Tissue Engineering and Regenerative Medicine

, Volume 13, Issue 6, pp 701–712 | Cite as

Immunomodulatory effects of adipose tissue-derived stem cells on elastin scaffold remodeling in diabetes

  • James P. Chow
  • Dan T. Simionescu
  • Anna L. Carter
  • Agneta Simionescu
Original Article Cell Biology


Diabetes is a major risk factor for the progression of vascular disease, contributing to elevated levels of glycoxidation, chronic inflammation and calcification. Tissue engineering emerges as a potential solution for the treatment of vascular diseases however there is a considerable gap in the understanding of how scaffolds and stem cells will perform in patients with diabetes. We hypothesized that adipose tissue-derived stem cells (ASCs) by virtue of their immunosuppressive potential would moderate the diabetes-intensified inflammatory reactions and induce positive construct remodeling. To test this hypothesis, we prepared arterial elastin scaffolds seeded with autologous ASCs and implanted them subdermally in diabetic rats and compared inflammatory markers, macrophage polarization, matrix remodeling, calcification and bone protein expression to control scaffolds implanted with and without cells in nondiabetic rats. ASC-seeded scaffolds exhibited lower levels of CD8+ T-cells and CD68+ pan-macrophages and higher numbers of M2 macrophages, smooth muscle cell-like and fibroblast-like cells. Calcification and osteogenic markers were reduced in ASCseeded scaffolds implanted in non-diabetic rats but remained unchanged in diabetes, unless the scaffolds were first pre-treated with penta-galloyl glucose (PGG), a known anti-oxidative elastin-binding polyphenol. In conclusion, autologous ASC seeding in elastin scaffolds is effective in combating diabetes-related complications. To prevent calcification, the oxidative milieu needs to be reduced by elastin-binding antioxidants such as PGG.

