ST266 inhibits neointimal hyperplasia after arterial balloon injury in rats

Objective    To examine the effect of Human Amnion-Derived Multipotent Progenitor (AMP) cells and their novel ST266 secretome on neointimal hyperplasia after arterial balloon injury in rats.
Material and Methods    Sprague-Dawley male rats were randomly divided into four groups (n=7): Control (PBS) group, systemic ST266 group, systemic AMP group and local AMP implant group. Neointimal hyperplasia was induced in the iliac using a 2F Fogarty embolectomy catheter. After surgery, the rats in the ST266 group were treated with 0.1, 0.5, or 1ml ST266 iv daily. In the systemic AMP groups, a single dose (SD) of 0.5 ×106 or 1×106 AMP cells was injected via the inferior vena cava after arterial balloon injury. In local AMP implant groups, 1×106, 5×106, or 20×106 AMP cells were implanted in 300 µl Matrigel (Mtgl) around the iliac artery after balloon injury. The iliac arteries were removed for histologic analysis at 28 days after the surgery. Re-endothelialization index was measured at 10 days after balloon injury.
Results    ST266 (1 ml) group had a lower level of the Neointima / Neointima+Media ratio (N / N+M) 0.3±0.1 vs 0.5±0.1, p=0.004) and luminal stenosis (LS) percentage (18.2±1.9 % vs 39.2±5.8 %, p=0.008) compared with the control group. Single-dose AMP (1×106) decreased LS compared to the control group (19.5±5.4 % vs 39.2±5.8 %, p=0.033). Significant reduction in N / N+M were found between implanted AMPs (20×106) and the control group (0.4±0.1 vs 0.5±0.1, p=0.003) and the Mtgl-only group (0.5±0.1, p=0.007). Implanted AMPs (20×106) decreased the LS compared with both the control (39.2±5.8 %, p=0.001) and Mtgl-only group (37.5±8.6 %, p=0.016). ST266 (1 ml) significantly increased the re-endothelialization index compared to the control (0.4±0.1 vs 0.1±0.1, p=0.002).
Conclusion    ST266 and AMP cells reduce neointimal formation and increase the re-endothelialization index after arterial balloon injury. ST266 is potentially a novel, therapeutic agent to prevent vascular restenosis in human.

1. Garg S, Serruys PW. Coronary Stents. Journal of the American College of Cardiology. 2010;56(10 Suppl):S1–42. DOI: 10.1016/j.jacc.2010.06.007

2. Tanaka H, Sukhova GK, Swanson SJ, Clinton SK, Ganz P, Cybulsky MI et al. Sustained activation of vascular cells and leukocytes in the rabbit aorta after balloon injury. Circulation. 1993;88(4):1788–803. DOI: 10.1161/01.CIR.88.4.1788

3. Banas RA, Trumpower C, Bentlejewski C, Marshall V, Sing G, Zeevi A. Immunogenicity and immunomodulatory effects of amnion-derived multipotent progenitor cells. Human Immunology. 2008;69(6):321–8. DOI: 10.1016/j.humimm.2008.04.007

4. Baker R, Urso-Baiarda F, Linge C, Grobbelaar A. Cutaneous scarring: a clinical review. Dermatology Research and Practice. 2009;2009:625376. DOI: 10.1155/2009/625376

5. Philip J, Hackl F, Canseco JA, Kamel RA, Kiwanuka E, Diaz-Siso JR et al. Amnion-derived multipotent progenitor cells improve achilles tendon repair in rats. Eplasty. 2013;13:e31. PMID: 23814634

6. Steed DL, Trumpower C, Duffy D, Smith C, Marshall V, Rupp R et al. Amnion-derived cellular cytokine solution: a physiological combination of cytokines for wound healing. Eplasty. 2008;8:e18. PMID: 18461121

7. Franz MG, Payne WG, Xing L, Naidu DK, Salas RE, Marshall VS et al. The use of amnion-derived cellular cytokine solution to improve healing in acute and chronic wound models. Eplasty. 2008;8:e21. PMID: 18470282

