Critical role of the endogenous renin-angiotensin system in maintaining self-renewal and regeneration potential of epidermal stem cells
Open accessAbstract
A tightly controlled activity of renin-angiotensin system (RAS) including renin, angiotensin-converting enzymes (ACEs), and angiotensin II (Ang II) receptors is critical not only for maintaining systemic hemodynamics and blood volume but also for controlling cell proliferation, differentiation, and tissue remodeling in target organs. ACE inhibitors or Ang II receptor type 1 (AT1R) blockers are widely used as first line drugs for the treatment of cardiovascular diseases that are caused by chronical activation of RAS. However, about 15% of patients using ACE inhibitors develop side effects in the skin and the underlying mechanisms have been poorly understood or even neglected. Herein we show an endogenous RAS in maintaining self-renewal and regeneration potential of epidermal stem cells (ESCs) thereby contributing to wound healing. Firstly, we found that ESCs may express ACE, and its members in wound edges were positively associated with wound healing in Captopril-treated rats. Secondly, we demonstrated that human ESCs had a functional RAS including ACE1, ACE2, Ang II, AT1R, and AT2R. ACE-Ang II axis maintains human ESC function via activation of both AT1R and AT2R, which are negatively regulated by each other. Ang II-induced activation of extracellular signal-regulated kinase (ERK) and signal transducers and activators of transcription (STAT)1 and STAT3 was mediated by the negative cross-talk between AT1R and AT2R in human ESCs. These results suggest that Ang II is a critical regulator of ESC function and ESC-mediated epidermal regeneration. Inappropriate interruption of Ang II-operated signaling may prejudice ESC function leading to impaired skin wound healing or even disease.
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Local RAS is key to regulating repair and regeneration in epidermal and vasculogenesis-related progenitor cells.
“Local RAS has been proved to be the key to regulating repair and regeneration in epidermal and vasculogenesis related progenitor cells [8, 9].”
From Transplantation of human umbilical cord-derived mesenchymal stem cells improves age-related ovarian functional decline via regulating the local renin–angiotensin system on inflammation and oxidative stress (2024) · cites this paper as [8]
The Discussion reports that endogenous RAS plays a critical role in the self-renewal and regeneration potential of epidermal stem cells during skin wound healing. It does not establish the claimed role in vasculogenesis-related progenitor cells. (LLM, conf=0.88)
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Cites
Renin-angiotensin system: biochemistry and mechanisms of action.
Peach, M. J. (1977) · Physiological Reviews · doi:10.1152/physrev.1977.57.2.313 · Cited by 1,380 · see citing works
Distinct contribution of stem and progenitor cells to epidermal maintenance
Mascré, G., Dekoninck, S., Drogat, B., Youssef, K. K., Brohée, S., Sotiropoulou, P. A., Simons, B. D., & Blanpain, C. (2012) · Nature · doi:10.1038/nature11393 · Cited by 567 · see citing works
Hunyady, L., & Catt, K. J. (2006) · Molecular Endocrinology · doi:10.1210/me.2004-0536 · Cited by 541 · see citing works
Identification and characterization of a functional mitochondrial angiotensin system
Abadir, P. M., Foster, D. B., Crow, M. T., Cooke, C. A., Rucker, J. J., Jain, A., Smith, B. J., Burks, T. N., Cohn, R. D., Fedarko, N. S., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1101507108 · Cited by 279 · see citing works
More than one way to skin . . .
