Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences65166510.31857/S0869813924030086CPLWKKEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИResearch ArticleActivated Endothelium Changes The Activity Of Multipotent Mesenchymal Stromal Cells During Physiological Hypoxia Or Short Hypoxic Stress In VitroАктивированный эндотелий стимулирует активность мультипотентных мезенхимальных стромальных клеток при физиологической гипоксии и коротком гипоксическом стрессе in vitroZhidkovaO. V.ЖидковаО. В.
Russian Federation
flain-fish@yandex.ruAndreevaE. R.АндрееваЕ. Р.
Russian Federation
andreeva1564@gmail.comBuravkovaL. B.БуравковаЛ. Б.
Russian Federation
buravkova@imbp.ruInstitute of Biomedical Problems, Russian Academy of SciencesИнститут медико-биологических проблем РАН15032024110344546801022025Copyright ©; 2024, Russian Academy of SciencesCopyright ©; 2024, Российская академия наук2024Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0869-8139/article/view/651665

Multipotent mesenchymal stromal cells (MSCs) are used for supplemental therapy of ischemic and inflammatory diseases. After systemic administration, transmigration of MSCs to the target tissue is accompanied by interaction with activated endothelial cells (ECs) at the site of injury. In this study, we investigated the influence of TNF-α-activated ECs on the functions of MSCs under different levels of hypoxia. For this purpose, MSCs and TNF-α activated ECs were cocultured in a direct cell-to-cell setting for a short period of time. MSCs retained their stromal phenotype and multilineage differentiation potential after interaction with activated ECs. At the same time, changes in molecules involved in MSC-cell and MSC-extracellular matrix interaction were detected. The paracrine activity of MSCs and activated ECs after interaction was demonstrated by both upregulated transcription and increased levels of pleiotropic IL-6 and IL-8. Proteases/antiproteases profiles were also altered after interaction. These data suggest that short-term interaction of MSCs with activated ECs may play an important role in tissue repair and remodeling processes. In particular, it may promote the migratory phenotype of MSCs. In comparison to physiological hypoxia – 5% O2, acute hypoxic stress (0.1% O2, 24 h) attenuated the stimulatory effects of ECs on MSCs.

Мультипотентные мезенхимальные стромальные клетки (МСК) применяются для дополнительной терапии ишемических и воспалительных заболеваний. При системном введении трансмиграция МСК в ткани-мишени сопровождается взаимодействием с активированными эндотелиальными клетками (ЭК), выстилающими сосуды в участках повреждений. В настоящей работе изучали эффекты активированных ФНО-α эндотелиальных клеток на активность МСК при гипоксии разной степени выраженности. Для этого использовали модель краткосрочного контактного сокультивирования МСК и предварительно активированных ФНО-α эндотелиальных клеток. После взаимодействия с активированными ЭК МСК сохраняли свой стромальный фенотип, потенциал к мультилинейной дифференцировке. В то же время выявлено изменение экспрессии молекул межклеточного взаимодействия, которые участвуют в формировании контактов МСК с другими клетками, матриксом, а также регулируют деградацию внеклеточного матрикса (ВКМ) и клеточную миграцию. Кроме того, кондиционированная среда от активированного эндотелия увеличивала направленную и ненаправленную миграцию МСК. Взаимодействие усиливало паракринный ответ МСК и активированных ЭК за счет увеличения транскрипции и продукции ИЛ-6, ИЛ-8. В совокупности эти данные указывают на то, что краткосрочное взаимодействие с активированными ЭК способствует формированию миграционного фенотипа МСК, а также увеличивает продукцию плейотропных цитокинов и протеаз/ингибиторов протеаз, которые регулируют процессы репарации и ремоделирования ткани. При этом по сравнению с физиологическими для МСК условиями (5% О2) острый гипоксический стресс (0.1% О2, 24 ч) ослаблял стимулирующее действие эндотелия на МСК.

