Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Clinical and Translational Medicine
Published in: Clinical and Translational Medicine 1/2018

Open Access 01-12-2018 | Research

Alk5/Runx1 signaling mediated by extracellular vesicles promotes vascular repair in acute respiratory distress syndrome

Authors: Trushil Shah, Shanshan Qin, Mona Vashi, Dan N. Predescu, Niranjan Jeganathan, Cristina Bardita, Balaji Ganesh, Salvatore diBartolo, Louis F. Fogg, Robert A. Balk, Sanda A. Predescu

Published in: Clinical and Translational Medicine | Issue 1/2018

Login to get access

Abstract

Background

Pulmonary endothelial cells’ (ECs) injury and apoptotic death are necessary and sufficient for the pathogenesis of the acute respiratory distress syndrome (ARDS), regardless of epithelial damage. Interaction of dysfunctional ECs with circulatory extracellular vesicles (EVs) holds therapeutic promise in ARDS. However, the presence in the blood of long-term ARDS survivors of EVs with a distinct phenotype compared to the EVs of non-surviving patients is not reported. With a multidisciplinary translational approach, we studied EVs from the blood of 33 patients with moderate-to-severe ARDS.

Results

The EVs were isolated from the blood of ARDS and control subjects. Immunoblotting and magnetic beads immunoisolation complemented by standardized flow cytometry and nanoparticles tracking analyses identified in the ARDS patients a subset of EVs with mesenchymal stem cell (MSC) origin (CD73+CD105+Cd34−CD45−). These EVs have 4.7-fold greater counts compared to controls and comprise the transforming growth factor-beta receptor I (TβRI)/Alk5 and the Runx1 transcription factor. Time course analyses showed that the expression pattern of two Runx1 isoforms is critical for ARDS outcome: the p52 isoform shows a continuous expression, while the p66 is short-lived. A high ratio Runx1p66/p52 provided a survival advantage, regardless of age, sex, disease severity or length of stay in the intensive care unit. Moreover, the Runx1p66 isoform is transiently expressed by cultured human bone marrow-derived MSCs, it is released in the EVs recoverable from the conditioned media and stimulates the proliferation of lipopolysaccharide (LPS)-treated ECs. The findings are consistent with a causal effect of Runx1p66 expression on EC proliferation. Furthermore, morphological and functional assays showed that the EVs bearing the Runx1p66 enhanced junctional integrity of LPS-injured ECs and decreased lung histological severity in the LPS-treated mice.