8. Uberti MG, Lufkin AE, Pierpont YN, Ko F, Smith CA, Robson MC et al. Amnion–Derived Cellular Cytokine Solution Promotes Macrophage Activity. Annals of Plastic Surgery. 2011;66(5):575–80. DOI: 10.1097/SAP.0b013e318212f1d0

9. Deng-Bryant Y, Readnower RD, Leung LY, Cunningham TL, Shear DA, Tortella FC. Treatment with amnion-derived cellular cytokine solution (ACCS) induces persistent motor improvement and ameliorates neuroinflammation in a rat model of penetrating ballistic-like brain injury. Restorative Neurology and Neuroscience. 2015;33(2):189–203. DOI: 10.3233/RNN-140455

10. Deng-Bryant Y, Chen Z, van der Merwe C, Liao Z, Dave JR, Rupp R et al. Long-term administration of amnion-derived cellular cytokine suspension promotes functional recovery in a model of penetrating ballistic-like brain injury. Journal of Trauma and Acute Care Surgery. 2012;73(2 Suppl 1):S156–64. DOI: 10.1097/TA.0b013e3182625f5f

11. Vazquez-Padron RI, Mateu D, Rodriguez-Menocal L, Wei Y, Webster KA, Pham SM. Novel role of Egr-1 in nicotine-related neointimal formation. Cardiovascular Research. 2010;88(2):296–303. DOI: 10.1093/cvr/cvq213

12. Niu C, Wang X, Zhao M, Cai T, Liu P, Li J et al. Macrophage Foam Cell–Derived Extracellular Vesicles Promote Vascular Smooth Muscle Cell Migration and Adhesion. Journal of the American Heart Association. 2016;5(10):e004099. DOI: 10.1161/JAHA.116.004099

13. Li L, Zhang H-N, Chen H-Z, Gao P, Zhu L-H, Li H-L et al. SIRT1 Acts as a Modulator of Neointima Formation Following Vascular Injury in Mice. Circulation Research. 2011;108(10):1180–9. DOI: 10.1161/CIRCRESAHA.110.237875

14. Khan RS, Dine K, Bauman B, Lorentsen M, Lin L, Brown H et al. Intranasal Delivery of A Novel Amnion Cell Secretome Prevents Neuronal Damage and Preserves Function In A Mouse Multiple Sclerosis Model. Scientific Reports. 2017;7(1):41768. DOI: 10.1038/srep41768

15. Forte A, Rinaldi B, Sodano L, Berrino L, Rossi F, Finicelli M et al. Stem Cell Therapy for Arterial Restenosis: Potential Parameters Contributing to the Success of Bone Marrow-Derived Mesenchymal Stromal Cells. Cardiovascular Drugs and Therapy. 2012;26(1):9–21. DOI: 10.1007/s10557-011-6359-8

16. Payne WG, Wachtel TL, Smith CA, Uberti MG, Ko F, Robson MC. Effect of Amnion-Derived Cellular Cytokine Solution on Healing of Experimental Partial-Thickness Burns. World Journal of Surgery. 2010;34(7):1663–8. DOI: 10.1007/s00268-010-0420-9

17. Swanson N, Hogrefe K, Javed Q, Malik N, Gershlick AH. Vascular endothelial growth factor (VEGF)-eluting stents: in vivo effects on thrombosis, endothelialization and intimal hyperplasia. The Journal of Invasive Cardiology. 2003;15(12):688–92. PMID: 14660819

18. Tang C, Wang G, Wu X, Li Z, Shen Y, Lee JC-M et al. The impact of vascular endothelial growth factor-transfected human endothelial cells on endothelialization and restenosis of stainless steel stents. Journal of Vascular Surgery. 2011;53(2):461–71. DOI: 10.1016/j.jvs.2010.08.020

19. Lijnen HR, Soloway P, Collen D. Tissue Inhibitor of Matrix Metalloproteinases-1 Impairs Arterial Neointima Formation After Vascular Injury in Mice. Circulation Research. 1999;85(12):1186–91. DOI: 10.1161/01.RES.85.12.1186

