Post-surgical adhesions are triggered by calcium-dependent membrane bridges between mesothelial surfaces.
Animals
Calcium
/ chemistry
Calcium Signaling
Cell Adhesion
Cell Line
Cell Membrane
/ metabolism
Computational Biology
Cytoskeleton
/ metabolism
Cytosol
/ metabolism
Disease Models, Animal
Epithelium
/ metabolism
Female
Humans
Imaging, Three-Dimensional
Male
Mice
Mice, Inbred C57BL
Postoperative Complications
Principal Component Analysis
RNA, Small Interfering
/ metabolism
Single-Cell Analysis
Tissue Adhesions
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 06 2020
17 06 2020
Historique:
received:
11
06
2019
accepted:
18
05
2020
entrez:
20
6
2020
pubmed:
20
6
2020
medline:
25
8
2020
Statut:
epublish
Résumé
Surgical adhesions are bands of scar tissues that abnormally conjoin organ surfaces. Adhesions are a major cause of post-operative and dialysis-related complications, yet their patho-mechanism remains elusive, and prevention agents in clinical trials have thus far failed to achieve efficacy. Here, we uncover the adhesion initiation mechanism by coating beads with human mesothelial cells that normally line organ surfaces, and viewing them under adhesion stimuli. We document expansive membrane protrusions from mesothelia that tether beads with massive accompanying adherence forces. Membrane protrusions precede matrix deposition, and can transmit adhesion stimuli to healthy surfaces. We identify cytoskeletal effectors and calcium signaling as molecular triggers that initiate surgical adhesions. A single, localized dose targeting these early germinal events completely prevented adhesions in a preclinical mouse model, and in human assays. Our findings classifies the adhesion pathology as originating from mesothelial membrane bridges and offer a radically new therapeutic approach to treat adhesions.
Identifiants
pubmed: 32555155
doi: 10.1038/s41467-020-16893-3
pii: 10.1038/s41467-020-16893-3
pmc: PMC7299976
doi:
Substances chimiques
RNA, Small Interfering
0
Calcium
SY7Q814VUP
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3068Références
ten Broek, R. P. G., Strik, C., Issa, Y., Bleichrodt, R. P. & van Goor, H. Adhesiolysis-related morbidity in abdominal surgery. Ann. Surg. 258, 98–106 (2013).
pubmed: 23013804
doi: 10.1097/SLA.0b013e31826f4969
Menzies, D. & Ellis, H. Intestinal obstruction from adhesions-how big is the problem? Ann. R. Coll. Surg. Engl. 72, 60–63 (1990).
pubmed: 2301905
pmcid: 2499092
Scott, F. I., Osterman, M. T., Mahmoud, N. N. & Lewis, J. D. Secular trends in small-bowel obstruction and adhesiolysis in the United States: 1988-2007. Am. J. Surg. 204, 315–320 (2012).
pubmed: 22575399
doi: 10.1016/j.amjsurg.2011.10.023
pmcid: 3419344
Bizer, L. S., Liebling, R. W., Delany, H. M. & Gliedman, M. L. Small bowel obstruction: the role of nonoperative treatment in simple intestinal obstruction and predictive criteria for strangulation obstruction. Surgery 89, 407–413 (1981).
pubmed: 7209787
Ellis, H. et al. Adhesion-related hospital readmissions after abdominal and pelvic surgery: a retrospective cohort study. Lancet Lond. Engl. 353, 1476–1480 (1999).
doi: 10.1016/S0140-6736(98)09337-4
Lower, A. M. et al. The impact of adhesions on hospital readmissions over ten years after 8849 open gynaecological operations: an assessment from the Surgical and Clinical Adhesions Research Study. BJOG Int. J. Obstet. Gynaecol. 107, 855–862 (2000).
doi: 10.1111/j.1471-0528.2000.tb11083.x
Parker, M. C. et al. Colorectal surgery: the risk and burden of adhesion-related complications. Colorectal Dis. 6, 506–511 (2004).
pubmed: 15521944
doi: 10.1111/j.1463-1318.2004.00709.x
Van Der Krabben, A. A. et al. Morbidity and mortality of inadvertent enterotomy during adhesiotomy. Br. J. Surg. 87, 467–471 (2000).