Conclusions

The expression pattern of Runx1 isoforms might be a reliable circulatory biomarker of ARDS activity and a novel determinant of the molecular mechanism for lung vascular/tissue repair and recovery after severe injury.
Appendix
Available only for authorised users
Literature
1.
2.
Cochi SE, Kempker JA, Annangi S, Kramer MR, Martin GS (2016) Mortality trends of acute respiratory distress syndrome in the United States from 1999 to 2013. Ann Am Thorac Soc 13(10):1742–1751PubMedPubMedCentral
3.
Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M et al (2005) Incidence and outcomes of acute lung injury. N Engl J Med 353(16):1685–1693CrossRefPubMed
4.
Herridge MS (2011) Recovery and long-term outcome in acute respiratory distress syndrome. Crit Care Clin 27(3):685–704CrossRefPubMed
5.
Herridge MS, Moss M, Hough CL, Hopkins RO, Rice TW, Bienvenu OJ et al (2016) Recovery and outcomes after the acute respiratory distress syndrome (ARDS) in patients and their family caregivers. Intensive Care Med 42(5):725–738CrossRefPubMed
6.
Zhu YG, Feng XM, Abbott J, Fang XH, Hao Q, Monsel A et al (2014) Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells 32(1):116–125CrossRefPubMedPubMedCentral
7.
Lindoso RS, Collino F, Vieyra A (2017) Extracellular vesicles as regulators of tumor fate: crosstalk among cancer stem cells, tumor cells and mesenchymal stem cells. Stem Cell Invest 4:75CrossRef
8.
Bern MM (2017) Extracellular vesicles: how they interact with endothelium, potentially contributing to metastatic cancer cell implants. Clin Transl Med 6(1):33CrossRefPubMedPubMedCentral
9.
Peired AJ, Sisti A, Romagnani P (2016) Mesenchymal stem cell-based therapy for kidney disease: a review of clinical evidence. Stem Cells Int 2016:4798639PubMedPubMedCentral
10.
Ponte AL, Marais E, Gallay N, Langonne A, Delorme B, Herault O et al (2007) The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells 25(7):1737–1745CrossRefPubMed
11.
Belema-Bedada F, Uchida S, Martire A, Kostin S, Braun T (2008) Efficient homing of multipotent adult mesenchymal stem cells depends on FROUNT-mediated clustering of CCR2. Cell Stem Cell 2(6):566–575CrossRefPubMed
12.
Bardita C, Predescu D, Justice MJ, Petrache I, Predescu S (2013) In vivo knockdown of intersectin-1s alters endothelial cell phenotype and causes microvascular remodeling in the mouse lungs. Apoptosis 18(1):57–76CrossRefPubMed
13.
Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E et al (2012) Acute respiratory distress syndrome: the Berlin Definition. JAMA 307(23):2526–2533
14.
Jeganathan N, Predescu D, Zhang J, Sha F, Bardita C, Patel M et al (2016) Rac1-mediated cytoskeleton rearrangements induced by intersectin-1s deficiency promotes lung cancer cell proliferation, migration and metastasis. Mol Cancer 15(1):59CrossRefPubMedPubMedCentral
15.
Bardita C, Predescu DN, Sha F, Patel M, Balaji G, Predescu SA (2015) Endocytic deficiency induced by ITSN-1s knockdown alters the Smad2/3-Erk1/2 signaling balance downstream of Alk5. J Cell Sci 128(8):1528–1541CrossRefPubMedPubMedCentral
16.
Witwer KW, Buzas EI, Bemis LT, Bora A, Lasser C, Lotvall J et al (2013) Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles 2:20360CrossRef
17.
Lotvall J, Hill AF, Hochberg F, Buzas EI, Di Vizio D, Gardiner C et al (2014) Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles 3:26913CrossRefPubMed
18.
19.
Predescu SA, Predescu DN, Timblin BK, Stan RV, Malik AB (2003) Intersectin regulates fission and internalization of caveolae in endothelial cells. Mol Biol Cell 14(12):4997–5010CrossRefPubMedPubMedCentral
20.
Fang X, Abbott J, Cheng L, Colby JK, Lee JW, Levy BD et al (2015) Human mesenchymal stem (stromal) cells promote the resolution of acute lung injury in part through lipoxin A4. J Immunol 195(3):875–881CrossRefPubMed
21.
Occhetta P, Pigeot S, Rasponi M, Dasen B, Mehrkens A, Ullrich T et al (2018) Developmentally inspired programming of adult human mesenchymal stromal cells toward stable chondrogenesis. Proc Natl Acad Sci USA 115(18):4625–4630PubMed
22.
Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B et al (2016) Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci USA 113(8):E968–E977CrossRefPubMedPubMedCentral
23.
Patel M, Predescu D, Bardita C, Chen J, Jeganathan N, Pritchard M et al (2017) Modulation of intersectin-1s lung expression induces obliterative remodeling and severe plexiform arteriopathy in the murine pulmonary vascular bed. Am J Pathol 187(3):528–542CrossRefPubMedPubMedCentral
24.