20. Cho A, Reidy MA. Matrix Metalloproteinase-9 Is Necessary for the Regulation of Smooth Muscle Cell Replication and Migration After Arterial Injury. Circulation Research. 2002;91(9):845–51. DOI: 10.1161/01.RES.0000040420.17366.2E

21. Hatzi E, Badet J. Expression of receptors for human angiogenin in vascular smooth muscle cells. European Journal of Biochemistry. 1999;260(3):825–32. DOI: 10.1046/j.1432-1327.1999.00222.x

22. Orlidge A, D’Amore PA. Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells. The Journal of Cell Biology. 1987;105(3):1455–62. DOI: 10.1083/jcb.105.3.1455

23. Dodge AB, Lu X, D’Amore PA. Density-dependent endothelial cell production of an inhibitor of smooth muscle cell growth. Journal of Cellular Biochemistry. 1993;53(1):21–31. DOI: 10.1002/jcb.240530104

24. Feige JN, Auwerx J. Transcriptional targets of sirtuins in the coordination of mammalian physiology. Current Opinion in Cell Biology. 2008;20(3):303–9. DOI: 10.1016/j.ceb.2008.03.012

25. Zhang Q -j., Wang Z, Chen H -z., Zhou S, Zheng W, Liu G et al. Endothelium-specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E-deficient mice. Cardiovascular Research. 2008;80(2):191–9. DOI: 10.1093/cvr/cvn224

26. Welt FG, Tso C, Edelman ER, Kjelsberg MA, Paolini JF, Seifert P et al. Leukocyte recruitment and expression of chemokines following different forms of vascular injury. Vascular Medicine. 2003;8(1):1–7. DOI: 10.1191/1358863x03vm462oa

27. Danenberg HD, Welt FGP, Walker M, Seifert P, Toegel GS, Edelman ER. Systemic Inflammation Induced by Lipopolysaccharide Increases Neointimal Formation After Balloon and Stent Injury in Rabbits. Circulation. 2002;105(24):2917–22. DOI: 10.1161/01.CIR.0000018168.15904.BB

28. Maiguel D, Faridi MH, Wei C, Kuwano Y, Balla KM, Hernandez D et al. Small Molecule–Mediated Activation of the Integrin CD11b/CD18 Reduces Inflammatory Disease. Science Signaling. 2011;4(189):ra57. DOI: 10.1126/scisignal.2001811

29. Banas R, Miller C, Guzik L, Zeevi A. Amnion-Derived Multipotent Progenitor Cells Inhibit Blood Monocyte Differentiation into Mature Dendritic Cells. Cell Transplantation. 2014;23(9):1111–25. DOI: 10.3727/096368913X670165

30. Rey FE, Pagano PJ. The Reactive Adventitia: Fibroblast Oxidase in Vascular Function. Arteriosclerosis, Thrombosis, and Vascular Biology. 2002;22(12):1962–71. DOI: 10.1161/01.ATV.0000043452.30772.18

31. Conte MS, Nugent HM, Gaccione P, Roy-Chaudhury P, Lawson JH. Influence of diabetes and perivascular allogeneic endothelial cell implants on arteriovenous fistula remodeling. Journal of Vascular Surgery. 2011;54(5):1383–9. DOI: 10.1016/j.jvs.2011.05.005

32. Nugent HM, Ng Y-S, White D, Groothius A, Kanner G, Edelman ER. Ultrasound-guided percutaneous delivery of tissue-engineered endothelial cells to the adventitia of stented arteries controls the response to vascular injury in a porcine model. Journal of Vascular Surgery. 2012;56(4):1078–88. DOI: 10.1016/j.jvs.2012.03.002

33. Hughes D, Fu AA, Puggioni A, Glockner JF, Anwer B, McGuire AM et al. Adventitial transplantation of blood outgrowth endothelial cells in porcine haemodialysis grafts alleviates hypoxia and decreases neointimal proliferation through a matrix metalloproteinase-9-mediated pathway--a pilot study. Nephrology Dialysis Transplantation. 2008;24(1):85–96. DOI: 10.1093/ndt/gfn433