multipotent mesenchymal stromal cellsendothelial cellshypoxiaproinflammatory activationcocultivationмультипотентные мезенхимальные стромальные клеткиэндотелиальные клеткигипоксияпровоспалительная активациясокультивированиеПравительство РФGovernment of the Russian FederationFMFR-2024-0032Правительство РФGovernment of the Russian Federation65.3Caplan AI, Correa D (2011) The MSC: An Injury Drugstore. Cell Stem Cell 9: 11–15. https://doi.org/10.1016/j.stem.2011.06.008Squillaro T, Peluso G, Galderisi U (2016) Clinical Trials with Mesenchymal Stem Cells: An Update. Cell Transplant 25: 829–848. https://doi.org/10.3727/096368915X689622Galipeau J, Sensébé L (2018) Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities. Cell Stem Cell 22: 824–833. https://doi.org/10.1016/j.stem.2018.05.004Fernández-Garza LE, Barrera-Barrera SA, Barrera-Saldaña HA (2023) Mesenchymal Stem Cell Therapies Approved by Regulatory Agencies around the World. Pharmaceuticals 16: 1334. https://doi.org/10.3390/ph16091334Buravkova LB, Andreeva ER, Gogvadze V, Zhivotovsky B (2014) Mesenchymal stem cells and hypoxia: Where are we? Mitochondrion 19: 105–112. https://doi.org/10.1016/j.mito.2014.07.005Egger D, Lavrentieva A, Kugelmeier P, Kasper C (2022) Physiologic isolation and expansion of human mesenchymal stem/stromal cells for manufacturing of cell-based therapy products. Eng Life Sci 22: 361–372. https://doi.org/10.1002/elsc.202100097Choi J-W, Shin S, Lee CY, Lee J, Seo H-H, Lim S, Lee S, Kim I-K, Lee H-B, Kim SW, Hwang K-C (2017) Rapid Induction of Osteogenic Markers in Mesenchymal Stem Cells by Adipose-Derived Stromal Vascular Fraction Cells. Cell Physiol Biochem 44: 53–65. https://doi.org/10.1159/000484582Lavrentieva A, Majore I, Kasper C, Hass R (2010) Effects of hypoxic culture conditions on umbilical cord-derived human mesenchymal stem cells. Cell Commun Signal CCS 8: 18. https://doi.org/10.1186/1478-811X-8-18Moniz I, Ramalho-Santos J, Branco AF (2022) Differential Oxygen Exposure Modulates Mesenchymal Stem Cell Metabolism and Proliferation through mTOR Signaling. Int J Mol Sci 23: 3749. https://doi.org/10.3390/ijms23073749Rosová I, Dao M, Capoccia B, Link D, Nolta JA (2008) Hypoxic Preconditioning Results in Increased Motility and Improved Therapeutic Potential of Human Mesenchymal Stem Cells. Stem Cells 26: 2173–2182. https://doi.org/10.1634/stemcells.2007-1104Udartseva OO, Lobanova MV, Andreeva ER, Buravkov SV, Ogneva IV, Buravkova LB (2016) Acute Hypoxic Stress Affects Migration Machinery of Tissue O2-Adapted Adipose Stromal Cells. Stem Cells Int 2016: 1–16. https://doi.org/10.1155/2016/7260562Busletta C, Novo E, Valfrè Di Bonzo L, Povero D, Paternostro C, Ievolella M, Mareschi K, Ferrero I, Cannito S, Compagnone A, Bandino A, Colombatto S, Fagioli F, Parola M (2011) Dissection of the Biphasic Nature of Hypoxia-Induced Motogenic Action in Bone Marrow-Derived Human Mesenchymal Stem Cells. Stem Cells 29: 952–963. https://doi.org/10.1002/stem.642Wang Q, Li X, Wang Q, Xie J, Xie C, Fu X (2019) Heat shock pretreatment improves mesenchymal stem cell viability by heat shock proteins and autophagy to prevent cisplatin-induced granulosa cell apoptosis. Stem Cell Res Ther 10: 348. https://doi.org/10.1186/s13287-019-1425-4Peterson KM, Aly A, Lerman A, Lerman LO, Rodriguez-Porcel M (2011) Improved survival of mesenchymal stromal cell after hypoxia preconditioning: role of oxidative stress. Life Sci 88: 65–73. https://doi.org/10.1016/j.lfs.2010.10.023Andreeva