Fuchs, E., & Horsley, V. (2008) · Genes & Development · doi:10.1101/gad.1645908 · Cited by 224 · see citing works
Epithelial stem cells and implications for wound repair
Plikus, M. V., Gay, D. L., Treffeisen, E. R., Wang, A., Supapannachart, R. J., & Cotsarelis, G. (2012) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2012.10.001 · Cited by 199 · see citing works
Rennert, R. C., Sorkin, M., Januszyk, M., Duscher, D., Kosaraju, R. S., Chung, M. T., Lennon, J., Radiya-Dixit, A., Raghvendra, S., Maan, Z. N., et al. (2014) · Stem Cell Research & Therapy · doi:10.1186/scrt468 · Cited by 175 · see citing works
Human skin: source of and target organ for angiotensin II
Steckelings, U. M., Wollschläger, T., Peters, J., Henz, B. M., Hermes, B., & Artuc, M. (2004) · Experimental Dermatology · doi:10.1111/j.0906-6705.2004.0139.x · Cited by 154 · see citing works
The role of the renin-angiotensin-aldosterone system in diabetes and its vascular complications
COOPER, M. (2004) · American Journal of Hypertension · doi:10.1016/j.amjhyper.2004.08.004 · Cited by 147 · see citing works
Janes, S. M., Lowell, S., & Hutter, C. (2002) · The Journal of Pathology · doi:10.1002/path.1156 · Cited by 147 · see citing works
A Novel Function of Angiotensin II in Skin Wound Healing
Yahata, Y., Shirakata, Y., Tokumaru, S., Yang, L., Dai, X., Tohyama, M., Tsuda, T., Sayama, K., Iwai, M., Horiuchi, M., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m509771200 · Cited by 140 · see citing works
Neuroendocrine System of the Skin
Slominski, A. T. (2005) · Dermatology · doi:10.1159/000087012 · Cited by 138 · see citing works
Tetzner, A., Gebolys, K., Meinert, C., Klein, S., Uhlich, A., Trebicka, J., Villacañas, Ó., & Walther, T. (2016) · Hypertension · doi:10.1161/hypertensionaha.116.07572 · Cited by 134 · see citing works
Colony Forming Unit Assays for MSCs
Pochampally, R. R. (2008) · Humana Press eBooks · doi:10.1007/978-1-60327-169-1_6 · Cited by 124 · see citing works
The past, present and future of renin–angiotensin aldosterone system inhibition
Mentz, R. J., Bakris, G. L., Waeber, B., McMurray, J. J. V., Gheorghiade, M., Ruilope, L. M., Maggioni, A. P., Swedberg, K. B., Piña, I. L., Fiuzat, M., et al. (2012) · International Journal of Cardiology · doi:10.1016/j.ijcard.2012.10.007 · Cited by 117 · see citing works
Rodriguez-Menocal, L., Salgado, M., Ford, D., & Badiavas, E. V. (2012) · Stem Cells Translational Medicine · doi:10.5966/sctm.2011-0029 · Cited by 95 · see citing works
Effects of Angiotensin II Receptor Signaling during Skin Wound Healing
Takeda, H., Katagata, Y., Hozumi, Y., & Kondô, S. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63422-0 · Cited by 92 · see citing works
Angiotensin-converting Enzyme Inhibitors as Inducers of Adverse Cutaneous Reactions
Steckelings, U. M. (2001) · Acta Dermato Venereologica · doi:10.1080/000155501317140007 · Cited by 86 · see citing works
Taniguchi, K., Arima, K., 増岡, 美., Ohta, S., Shiraishi, H., Ontsuka, K., Suzuki, S., Inamitsu, M., Yamamoto, K.-I., Simmons, O., et al. (2013) · Journal of Investigative Dermatology · doi:10.1038/jid.2013.500 · Cited by 83 · see citing works
Cheng, B., Liu, H.-W., Fu, X.-B., Sheng, Z.-Y., & Li, J.-F. (2008) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2008.08449.x · Cited by 78 · see citing works
Self-citationRenin–Angiotensin System Blocking Drugs
Robles, N. R., Cerezo, I., & Hernández‐Gallego, R. (2013) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/1074248413501018 · Cited by 72 · see citing works
Fang, Q., Wang, X., Zhao, W.-Y., Ding, S.-L., Shi, B., Xia, Y., Yang, H., Wu, L., Li, C., & Tan, W. (2018) · Scientific Reports · doi:10.1038/s41598-018-21600-w · Cited by 68 · see citing works
Liao, X., Xie, G.-H., Liu, H., Cheng, B., Li, S., Xie, S., Xiao, L., & Fu, X. (2014) · Photomedicine and Laser Surgery · doi:10.1089/pho.2013.3667 · Cited by 61 · see citing works
Self-citationScholzen, T. E., & Luger, T. A. (2004) · Experimental Dermatology · doi:10.1111/j.1600-0625.2004.00260.x · Cited by 60 · see citing works