doi: 10.1046/j.1365-2168.2000.01394.x
Ouaïssi, M. et al. Post-operative adhesions after digestive surgery: their incidence and prevention: review of the literature. J. Visc. Surg. 149, e104–e114 (2012).
pubmed: 22261580
doi: 10.1016/j.jviscsurg.2011.11.006
Stovall, T. G., Elder, R. F. & Ling, F. W. Predictors of pelvic adhesions. J. Reprod. Med. 34, 345–348 (1989).
pubmed: 2525188
Ray, N. F., Denton, W. G., Thamer, M., Henderson, S. C. & Perry, S. Abdominal adhesiolysis: inpatient care and expenditures in the United States in 1994. J. Am. Coll. Surg. 186, 1–9 (1998).
pubmed: 9449594
doi: 10.1016/S1072-7515(97)00127-0
Holtz, G. Prevention and management of peritoneal adhesions. Fertil. Steril. 41, 497–507 (1984).
pubmed: 6200365
doi: 10.1016/S0015-0282(16)47731-9
Schade, D. S. & Williamson, J. R. The pathogenesis of peritoneal adhesions: an ultrastructural study. Ann. Surg. 167, 500–510 (1968).
pubmed: 4296268
doi: 10.1097/00000658-196804000-00006
pmcid: 1387240
Witz, C. A. et al. Culture of menstrual endometrium with peritoneal explants and mesothelial monolayers confirms attachment to intact mesothelial cells. Hum. Reprod. Oxf. Engl. 17, 2832–2838 (2002).
doi: 10.1093/humrep/17.11.2832
Rinkevich, Y. et al. Identification and prospective isolation of a mesothelial precursor lineage giving rise to smooth muscle cells and fibroblasts for mammalian internal organs, and their vasculature. Nat. Cell Biol. 14, 1251–1260 (2012).
pubmed: 23143399
doi: 10.1038/ncb2610
pmcid: 3685475
Tsai, J. M. et al. Surgical adhesions in mice are derived from mesothelial cells and can be targeted by antibodies against mesothelial markers. Sci. Transl. Med. 10, 1–16 (2018).
doi: 10.1126/scitranslmed.aan6735
Carpinteri, S. et al. Experimental study of delivery of humidified-warm carbon dioxide during open abdominal surgery. Br. J. Surg. 105, 597–605 (2018).
pubmed: 29193022
doi: 10.1002/bjs.10685
Robertson, D. & Lefebvre, G., CLINICAL PRACTICE GYNAECOLOGY COMMITTEE. Adhesion prevention in gynaecological surgery. J. Obstet. Gynaecol. Can. JOGC J. Obstet. Gynecol. Can. JOGC 32, 598–602 (2010).
doi: 10.1016/S1701-2163(16)34530-3
Wang, D. et al. Identification of multipotent mammary stem cells by protein C receptor expression. Nature 517, 81–84 (2015).
pubmed: 25327250
doi: 10.1038/nature13851
Macosko, E. Z. et al. Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets. Cell 161, 1202–1214 (2015).
pubmed: 26000488
doi: 10.1016/j.cell.2015.05.002
pmcid: 4481139
Ziegenhain, C. et al. Comparative analysis of single-cell rna sequencing methods. Mol. Cell 65, 631–643.e4 (2017).
pubmed: 28212749
doi: 10.1016/j.molcel.2017.01.023
McDavid, A. et al. Data exploration, quality control and testing in single-cell qPCR-based gene expression experiments. Bioinforma. Oxf. Engl. 29, 461–467 (2013).
doi: 10.1093/bioinformatics/bts714
Medjkane, S., Perez-Sanchez, C., Gaggioli, C., Sahai, E. & Treisman, R. Myocardin-related transcription factors and SRF are required for cytoskeletal dynamics and experimental metastasis. Nat. Cell Biol. 11, 257–268 (2009).
pubmed: 19198601
doi: 10.1038/ncb1833
pmcid: 6089348
Rothman, J. E. Mechanisms of intracellular protein transport. Nature 372, 55–63 (1994).
pubmed: 7969419
doi: 10.1038/372055a0
Etienne-Manneville, S. & Hall, A. Rho GTPases in cell biology. Nature 420, 629–635 (2002).
pubmed: 12478284
doi: 10.1038/nature01148
Tao, J., Shumay, E., McLaughlin, S., Wang, H. & Malbon, C. C. Regulation of AKAP-membrane interactions by calcium. J. Biol. Chem. 281, 23932–23944 (2006).
pubmed: 16762919
doi: 10.1074/jbc.M601813200
Ahmad, G. et al. Fluid and pharmacological agents for adhesion prevention after gynaecological surgery. Cochrane Database Syst. Rev. CD001298 (2014) https://doi.org/10.1002/14651858.CD001298.pub4 .