ER, Lobanova MV, Udartseva OO, Buravkova LB (2014) Response of Adipose Tissue-Derived Stromal Cells in Tissue-Related O2 Microenvironment to Short-Term Hypoxic Stress. Cells Tissues Organs 200: 307–315. https://doi.org/10.1159/000438921Caplan AI (2007) Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol 213: 341–347. https://doi.org/10.1002/jcp.21200Wei X, Yang X, Han Z, Qu F, Shao L, Shi Y (2013) Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacol Sin 34: 747–754. https://doi.org/10.1038/aps.2013.50Lu L, Xu A, Gao F, Tian C, Wang H, Zhang J, Xie Y, Liu P, Liu S, Yang C, Ye Z, Wu X (2022) Mesenchymal Stem Cell-Derived Exosomes as a Novel Strategy for the Treatment of Intervertebral Disc Degeneration. Front Cell Dev Biol 9: 770510. https://doi.org/10.3389/fcell.2021.770510Sanchez-Diaz M, Quiñones-Vico MI, Sanabria De La Torre R, Montero-Vílchez T, Sierra-Sánchez A, Molina-Leyva A, Arias-Santiago S (2021) Biodistribution of Mesenchymal Stromal Cells after Administration in Animal Models and Humans: A Systematic Review. J Clin Med 10: 2925. https://doi.org/10.3390/jcm10132925Becker AD, Riet IV (2016) Homing and migration of mesenchymal stromal cells: How to improve the efficacy of cell therapy? World J Stem Cells 8: 73. https://doi.org/10.4252/wjsc.v8.i3.73Szydlak R (2021) Biological, chemical and mechanical factors regulating migration and homing of mesenchymal stem cells. World J Stem Cells 13: 619–631. https://doi.org/10.4252/wjsc.v13.i6.619Leibacher J, Dauber K, Ehser S, Brixner V, Kollar K, Vogel A, Spohn G, Schäfer R, Seifried E, Henschler R (2017) Human mesenchymal stromal cells undergo apoptosis and fragmentation after intravenous application in immune-competent mice. Cytotherapy 19: 61–74. https://doi.org/10.1016/j.jcyt.2016.09.010Zachar L, Bačenková D, Rosocha J (2016) Activation, homing, and role of the mesenchymal stem cells in the inflammatory environment. J Inflamm Res 9: 231–240. https://doi.org/10.2147/JIR.S121994Nitzsche F, Müller C, Lukomska B, Jolkkonen J, Deten A, Boltze J (2017) Concise Review: MSC Adhesion Cascade—Insights into Homing and Transendothelial Migration. Stem Cells 35: 1446–1460. https://doi.org/10.1002/stem.2614Teo GSL, Ankrum JA, Martinelli R, Boetto SE, Simms K, Sciuto TE, Dvorak AM, Karp JM, Carman CV (2012) Mesenchymal Stem Cells Transmigrate Between and Directly Through Tumor Necrosis Factor-α-Activated Endothelial Cells Via Both Leukocyte-Like and Novel Mechanisms. Stem Cells 30: 2472–2486. https://doi.org/10.1002/stem.1198Guo Y-C, Chiu Y-H, Chen C-P, Wang H-S (2018) Interleukin-1β induces CXCR3-mediated chemotaxis to promote umbilical cord mesenchymal stem cell transendothelial migration. Stem Cell Res Ther 9: 281. https://doi.org/10.1186/s13287-018-1032-9Merfeld-Clauss S, Lupov IP, Lu H, Feng D, Compton-Craig P, March KL, Traktuev DO (2014) Adipose Stromal Cells Differentiate Along a Smooth Muscle Lineage Pathway Upon Endothelial Cell Contact via Induction of Activin A. Circ Res 115: 800–809. https://doi.org/10.1161/CIRCRESAHA.115.304026Lin C-H, Lilly B (2014) Endothelial Cells Direct Mesenchymal Stem Cells Toward a Smooth Muscle Cell Fate. Stem Cells Dev 23: 2581–2590. https://doi.org/10.1089/scd.2014.0163Li C, Wu X, Tong J, Yang X, Zhao J, Zheng Q, Zhao G, Ma Z (2015) Comparative analysis of human mesenchymal stem cells from bone marrow and adipose tissue under xeno-free conditions for cell therapy. Stem Cell Res Ther 6: 55. https://doi.org/10.1186/s13287-015-0066-5Buravkova