Patel M, Predescu D, Tandon R, Bardita C, Pogoriler J, Bhorade S et al (2013) A novel p38 mitogen-activated protein kinase/Elk-1 transcription factor-dependent molecular mechanism underlying abnormal endothelial cell proliferation in plexogenic pulmonary arterial hypertension. J Biol Chem 288(36):25701–25716CrossRefPubMedPubMedCentral
25.
Enjeti AK, Ariyarajah A, D’Crus A, Seldon M, Lincz LF (2016) Correlative analysis of nanoparticle tracking, flow cytometric and functional measurements for circulating microvesicles in normal subjects. Thromb Res 145:18–23CrossRefPubMed
26.
Nguyen DC, Lewis HC, Joyner C, Warren V, Xiao H, Kissick HT et al (2018) Extracellular vesicles from bone marrow-derived mesenchymal stromal cells support ex vivo survival of human antibody secreting cells. J Extracell Vesicles 7(1):1463778CrossRefPubMedPubMedCentral
27.
Gardiner C, Ferreira YJ, Dragovic RA, Redman CW, Sargent IL (2013) Extracellular vesicle sizing and enumeration by nanoparticle tracking analysis. J Extracell Vesicles 2:19671CrossRef
28.
Cohen J (1988) Statistical power analysis for the behavioral sciences. In: Erlbaum L (ed), 2nd edn. Academic Press, Hillsdale
29.
30.
Lacroix R, Judicone C, Mooberry M, Boucekine M, Key NS, Dignat-George F et al (2013) Standardization of pre-analytical variables in plasma microparticle determination: results of the International Society on Thrombosis and Haemostasis SSC Collaborative workshop. J Thromb Haemost 11:1190–1193CrossRef
31.
Kanada M, Bachmann MH, Hardy JW, Frimannson DO, Bronsart L, Wang A et al (2015) Differential fates of biomolecules delivered to target cells via extracellular vesicles. Proc Natl Acad Sci USA 112(12):E1433–E1442PubMedPubMedCentral
32.
Chen J, Li C, Chen L (2015) The role of microvesicles derived from mesenchymal stem cells in lung diseases. Biomed Res Int 2015:985814PubMedPubMedCentral
33.
Morel O, Toti F, Hugel B, Bakouboula B, Camoin-Jau L, Dignat-George F et al (2006) Procoagulant microparticles: disrupting the vascular homeostasis equation? Arterioscler Thromb Vasc Biol 26(12):2594–2604CrossRefPubMed
34.
Kim W, Barron DA, San Martin R, Chan KS, Tran LL, Yang F et al (2014) RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation. Proc Natl Acad Sci USA 111(46):16389–16394CrossRefPubMedPubMedCentral
35.
Tanaka T, Kurokawa M, Ueki K, Tanaka K, Imai Y, Mitani K et al (1996) The extracellular signal-regulated kinase pathway phosphorylates AML1, an acute myeloid leukemia gene product, and potentially regulates its transactivation ability. Mol Cell Biol 16(7):3967–3979CrossRefPubMedPubMedCentral
36.
Sinclair KA, Yerkovich ST, Chen T, McQualter JL, Hopkins PM, Wells CA et al (2016) Mesenchymal stromal cells are readily recoverable from lung tissue, but not the alveolar space, in healthy humans. Stem Cells 34(10):2548–2558CrossRefPubMed
37.
Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR, Stripp BR et al (2013) Type 2 alveolar cells are stem cells in adult lung. J Clin Invest 123(7):3025–3036CrossRefPubMedPubMedCentral
38.
Hall JB, Kress JP (2011) The burden of functional recovery from ARDS. N Engl J Med 364(14):1358–1359CrossRefPubMed
39.
Rich JT, Neely JG, Paniello RC, Voelker CC, Nussenbaum B, Wang EW (2010) A practical guide to understanding Kaplan–Meier curves. Otolaryngol Head Neck Surg 143(3):331–336CrossRefPubMedPubMedCentral
40.
Wu C, Evans CE, Dai Z, Huang X, Zhang X, Jin H et al (2017) Lipopolysaccharide-induced endotoxemia in corn oil-preloaded mice causes an extended course of lung injury and repair and pulmonary fibrosis: a translational mouse model of acute respiratory distress syndrome. PLoS ONE 12(3):e0174327CrossRefPubMedPubMedCentral
41.
Guervilly C, Lacroix R, Forel JM, Roch A, Camoin-Jau L, Papazian L et al (2011) High levels of circulating leukocyte microparticles are associated with better outcome in acute respiratory distress syndrome. Crit Care 15(1):R31CrossRefPubMedPubMedCentral
42.
Shaver CM, Woods J, Clune JK, Grove BS, Wickersham NE, McNeil JB et al (2017) Circulating microparticle levels are reduced in patients with ARDS. Crit Care 21(1):120CrossRefPubMedPubMedCentral
43.
Martinez M, Hinojosa M, Trombly D, Morin V, Stein J, Stein G et al (2016) Transcriptional auto-regulation of RUNX1 P1 promoter. PLoS ONE 11(2):e0149119CrossRefPubMedPubMedCentral
44.
Gupta N, Su X, Popov B, Lee JW, Serikov V, Matthay MA (2007) Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 179(3):1855–1863CrossRefPubMed
45.
Lahm T, Crisostomo PR, Markel TA, Wang M, Lillemoe KD, Meldrum DR (2007) The critical role of vascular endothelial growth factor in pulmonary vascular remodeling after lung injury. Shock 28(1):4–14CrossRefPubMed
46.