Key Words

Streptozotocin-induced diabetes Arterial scaffolds Macrophage polarization Calcification 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Bierhaus A, Hofmann MA, Ziegler R, Nawroth PP. AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovasc Res 1998;37:586–600.CrossRefPubMedGoogle Scholar
  2. 2.
    Peterson LR, McKenzie CR, Schaffer JE. Diabetic cardiovascular disease: getting to the heart of the matter. J Cardiovasc Transl Res 2012;5:436–445.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Fein FS. Diabetic cardiomyopathy. Diabetes Care 1990;13:1169–1179.CrossRefPubMedGoogle Scholar
  4. 4.
    Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010;107:1058–1070.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, et al. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation 2011;123:e18-e209.CrossRefGoogle Scholar
  6. 6.
    Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011;94:311–321.CrossRefPubMedGoogle Scholar
  7. 7.
    Bansal S, Siddarth M, Chawla D, Banerjee BD, Madhu SV, Tripathi AK. Advanced glycation end products enhance reactive oxygen and nitrogen species generation in neutrophils in vitro. Mol Cell Biochem 2012;361:289–296.CrossRefPubMedGoogle Scholar
  8. 8.
    Davì G, Falco A, Patrono C. Lipid peroxidation in diabetes mellitus. Antioxid Redox Signal 2005;7:256–268.CrossRefPubMedGoogle Scholar
  9. 9.
    Förstermann U. Oxidative stress in vascular disease: causes, defense mechanisms and potential therapies. Nat Clin Pract Cardiovasc Med 2008;5:338–349.CrossRefPubMedGoogle Scholar
  10. 10.
    Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl) 2005;83:876–886.CrossRefGoogle Scholar
  11. 11.
    Del Turco S, Basta G. An update on advanced glycation endproducts and atherosclerosis. Biofactors 2012;38:266–274.CrossRefPubMedGoogle Scholar
  12. 12.
    Mezzetti A, Cipollone F, Cuccurullo F. Oxidative stress and cardiovascular complications in diabetes: isoprostanes as new markers on an old paradigm. Cardiovasc Res 2000;47:475–488.CrossRefPubMedGoogle Scholar
  13. 13.
    Forbes JM, Coughlan MT, Cooper ME. Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 2008;57:1446–1454.CrossRefPubMedGoogle Scholar
  14. 14.
    Tintut Y, Parhami F, Tsingotjidou A, Tetradis S, Territo M, Demer LL. 8-Isoprostaglandin E2 enhances receptor-activated NFkappa B ligand (RANKL)-dependent osteoclastic potential of marrow hematopoietic precursors via the cAMP pathway. J Biol Chem 2002;277:14221–14226.CrossRefPubMedGoogle Scholar
  15. 15.
    Al-Aly Z. Arterial calcification: a tumor necrosis factor-alpha mediated vascular Wnt-opathy. Transl Res 2008;151:233–239.CrossRefPubMedGoogle Scholar
  16. 16.
    Qasim AN, Martin SS, Mehta NN, Wolfe ML, Park J, Schwartz S, et al. Lipoprotein(a) is strongly associated with coronary artery calcification in type-2 diabetic women. Int J Cardiol 2011;150:17–21.CrossRefPubMedGoogle Scholar
  17. 17.
    Alman AC, Maahs DM, Rewers MJ, Snell-Bergeon JK. Ideal cardiovascular health and the prevalence and progression of coronary artery calcification in adults with and without type 1 diabetes. Diabetes Care 2014;37:521–528.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Mikos AG, Herring SW, Ochareon P, Elisseeff J, Lu HH, Kandel R, et al. Engineering complex tissues. Tissue Eng 2006;12:3307–3339.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Bouten CV, Dankers PY, Driessen-Mol A, Pedron S, Brizard AM, Baaijens FP. Substrates for cardiovascular tissue engineering. Adv Drug Deliv Rev 2011;63:221–241.CrossRefPubMedGoogle Scholar
  20. 20.
    Chow JP, Simionescu DT, Warner H, Wang B, Patnaik SS, Liao J, et al. Mitigation of diabetes-related complications in implanted collagen and elastin scaffolds using matrix-binding polyphenol. Biomaterials 2013;34:685–695.CrossRefPubMedGoogle Scholar
  21. 21.
    Zhao J, Liu L, Wei J, Ma D, Geng W, Yan X, et al. A novel strategy to engineer small-diameter vascular grafts from marrow-derived mesenchymal stem cells. Artif Organs 2012;36:93–101.CrossRefPubMedGoogle Scholar
  22. 22.
    Kumar VA, Brewster LP, Caves JM, Chaikof EL. Tissue engineering of blood vessels: functional requirements, progress, and future challenges. Cardiovasc Eng Technol 2011;2:137–148.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Harris LJ, Zhang P, Abdollahi H, Tarola NA, DiMatteo C, McIlhenny SE, et al. Availability of adipose-derived stem cells in patients undergoing vascular surgical procedures. J Surg Res 2010;163:e105-e112.CrossRefGoogle Scholar
  24. 24.
    Gimble J, Guilak F. Adipose-derived adult stem cells: isolation, characterization, and differentiation potential. Cytotherapy 2003;5:362–369.CrossRefPubMedGoogle Scholar
  25. 25.
    Gimble JM, Katz AJ, Bunnell BA. Adipose-derived stem cells for regenerative medicine. Circ Res 2007;100:1249–1260.CrossRefPubMedGoogle Scholar
  26. 26.