Topical Reformulation of Valsartan for Treatment of Chronic Diabetic Wounds
Abadir, P. M., Hosseini, S. M., Faghih, M., Ansari, A. M., Lay, F., Smith, B., Beselman, A., Vuong, D., Berger, A. E., Tian, J., et al. (2017) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2017.09.030 · Cited by 59 · see citing works
Eghlidospour, M., Ghanbari, A., Mortazavi, S. M. J., & Azari, H. (2017) · Anatomy & Cell Biology · doi:10.5115/acb.2017.50.2.115 · Cited by 58 · see citing works
Kang, C. W., Han, Y. E., Kim, J., Oh, J. H., Cho, Y. H., & Lee, E. J. (2017) · Scientific Reports · doi:10.1038/s41598-017-14368-y · Cited by 54 · see citing works
Min, L., Cui, T., Yahata, Y., Yamasaki, K., Shiuchi, T., Liu, H., Chen, R., Li, J., Okumura, M., Jinno, T., et al. (2003) · Endocrinology · doi:10.1210/en.2003-0673 · Cited by 52 · see citing works
Self-citationExpression of β-catenin and cyclin D1 in epidermal stem cells of diabetic rats
Liu (2011) · Molecular Medicine Reports · doi:10.3892/mmr.2011.435 · Cited by 47 · see citing works
Label-retaining Cells in the Rat Submandibular Gland
Kimoto, M., Yura, Y., Kishino, M., Toyosawa, S., & Ogawa, Y. (2007) · Journal of Histochemistry & Cytochemistry · doi:10.1369/jhc.7a7269.2007 · Cited by 42 · see citing works
Activation of skin renin–angiotensin system in diabetic rats
Hao, S. Y., Ren, M., Yang, C. H., Lin, D. Z., Chen, L. H., Zhu, P., Cheng, H., & Yan, L. (2011) · Endocrine · doi:10.1007/s12020-010-9428-z · Cited by 35 · see citing works
Liu, H., Cheng, B., Yu, W.-L., Sun, R., Zeng, D., Wang, J., Yuan-xing, L., & Fu, X. (2006) · Life Sciences · doi:10.1016/j.lfs.2006.01.031 · Cited by 32 · see citing works
Self-citationACE and ACE2 expression in normal and malignant skin lesions
Grzegrzółka, J., Swiatko, K., Puła, B., Zamirska, A., Olbromski, M., Bieniek, A., Szepietowski, J. C., Ryś, J., Dzięgiel, P., & Podhorska‐Okołów, M. (2013) · Folia Histochemica et Cytobiologica · doi:10.5603/fhc.2013.0033 · Cited by 26 · see citing works
Angiotensin II-Induced Signaling Pathways in Diabetes
Marrero, M. B., Fulton, D. J., Stepp, D. W., & Stern, D. M. (2005) · Current Diabetes Reviews · doi:10.2174/1573399054022802 · Cited by 22 · see citing works
Functional characterization of highly adherent CD34+ keratinocytes isolated from human skin
Gutiérrez‐Rivera, A., Pavón‐Rodríguez, A., Jiménez‐Acosta, F., Poblet, E., Braun, K. M., Cormenzana, P., Ciria, J. P., Larretxea, R., Cárdenas, J. M., & Izeta, A. (2010) · Experimental Dermatology · doi:10.1111/j.1600-0625.2010.01075.x · Cited by 21 · see citing works
Matsuura‐Hachiya, Y., Arai, K. Y., Ozeki, R., Kikuta, A., & Nishiyama, T. (2013) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2013.10.162 · Cited by 15 · see citing works
Liu, H.-W., Cheng, B., Li, J.-F., Wu, H.-J., Li, K.-Y., Sun, T.-Z., & Fu, X.-B. (2008) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2008.08970.x · Cited by 15 · see citing works
Self-citationMargolis, D. J., Hoffstad, O., Thom, S. R., Bilker, W. B., Maldonado, A. R., Cohen, R. M., Aronow, B. J., & Crombleholme, T. M. (2010) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2010.00624.x · Cited by 14 · see citing works
Zeeuwen-Franssen, M. E. J., Boezeman, J. B. M., van de Kerkhof, P. C. M., & van Erp, P. E. J. (2003) · Cytometry Part B Clinical Cytometry · doi:10.1002/cyto.b.10069 · Cited by 14 · see citing works
Purushothaman, K., Krishnan, P., Meerarani, P., Wiley, J. M., Alviar, C. L., Ruiz, F. J., Zubatov, Y., Kini, A. S., Sharma, S. K., Fuster, V., et al. (2012) · Cardiovascular Pathology · doi:10.1016/j.carpath.2012.05.004 · Cited by 12 · see citing works
Flow cytometric sorting and analysis of human epidermal stem cell candidates
Pikuła, M., Kondej, K., Jaśkiewicz, J., Skokowski, J., & Trzonkowski, P. (2010) · Cell Biology International · doi:10.1042/cbi20100223 · Cited by 12 · see citing works
The Detection of Antibodies to the Angiotensin II-Type 1 Receptor in Transplantation
Dragun, D. (2013) · Methods in molecular biology · doi:10.1007/978-1-62703-493-7_19 · Cited by 11 · see citing works
[Biology of epidermal stem cells: impact on medicine].
