels and extracellular matrix content differ from a normal wound. Recent studies point at apoptosis as a key role player in regulating cell numbers in fibrosis (5). The persistence of inflammatory cells and an imbalance in fibroblast cell turnover mainly contribute to pathologic conditions (10,11). Increased endothelial cell apoptotic load with a correlation to angiogenesis has been implicated in fibrotic outcomes (10). The upregulation and downregulation of apoptotic proteins such as Bcl2 and p53 are being studied as indicators of apoptotic levels in abnormal wounds (5). Studies have shown that under stress, apoptotic cells can release mitotic signals affecting the neighbouring cells which can have implications in wound healing (12). Further research into the molecular signals involved in initiating or preventing apoptosis in cutaneous fibrotic conditions will benefit treatment options. In conclusion, research in apoptosis has come a long way since the coining of this term and formal recognition of the underlying process. The tremendous explosion of apoptosis research has led to the discovery of a number of molecular regulators of this process. A very exciting frontier is the development of anti-apoptotic drugs to target these regulators. Anti-apoptotic drugs which were just a prospect a few years back are currently being used in human phase trials along with other treatment strategies (13). Any signs of success would only further the realms of apoptosis research and keep this an intriguing field for decades to come.
Acknowledgement This work was supported by the Restoration of Appearance and Function Trust (UK, registered charity number 299811) charitable funds.
Author contribution NR performed the research and wrote the paper. EG designed the commentary, wrote the paper and critically revised it. Both authors approved the submitted and final version.
Conflict of interest The authors have declared no conflicting interests.
References 1 Kerr J F, Wyllie A H, Currie A R. Br J Cancer 1972: 26: 239. 2 Majno G, Joris I. Am J Pathol 1995: 146: 1. 3 Kerr J F. Toxicology 2002: 181–182: 471–474. 4 Kerr J F. J Pathol 1971: 105: 13–20. 5 Huang N F, Varghese S Z, Luke S. Wounds 2003: 15: 7. 6 Scharadin T M, Eckert R L. J Invest Dermatol 2014: 134: 1811–1816. 7 Liu H, Jian Q, Xue K et al. Exp Dermatol 2014: 23: 896–901. 8 Plotz M, Eberle J. Exp Dermatol 2014: 23: 375– 378. 9 Miyazaki T, Kadono N, Konishi Y et al. Exp Dermatol 2013: 22: 845–847.
100
10 Johnson A, DiPietro L A. FASEB J 2013: 27: 3893–3901. 11 Shih B, Garside E, McGrouther D A et al. Wound Repair Regen 2010: 18: 139–153. 12 Suzanne M, Stellar H. Cell Death Differ 2013: 20: 669–675. 13 Nikolaou V, Stratigos A, Bafaloukos D, Katsambas A. Clin Dermatol 2013: 31: 257–263. 14 Wlodkowic D, Telford W, Skommer J, Darzynkiewicz Z. Methods Cell Biol 2011: 103: 55–98. 15 Gilmore A P. Cell Death Differ 2005: 12: 1473–1477. 16 Shen H M, Codogno P. Autophagy 2011: 7: 457–465. 17 Kroemer G, Galluzzi L, Vandenabeele P et al. Cell Death Differ 2009: 16: 3–11.
18 Vanden Berghe T, Linkermann A, JouanLanhouet S et al. Nat Rev Mol Cell Biol 2014: 15 : 135–147. 19 Saeed W K, Jun D W. World J Gastroenterol 2014: 20: 12526–12532. 20 Weerasinghe P, Buja L M. Exp Mol Pathol 2012: 93: 302–308. 21 Bergsbaken T, Fink SL, Cookson BT. Nat Rev Microbiol 2009: 7: 99–109.
ª 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Experimental Dermatology, 2015, 24, 99–100