Yamada M, Kubo H, Kobayashi S, Ishizawa K, Numasaki M, Ueda S et al (2004) Bone marrow-derived progenitor cells are important for lung repair after lipopolysaccharide-induced lung injury. J Immunol 172(2):1266–1272CrossRefPubMed
47.
Krasnodembskaya A, Song Y, Fang X, Gupta N, Serikov V, Lee JW et al (2010) Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells 28(12):2229–2238CrossRefPubMedPubMedCentral
48.
49.
Monsel A, Zhu YG, Gennai S, Hao Q, Hu S, Rouby JJ et al (2015) Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice. Am J Respir Crit Care Med 192(3):324–336CrossRefPubMedPubMedCentral
50.
Armstrong SM, Wang C, Tigdi J, Si X, Dumpit C, Charles S et al (2012) Influenza infects lung microvascular endothelium leading to microvascular leak: role of apoptosis and claudin-5. PLoS ONE 7(10):e47323CrossRefPubMedPubMedCentral
51.
David S, Ghosh CC, Kumpers P, Shushakova N, Van Slyke P, Khankin EV et al (2011) Effects of a synthetic PEG-ylated Tie-2 agonist peptide on endotoxemic lung injury and mortality. Am J Physiol Lung Cell Mol Physiol 300(6):L851–L862CrossRefPubMedPubMedCentral
52.
Lebrin F, Deckers M, Bertolino P, Ten Dijke P (2005) TGF-beta receptor function in the endothelium. Cardiovasc Res 65(3):599–608CrossRefPubMed
53.
Shah TG, Bardita C, Jeganathan N, Balk RA, Predescu DN, Predescu SA (2016) Circulatory microparticles and lung endothelial cell function in acute respiratory distress syndrome patients. Am J Respir Crit Care Med 193:A5671CrossRef
54.
Zhang L, Fried FB, Guo H, Friedman AD (2008) Cyclin-dependent kinase phosphorylation of RUNX1/AML1 on 3 sites increases transactivation potency and stimulates cell proliferation. Blood 111(3):1193–1200CrossRefPubMedPubMedCentral
55.
Iwatsuki K, Tanaka K, Kaneko T, Kazama R, Okamoto S, Nakayama Y et al (2005) Runx1 promotes angiogenesis by downregulation of insulin-like growth factor-binding protein-3. Oncogene 24(7):1129–1137CrossRefPubMed
56.
57.
Tang X, Sun L, Jin X, Chen Y, Zhu H, Liang Y et al (2017) Runt-related transcription factor 1 regulates LPS-induced acute lung injury via NF-kappaB signaling. Am J Respir Cell Mol Biol 57:174–183CrossRefPubMed
58.
Shaver CM, Bastarache JA (2014) Clinical and biological heterogeneity in acute respiratory distress syndrome: direct versus indirect lung injury. Clin Chest Med 35(4):639–653CrossRefPubMedPubMedCentral
59.
Garcia BA, Smalley DM, Cho H, Shabanowitz J, Ley K, Hunt DF (2005) The platelet microparticle proteome. J Proteome Res 4(5):1516–1521CrossRefPubMed
60.
Leroyer AS, Rautou PE, Silvestre JS, Castier Y, Leseche G, Devue C et al (2008) CD40 ligand+ microparticles from human atherosclerotic plaques stimulate endothelial proliferation and angiogenesis a potential mechanism for intraplaque neovascularization. J Am Coll Cardiol 52(16):1302–1311CrossRefPubMed
61.
Vasina EM, Cauwenberghs S, Feijge MA, Heemskerk JW, Weber C, Koenen RR (2011) Microparticles from apoptotic platelets promote resident macrophage differentiation. Cell Death Dis 2:e211CrossRefPubMed
62.
Mause SF, Ritzel E, Liehn EA, Hristov M, Bidzhekov K, Muller-Newen G et al (2010) Platelet microparticles enhance the vasoregenerative potential of angiogenic early outgrowth cells after vascular injury. Circulation 122(5):495–506CrossRefPubMed
63.
Mause SF, Weber C (2010) Microparticles: protagonists of a novel communication network for intercellular information exchange. Circ Res 107(9):1047–1057CrossRefPubMed
Metadata
Title
Alk5/Runx1 signaling mediated by extracellular vesicles promotes vascular repair in acute respiratory distress syndrome
Authors
Trushil Shah
Shanshan Qin
Mona Vashi
Dan N. Predescu
Niranjan Jeganathan
Cristina Bardita
Balaji Ganesh
Salvatore diBartolo
Louis F. Fogg
Robert A. Balk
Sanda A. Predescu
Publication date
01-12-2018
Publisher
Springer Berlin Heidelberg
Published in
Clinical and Translational Medicine / Issue 1/2018
Electronic ISSN: 2001-1326
DOI
https://doi.org/10.1186/s40169-018-0197-2

Other articles of this Issue 1/2018

Clinical and Translational Medicine 1/2018 Go to the issue

Commentary

Lipidomics: a promising cancer biomarker

Research

Biobank integration of large-scale clinical and histopathology melanoma studies within the European Cancer Moonshot Lund Center

Review

Potential important roles and signaling mechanisms of YPEL4 in pulmonary diseases

Research

Comparison of paired human nasal and bronchial airway epithelial cell responses to rhinovirus infection and IL-13 treatment

Review

Lipidomics unveils the complexity of the lipidome in metabolic diseases

Review

Pros and cons of mouse models for studying osteoarthritis