Pikuła, M., & Trzonkowski, P. (2009) · PubMed · Cited by 7 · see citing works
Effects of Hypertension on Abdominal Wall Healing: Experimental Study in Rats
Tostes, J. M., Watanabe, A. L. C., & Watanabé, L. M. (2007) · Surgery Today · doi:10.1007/s00595-006-3368-5 · Cited by 6 · see citing works
Epidermal Stem Cells in Orthopaedic Regenerative Medicine
Li, J., Zhen, G., Tsai, S., & Jia, X. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140611626 · Cited by 2 · see citing works
Li, H., Shi, C., Liu, H., Zhang, H., Sang, H., Soyfoo, M. D., Cao, J., Xu, S., & Jiang, J. (2018) · Oncology Letters · doi:10.3892/ol.2018.8585 · Cited by 1 · see citing works
Self-citation
Flagged first, then by citations
1 of the 47 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- T. Hikaru, K. Yohtaro, H. Yutaka, K. Shigeo, Effects of angiotensin II recepter sig- naling during skin wound healing, Am. J. Pathol. 165 (2004) 1653-1662, https:// doi.org/10.1016/S0002-9440(10)63422-0. · DOI
Cited by
Sorted by citations
Skin Aging, Cellular Senescence and Natural Polyphenols
Csekes, E., & Račková, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222312641 · Cited by 335 · see citing works
Body Localization of ACE-2: On the Trail of the Keyhole of SARS-CoV-2
Salamanna, F., Maglio, M., Landini, M. P., & Fini, M. (2020) · Frontiers in Medicine · doi:10.3389/fmed.2020.594495 · Cited by 283 · see citing works
COVID‐19 and cutaneous manifestations: a systematic review
Zhao, Q. S., Fang, X., Pang, Z., Zhang, B., Liu, H., & Zhang, F. (2020) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/jdv.16778 · Cited by 130 · see citing works
Self-citationMunavalli, G. G., Knutsen-Larson, S., Lupo, M. P., & Geronemus, R. G. (2021) · JAAD Case Reports · doi:10.1016/j.jdcr.2021.02.018 · Cited by 77 · see citing works
Ziaja, M., Urbanek, K. A., Kowalska, K., & Piastowska‐Ciesielska, A. W. (2021) · Cells · doi:10.3390/cells10020381 · Cited by 46 · see citing works
Li, Z., Li, S., Li, K., Jiang, X. G., Zhang, J., & Liu, H. (2020) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2020.03.140 · Cited by 18 · see citing works
Self-citationThe Potential Role of 6-gingerol and 6-shogaol as ACE Inhibitors in Silico Study
Bare, Y., Helvina, M., Krisnamurti, G. C., & Mansur, S. (2020) · Biogenesis Jurnal Ilmiah Biologi · doi:10.24252/bio.v8i2.15704 · Cited by 14 · see citing works
The Renin-Angiotensin System: The Challenge behind Autoimmune Dermatological Diseases
Maranducă, M. A., Cosovanu, M. A., Clim, A., Pînzariu, A. C., Filip, N., Drochioi, I. C., Vlăsceanu, V. I., Timofte, D. V., Nemțeanu, R., Pleşa, A., et al. (2023) · Diagnostics · doi:10.3390/diagnostics13223398 · Cited by 13 · see citing works
Wei, L., Bo, L., Luo, C., Yin, N., Jiang, W., Qian, F., Zhou, A., Lu, X., Guo, H., & Mao, C. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-03997-6 · Cited by 11 · see citing works
“Local RAS has been proved to be the key to regulating repair and regeneration in epidermal and vasculogenesis related progenitor cells [8, 9].”