    Kronsteiner B, Wolbank S, Peterbauer A, Hackl C, Redl H, van Griensven M, et al. Human mesenchymal stem cells from adipose tissue and amnion influence T-cells depending on stimulation method and presence of other immune cells. Stem Cells Dev 2011;20:2115–2126.CrossRefPubMedGoogle Scholar
  27. 27.
    DelaRosa O, Lombardo E, Beraza A, Mancheño-Corvo P, Ramirez C, Menta R, et al. Requirement of IFN-gamma-mediated indoleamine 2,3-dioxygenase expression in the modulation of lymphocyte proliferation by human adipose-derived stem cells. Tissue Eng Part A 2009;15:2795–2806.CrossRefPubMedGoogle Scholar
  28. 28.
    Gonzalez-Rey E, Gonzalez MA, Varela N, O’Valle F, Hernandez-Cortes P, Rico L, et al. Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis. Ann Rheum Dis 2010;69:241–248.CrossRefPubMedGoogle Scholar
  29. 29.
    Rabbah JP, Saikrishnan N, Yoganathan AP. A novel left heart simulator for the multi-modality characterization of native mitral valve geometry and fluid mechanics. Ann Biomed Eng 2013;41:305–315.CrossRefPubMedGoogle Scholar
  30. 30.
    Anderson P, Souza-Moreira L, Morell M, Caro M, O’Valle F, Gonzalez-Rey E, et al. Adipose-derived mesenchymal stromal cells induce immunomodulatory macrophages which protect from experimental colitis and sepsis. Gut 2013;62:1131–1141.CrossRefPubMedGoogle Scholar
  31. 31.
    Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an Immunosuppressive MSC2 phenotype. PLoS One 2010;5:e10088.CrossRefGoogle Scholar
  32. 32.
    Ebrahimi B, Eirin A, Li Z, Zhu XY, Zhang X, Lerman A, et al. Mesenchymal stem cells improve medullary inflammation and fibrosis after revascularization of swine atherosclerotic renal artery stenosis. PLoS One 2013;8:e67474.CrossRefGoogle Scholar
  33. 33.
    Tidball JG, Villalta SA. Regulatory interactions between muscle and the immune system during muscle regeneration. Am J Physiol Regul Integr Comp Physiol 2010;298:R1173–R1187.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Badylak SF, Valentin JE, Ravindra AK, McCabe GP, Stewart-Akers AM. Macrophage phenotype as a determinant of biologic scaffold remodeling. Tissue Eng Part A 2008;14:1835–1842.CrossRefPubMedGoogle Scholar
  35. 35.
    Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 2001;7:211–228.CrossRefPubMedGoogle Scholar
  36. 36.
    Tuominen VJ, Ruotoistenmäki S, Viitanen A, Jumppanen M, Isola J. ImmunoRatio: a publicly available web application for quantitative image analysis of estrogen receptor (ER), progesterone receptor (PR), and Ki-67. Breast Cancer Res 2010;12:R56.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Brown BN, Ratner BD, Goodman SB, Amar S, Badylak SF. Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine. Biomaterials 2012;33:3792–3802.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Stöhr R, Federici M. Insulin resistance and atherosclerosis: convergence between metabolic pathways and inflammatory nodes. Biochem J 2013;454:1–11.CrossRefPubMedGoogle Scholar
  39. 39.
    Johansen JS, Harris AK, Rychly DJ, Ergul A. Oxidative stress and the use of antioxidants in diabetes: linking basic science to clinical practice. Cardiovasc Diabetol 2005;4:5.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Tollervey JR, Lunyak VV. Adult stem cells: simply a tool for regenerative medicine or an additional piece in the puzzle of human aging? Cell Cycle 2011;10:4173–4176.CrossRefPubMedGoogle Scholar
  41. 41.
    Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 2004;109:1292–1298.CrossRefPubMedGoogle Scholar
  42. 42.
    Miranville A, Heeschen C, Sengenès C, Curat CA, Busse R, Bouloumié A. Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation 2004;110:349–355.CrossRefPubMedGoogle Scholar
  43. 43.
    Gimble JM, Guilak F, Bunnell BA. Clinical and preclinical translation of cell-based therapies using adipose tissue-derived cells. Stem Cell Res Ther 2010;1:19.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Yañez R, Oviedo A, Aldea M, Bueren JA, Lamana ML. Prostaglandin E2 plays a key role in the immunosuppressive properties of adipose and bone marrow tissue-derived mesenchymal stromal cells. Exp Cell Res 2010;316:3109–3123.CrossRefPubMedGoogle Scholar
  45. 45.
    Jacobs E, Fuchte K, Bredt W. Amino acid sequence and antigenicity of the amino-terminus of the 168 kDa adherence protein of Mycoplasma pneumoniae. J Gen Microbiol 1987;133:2233–2236.PubMedGoogle Scholar
  46. 46.
    Duca L, Floquet N, Alix AJ, Haye B, Debelle L. Elastin as a matrikine. Crit Rev Oncol Hematol 2004;49:235–244.CrossRefPubMedGoogle Scholar
  47. 47.
    Hinek A, Rabinovitch M. 67-kD elastin-binding protein is a protective “companion” of extracellular insoluble elastin and intracellular tropoelastin. J Cell Biol 1994;126:563–574.CrossRefPubMedGoogle Scholar
  48. 48.