LB, Grinakovskaya OS, Andreeva ER, Zhambalova AP, Kozionova MP (2009) Characteristics of human lipoaspirate-isolated mesenchymal stromal cells cultivated under lower oxygen tension. Cell Tissue Biol 3: 23–28. https://doi.org/10.1134/S1990519X09010039Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS, Deans RJ, Keating A, Prockop DJ, Horwitz EM (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8: 315–317. https://doi.org/10.1080/14653240600855905Tondreau T, Meuleman N, Stamatopoulos B, De Bruyn C, Delforge A, Dejeneffe M, Martiat P, Bron D, Lagneaux L (2009) In vitro study of matrix metalloproteinase/tissue inhibitor of metalloproteinase production by mesenchymal stromal cells in response to inflammatory cytokines: the role of their migration in injured tissues. Cytotherapy 11: 559–569. https://doi.org/10.1080/14653240903051541Lozito TP, Jackson WM, Nesti LJ, Tuan RS (2014) Human mesenchymal stem cells generate a distinct pericellular zone of MMP activities via binding of MMPs and secretion of high levels of TIMPs. Matrix Biol 34: 132–143. https://doi.org/10.1016/j.matbio.2013.10.003Beloglazova IB, Zubkova ES, Tsokolaeva ZI, Stafeev YuS, Dergilev KV, Ratner EI, Shestakova MV, Sukhareva OYu, Parfenova EV, Menshikov MYu (2016) Regulatory Effects of Urokinase on Mesenchymal Stromal Cell Migration, Proliferation, and Matrix Metalloproteinase Secretion. Bull Exp Biol Med 161: 775–778. https://doi.org/10.1007/s10517-016-3507-yWei L, Xu Y, Zhang L, Yang L, Zhao RC, Zhao D (2023) Mesenchymal Stem Cells Promote Wound Healing and Effects on Expression of Matrix Metalloproteinases-8 and 9 in the Wound Tissue of Diabetic Rats. Stem Cells Dev 32: 25–31. https://doi.org/10.1089/scd.2021.0218Lee JA, Kim BI, Jo CH, Choi CW, Kim E-K, Kim H-S, Yoon K-S, Choi J-H (2010) Mesenchymal stem-cell transplantation for hypoxic-ischemic brain injury in neonatal rat model. Pediatr Res 67: 42–46. https://doi.org/10.1203/PDR.0b013e3181bf594bPogodina MV, Buravkova LB (2014) Expression of hypoxia-associated genes in multipotent mesenchymal stromal cells during long-term cultivation at low oxygen. Dokl Biol Sci 458: 310–312. https://doi.org/10.1134/S0012496614050056Pulido-Escribano V, Torrecillas-Baena B, Camacho-Cardenosa M, Dorado G, Gálvez-Moreno MÁ, Casado-Díaz A (2022) Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles. World J Stem Cells 14: 453–472. https://doi.org/10.4252/wjsc.v14.i7.453Fontani F, Domazetovic V, Marcucci T, Vincenzini MT, Iantomasi T (2016) Tumor Necrosis Factor-Alpha Up-Regulates ICAM-1 Expression and Release in Intestinal Myofibroblasts by Redox-Dependent and -Independent Mechanisms: ICAM-1 Expression and Release in 18C o Cells. J Cell Biochem 117: 370–381. https://doi.org/10.1002/jcb.25279Li M, Van Esch BCAM, Wagenaar GTM, Garssen J, Folkerts G, Henricks PAJ (2018) Pro- and anti-inflammatory effects of short chain fatty acids on immune and endothelial cells. Eur J Pharmacol 831: 52–59. https://doi.org/10.1016/j.ejphar.2018.05.003Sigfrid LA, Cunningham JM, Beeharry N, Lortz S, Tiedge M, Lenzen S, Carlsson C, Green IC (2003) Cytokines and nitric oxide inhibit the enzyme activity of catalase but not its protein or mRNA expression in insulin-producing cells. J Mol Endocrinol 31: 509–518. https://doi.org/10.1677/jme.0.0310509Bauer G (2015) Increasing the endogenous NO level causes catalase inactivation and reactivation of intercellular apoptosis signaling specifically in tumor cells. Redox Biol 6: 