BackgroundQoreishi, S. H., Tabari, M. A. K., Găman, M., & Kazeminejad, A. (2024) · Avicenna Journal of Medical Biotechnology · doi:10.18502/ajmb.v16i3.15740 · Cited by 5 · see citing works
da Silva, J. R., Souza‐Fabjan, J. M. G., Bento, T. F. M., Silva, R. C., Moura, C. R. F., Bartlewski, P. M., & Batista, R. I. T. P. (2023) · Biology of Reproduction · doi:10.1093/biolre/ioad133 · Cited by 4 · see citing works
Macedo, L. M., de Ávila, R. I., Pedrino, G. R., Colugnati, D. B., Valadares, M. C., Lima, E. M., Borges, C. L., Kitten, G. T., Gava, E., & Castro, C. H. (2020) · Journal of Cellular Physiology · doi:10.1002/jcp.29862 · Cited by 3 · see citing works
Macchi, R., Sotelo, A. D., Parrado, A. C., Salaverry, L. S., Blanco, G. A. C., Castro, M. S., Rey-Roldán, E. B., & Canellada, A. M. (2023) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2023.116383 · Cited by 2 · see citing works
Hotowy, A., Strojny, B., Ostrowska, A., Zielińska-Górska, M. K., Kutwin, M., Wierzbicki, M., Sosnowska, M., Jaworski, S., Chwalibóg, A., Kotela, I., et al. (2024) · Molecules · doi:10.3390/molecules29153581 · Cited by 2 · see citing works
Huang, C., Yang, Y., Cheng, L., Guo, L., Liu, M., & Xiong, G. (2025) · Biochemical Genetics · doi:10.1007/s10528-025-11056-9 · Cited by 2 · see citing works
Renin Angiotensin System in Aging and Regeneration
Rawal, N., Mittal, A., & Khullar, M. (2023) · Advances in biochemistry in health and disease · doi:10.1007/978-3-031-14952-8_17 · Cited by 1 · see citing works
Literature review: manifestation of skin lesion on COVID-19
Firmansyah, Y., Tan, S. T., Elizabeth, J., & Lauren, C. (2021) · International Journal of Research in Dermatology · doi:10.18203/issn.2455-4529.intjresdermatol20210589
Mao, C., Wei, L., Guo, H., Luo, C., Yin, N., Jiang, W., Qian, F., Zhou, A., Lu, X., & Bo, L. (2024) · Research Square · doi:10.21203/rs.3.rs-4569611/v1
Role of epigenetic factors during blockade of the renin-angiotensin system across aging
de Cavanagh, E. M. V., Inserra, F., & Ferder, L. (2026) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00417.2026
Burckart, G. J., Samuels, S., Abdel‐Rahman, S. M., Abulwerdi, G. A., Fletcher, E. P., Mohamoud, M., Srinivasan, A., Tatonetti, N. P., & Racz, R. (2026) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.70465
- Authors
- Liao, X., Xiao, J., Li, S.-H., Xiao, L.-L., Cheng, B., Fu, X.-B., Cui, T., & Liu, H.-W.
- Affiliations
- First Affiliated Hospital of Jinan University (CN)
- University of South Carolina (US)
- Corresponding author
- Cui, Taixing
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 1865
- Issue
- 10
- Pages
- 2647-2656
- ISSN
- 0925-4439 (ISSN-L)
- OpenAlex
- W2961619793
- Cited by
- 21
- References
- 47
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 5 · 2023: 4 · 2021: 4 · 2020: 5
- FWCI
- 1.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundamental Research Funds for the Central Universities
- National Natural Science Foundation of China
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Keywords
- renin-angiotensin system, epidermal stem cells, epidermal regeneration, wound healing, angiotensin II, angiotensin II type 1 receptor, angiotensin II type 2 receptor, ACE1, ACE2, captopril, ACE inhibitors, ERK signaling, STAT1, STAT3, skin
- MeSH terms
- Epidermal Cells, Angiotensin-Converting Enzyme 2, Angiotensin II, Angiotensin-Converting Enzyme Inhibitors, Animals, Captopril, Cardiovascular Diseases, Cell Movement, Humans, Peptidyl-Dipeptidase A, Regeneration, Renin-Angiotensin System, Skin, Stem Cells, Wound Healing, Rats, Wistar, Apoptosis, Receptor, Angiotensin, Type 1, Cell Proliferation, STAT1 Transcription Factor, STAT3 Transcription Factor, Rats
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