Hindocha, A., Beere, L., Dias, S., Watson, A. & Ahmad, G. Adhesion prevention agents for gynaecological surgery: an overview of Cochrane reviews. Cochrane Database Syst. Rev. 1, CD011254 (2015).
pubmed: 25561409
Harder, D. R. & Sperelakis, N. Bepridil blockade of Ca2+-dependent action potentials in vascular smooth muscle of dog coronary artery. J. Cardiovasc. Pharmacol. 3, 906–914 (1981).
pubmed: 6167820
doi: 10.1097/00005344-198107000-00024
DiBianco, R. et al. Bepridil for chronic stable angina pectoris: results of a prospective multicenter, placebo-controlled, dose-ranging study in 77 patients. Am. J. Cardiol. 53, 35–41 (1984).
pubmed: 6362386
doi: 10.1016/0002-9149(84)90680-5
Gill, A., Flaim, S. F., Damiano, B. P., Sit, S. P. & Brannan, M. D. Pharmacology of bepridil. Am. J. Cardiol. 69, 11D–16D (1992).
pubmed: 1372785
doi: 10.1016/0002-9149(92)90953-V
Hollingshead, L. M., Faulds, D. & Fitton, A. Bepridil. A review of its pharmacological properties and therapeutic use in stable angina pectoris. Drugs 44, 835–857 (1992).
pubmed: 1280569
doi: 10.2165/00003495-199244050-00009
Manouvrier, J. et al. Nine cases of torsade de pointes with bepridil administration. Am. Heart J. 111, 1005–1007 (1986).
pubmed: 3486580
doi: 10.1016/0002-8703(86)90660-5
Nakazato, Y. The resurfacing of bepridil hydrochloride on the world stage as an antiarrhythmic drug for atrial fibrillation. J. Arrhythmia 25, 4–9 (2009).
doi: 10.1016/S1880-4276(09)80027-6
Coumel, P. Safety of bepridil: from review of the European data. Am. J. Cardiol. 69, 75D–78D (1992).
pubmed: 1553894
doi: 10.1016/0002-9149(92)90963-Y
Boettiger, D. Quantitative measurements of integrin-mediated adhesion to extracellular matrix. Methods Enzymol. 426, 1–25 (2007).
pubmed: 17697877
doi: 10.1016/S0076-6879(07)26001-X
Ertürk, A. et al. Three-dimensional imaging of solvent-cleared organs using 3DISCO. Nat. Protoc. 7, 1983–1995 (2012).
pubmed: 23060243
doi: 10.1038/nprot.2012.119
Arganda-Carreras, I. et al. Trainable Weka segmentation: a machine learning tool for microscopy pixel classification. Bioinforma. Oxf. Engl. 33, 2424–2426 (2017).
doi: 10.1093/bioinformatics/btx180
Steger, C. An unbiased detector of curvilinear structures. IEEE Trans. PATTERN Anal. Mach. Intell. 20, 13 (1998).
doi: 10.1109/34.659930
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
doi: 10.1093/bioinformatics/bts635
pubmed: 23104886
Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15 (2018).
pubmed: 29409532
doi: 10.1186/s13059-017-1382-0
pmcid: 5802054
Schiller, H. B. et al. Time- and compartment-resolved proteome profiling of the extracellular niche in lung injury and repair. Mol. Syst. Biol. 11, 819 (2015).
pubmed: 26174933
doi: 10.15252/msb.20156123
pmcid: 4547847
Krämer, A., Green, J., Pollard, J. & Tugendreich, S. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics 30, 523–530 (2014).
doi: 10.1093/bioinformatics/btt703
pubmed: 24336805
pmcid: 24336805
Wickham, H. ggplot2: Elegant Graphics for Data Analysis. (Springer-Verlag, 2009).
R Development Core Team. R: A Language and Environment for Statistical Computing. gbif.org/tool/81287/r-a-language-and-environment-for statistical-computing.