353–371. https://doi.org/10.1016/j.redox.2015.07.017Mussbacher M, Salzmann M, Brostjan C, Hoesel B, Schoergenhofer C, Datler H, Hohensinner P, Basílio J, Petzelbauer P, Assinger A, Schmid JA (2019) Cell Type-Specific Roles of NF-κB Linking Inflammation and Thrombosis. Front Immunol 10: 85. https://doi.org/10.3389/fimmu.2019.00085Frith JE, Mills RJ, Hudson JE, Cooper-White JJ (2012) Tailored Integrin–Extracellular Matrix Interactions to Direct Human Mesenchymal Stem Cell Differentiation. Stem Cells Dev 21: 2442–2456. https://doi.org/10.1089/scd.2011.0615Steward AJ, Kelly DJ (2015) Mechanical regulation of mesenchymal stem cell differentiation. J Anat 227: 717–731. https://doi.org/10.1111/joa.12243Huttenlocher A, Horwitz AR (2011) Integrins in Cell Migration. Cold Spring Harb Perspect Biol 3: a005074–a005074. https://doi.org/10.1101/cshperspect.a005074Becerra-Bayona SM, Guiza-Arguello VR, Russell B, Höök M, Hahn MS (2018) Influence of collagen-based integrin α1 and α2 mediated signaling on human mesenchymal stem cell osteogenesis in three dimensional contexts. J Biomed Mater Res A 106: 2594–2604. https://doi.org/10.1002/jbm.a.36451Winning S, Splettstoesser F, Fandrey J, Frede S (2010) Acute Hypoxia Induces HIF-Independent Monocyte Adhesion to Endothelial Cells through Increased Intercellular Adhesion Molecule-1 Expression: The Role of Hypoxic Inhibition of Prolyl Hydroxylase Activity for the Induction of NF-κB. J Immunol 185: 1786–1793. https://doi.org/10.4049/jimmunol.0903244Thin Luu N, Mcgettrick HM, Buckley CD, Newsome PN, Ed Rainger G, Frampton J, Nash GB (2013) Crosstalk Between Mesenchymal Stem Cells and Endothelial Cells Leads to Downregulation of Cytokine-Induced Leukocyte Recruitment. Stem Cells 31: 2690–2702. https://doi.org/10.1002/stem.1511Bartaula-Brevik S (2017) Secretome of Mesenchymal Stem Cells Grown in Hypoxia Accelerates Wound Healing and Vessel Formation In Vitro. Int J Stem Cell Res Ther 4. https://doi.org/10.23937/2469-570X/1410045Hao Q, Wang L, Tang H (2009) Vascular endothelial growth factor induces protein kinase D-dependent production of proinflammatory cytokines in endothelial cells. Am J Physiol-Cell Physiol 296: C821–C827. https://doi.org/10.1152/ajpcell.00504.2008Guillamat-Prats R (2022) Role of Mesenchymal Stem/Stromal Cells in Coagulation. Int J Mol Sci 23: 10393. https://doi.org/10.3390/ijms231810393Lund LR, Green KA, Stoop AA, Ploug M, Almholt K, Lilla J, Nielsen BS, Christensen IJ, Craik CS, Werb Z, Danø K, Rømer J (2006) Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice. EMBO J 25: 2686–2697. https://doi.org/10.1038/sj.emboj.7601173Rundhaug JE (2005) Matrix metalloproteinases and angiogenesis. J Cell Mol Med 9: 267–285. https://doi.org/10.1111/j.1582-4934.2005.tb00355.xMcCarty SM, Percival SL (2013) Proteases and Delayed Wound Healing. Adv Wound Care 2: 438–447. https://doi.org/10.1089/wound.2012.0370Shalini S, Dorstyn L, Dawar S, Kumar S (2015) Old, new and emerging functions of caspases. Cell Death Differ 22: 526–539. https://doi.org/10.1038/cdd.2014.216Habič A, Novak M, Majc B, Lah Turnšek T, Breznik B (2021) Proteases Regulate Cancer Stem Cell Properties and Remodel Their Microenvironment. J Histochem Cytochem 69: 775–794. https://doi.org/10.1369/00221554211035192Brauer PR (2006) MMPs-Role in Cardiovascular Development and Disease. Front Biosci 11: 447. https://doi.org/10.2741/1810Kasper G, Glaeser JD, Geissler S, Ode A, Tuischer J, Matziolis G, Perka C, Duda GN (2007) Matrix Metalloprotease Activity Is an Essential Link Between Mechanical Stimulus and Mesenchymal Stem Cell Behavior. Stem Cells 25: 1985–1994. https://doi.org/10.1634/stemcells.2006-0676De Becker A, Van Hummelen P, Bakkus M, Vande Broek I, De Wever J, De Waele M, Van Riet I (2007) Migration of culture-expanded human mesenchymal stem cells through bone marrow endothelium is regulated by matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-3. Haematologica 92: 440–449. https://doi.org/10.3324/haematol.10475Ries C, Egea V, Karow M, Kolb H, Jochum M, Neth P (2007) MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines. Blood 109: 4055–4063. https://doi.org/10.1182/blood-2006-10-051060Tong B, Wan B, Wei Z, Wang T, Zhao P, Dou Y, Lv Z, Xia Y, Dai Y (2014) Role of cathepsin B in regulating migration and invasion of fibroblast-like synoviocytes into inflamed tissue from patients with rheumatoid arthritis. Clin Exp Immunol 177: 586–597. https://doi.org/10.1111/cei.12357Vangala G, Imhoff FM, Squires CML, Cridge AG, Baird SK (2019) Mesenchymal stem cell homing towards cancer cells is increased by enzyme activity of cathepsin D. Exp Cell Res 383: 111494. https://doi.org/10.1016/j.yexcr.2019.07.007Vidak E, Javoršek U, Vizovišek M, Turk B (2019) Cysteine Cathepsins and their Extracellular Roles: Shaping the Microenvironment. Cells 8: 264. https://doi.org/10.3390/cells8030264Park S, Huang H, Kwon W, Kim H, Park J, Han JE, Cho G, Han S, Sung Y, Ryoo ZY, Kim MO, Choi S (2021) Cathepsin A regulates pluripotency, proliferation and differentiation in mouse embryonic stem cells. Cell Biochem Funct 39: 67–76. https://doi.org/10.1002/cbf.3554Mott JD, Werb Z (2004) Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol 16: 558–564. https://doi.org/10.1016/j.ceb.2004.07.010Stefansson S, Lawrence DA (1996) The serpin PAI-1 inhibits cell migration by blocking integrin αvβ3 binding to vitronectin. Nature 383: 441–443. https://doi.org/10.1038/383441a0Richard B, Pichon S, Arocas V, Venisse L, Berrou E, Bryckaert M, Jandrot Perrus M, Bouton MC (2006) The serpin protease nexin-1 regulates vascular smooth muscle cell adhesion, spreading, migration and response to thrombin. J Thromb Haemost 4: 322–328. https://doi.org/10.1111/j.1538-7836.2006.01710.xProvençal M, Michaud M, Beaulieu É, Ratel D, Rivard G-É, Gingras D, Béliveau R (2008) Tissue factor pathway inhibitor (TFPI) interferes with endothelial cell migration by inhibition of both the Erk pathway and focal adhesion proteins. Thromb Haemost 99: 576–585. https://doi.org/10.1160/TH07-10-0623Saller MM, Prall WC, Docheva D, Schönitzer V, Popov T, Anz D, Clausen-Schaumann H, Mutschler W, Volkmer E, Schieker M, Polzer H (2012) Increased stemness and migration of human mesenchymal stem cells in hypoxia is associated with altered integrin expression. Biochem Biophys Res Commun 423: 379–385. https://doi.org/10.1016/j.bbrc.2012.05.134Choi JH, Lee YB, Jung J, Hwang SG, Oh I-H, Kim GJ (2016) Hypoxia Inducible Factor-1 α Regulates the Migration of Bone Marrow Mesenchymal Stem Cells via Integrin α4. Stem Cells Int 2016: 1–11. https://doi.org/10.1155/2016/7932185Ren G, Roberts AI, Shi Y (2011) Adhesion molecules: Key players in mesenchymal stem cell-mediated immunosuppression. Cell Adhes Migr 5: 20–22. https://doi.org/10.4161/cam.5.1.13491Mai J, Virtue A, Shen J, Wang H, Yang X-F (2013) An evolving new paradigm: endothelial cells – conditional innate immune cells. J Hematol Oncol 6: 61. https://doi.org/10.1186/1756-8722-6-61