    Schulte JB, Simionescu A, Simionescu DT. The acellular myocardial flap: a novel extracellular matrix scaffold enriched with patent microvascular networks and biocompatible cell niches. Tissue Eng Part C Methods 2013;19:518–530.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Barnes CA, Brison J, Michel R, Brown BN, Castner DG, Badylak SF, et al. The surface molecular functionality of decellularized extracellular matrices. Biomaterials 2011;32:137–143.CrossRefPubMedGoogle Scholar
  50. 50.
    Belkin AM, Stepp MA. Integrins as receptors for laminins. Microsc Res Tech 2000;51:280–301.CrossRefPubMedGoogle Scholar
  51. 51.
    Lanasa SM, Bryant SJ. Influence of ECM proteins and their analogs on cells cultured on 2-D hydrogels for cardiac muscle tissue engineering. Acta Biomater 2009;5:2929–2938.CrossRefPubMedGoogle Scholar
  52. 52.
    Taki K, Takayama F, Tsuruta Y, Niwa T. Oxidative stress, advanced glycation end product, and coronary artery calcification in hemodialysis patients. Kidney Int 2006;70:218–224.CrossRefPubMedGoogle Scholar
  53. 53.
    Chen NX, Moe SM. Arterial calcification in diabetes. Curr Diab Rep 2003;3:28–32.CrossRefPubMedGoogle Scholar
  54. 54.
    Lehto S, Niskanen L, Suhonen M, Rönnemaa T, Laakso M. Medial artery calcification. A neglected harbinger of cardiovascular complications in non-insulin-dependent diabetes mellitus. Arterioscler Thromb Vasc Biol 1996;16:978–983.CrossRefPubMedGoogle Scholar
  55. 55.
    Moe SM, O’Neill KD, Duan D, Ahmed S, Chen NX, Leapman SB, et al. Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins. Kidney Int 2002;61:638–647.CrossRefPubMedGoogle Scholar
  56. 56.
    Sakata N, Noma A, Yamamoto Y, Okamoto K, Meng J, Takebayashi S, et al. Modification of elastin by pentosidine is associated with the calcification of aortic media in patients with end-stage renal disease. Nephrol Dial Transplant 2003;18:1601–1619.CrossRefPubMedGoogle Scholar
  57. 57.
    Anastasiadis K, Moschos G. Diabetes mellitus and coronary revascularization procedures. Int J Cardiol 2007;119:10–14.CrossRefPubMedGoogle Scholar
  58. 58.
    Isenburg JC, Karamchandani NV, Simionescu DT, Vyavahare NR. Structural requirements for stabilization of vascular elastin by polyphenolic tannins. Biomaterials 2006;27:3645–3651.PubMedGoogle Scholar
  59. 59.
    Chuang TH, Stabler C, Simionescu A, Simionescu DT. Polyphenol-stabilized tubular elastin scaffolds for tissue engineered vascular grafts. Tissue Eng Part A 2009;15:2837–2851.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Yamauchi H, Motomura N, Chung UI, Sata M, Takai D, Saito A, et al. Growth-associated hyperphosphatemia in young recipients accelerates aortic allograft calcification in a rat model. J Thorac Cardiovasc Surg 2013;145:522–530.CrossRefPubMedGoogle Scholar
  61. 61.
    Simionescu A, Philips K, Vyavahare N. Elastin-derived peptides and TGF-beta1 induce osteogenic responses in smooth muscle cells. Biochem Biophys Res Commun 2005;334:524–532.CrossRefPubMedGoogle Scholar
  62. 62.
    Simionescu A, Simionescu DT, Vyavahare NR. Osteogenic responses in fibroblasts activated by elastin degradation products and transforming growth factor-beta1: role of myofibroblasts in vascular calcification. Am J Pathol 2007;171:116–123.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Takemoto M, Yokote K, Yamazaki M, Ridall AL, Butler WT, Matsumoto T, et al. Enhanced expression of osteopontin by high glucose. Involvement of osteopontin in diabetic macroangiopathy. Ann N Y Acad Sci 2000;902:357–363.CrossRefPubMedGoogle Scholar
  64. 64.
    Sodhi CP, Phadke SA, Batlle D, Sahai A. Hypoxia stimulates osteopontin expression and proliferation of cultured vascular smooth muscle cells: potentiation by high glucose. Diabetes 2001;50:1482–1490.CrossRefPubMedGoogle Scholar
  65. 65.
    Choi ST, Kim JH, Kang EJ, Lee SW, Park MC, Park YB, et al. Osteopontin might be involved in bone remodelling rather than in inflammation in ankylosing spondylitis. Rheumatology (Oxford) 2008;47:1775–1779.CrossRefGoogle Scholar
  66. 66.
    Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials. Semin Immunol 2008;20:86–100.CrossRefPubMedGoogle Scholar
  67. 67.
    Higai K, Shimamura A, Matsumoto K. Amadori-modified glycated albumin predominantly induces E-selectin expression on human umbilical vein endothelial cells through NADPH oxidase activation. Clin Chim Acta 2006;367:137–143.CrossRefPubMedGoogle Scholar
  68. 68.
    Zhang J, Li L, Kim SH, Hagerman AE, Lü J. Anti-cancer, anti-diabetic and other pharmacologic and biological activities of penta-galloyl-glucose. Pharm Res 2009;26:2066–2080.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab 2001;280: E685–E694.PubMedGoogle Scholar
  70. 70.
    Thallas-Bonke V, Thorpe SR, Coughlan MT, Fukami K, Yap FY, Sourris KC, et al. Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C-alpha-dependent pathway. Diabetes 2008;57:460–469.CrossRefPubMedGoogle Scholar

Copyright information

© The Korean Tissue Engineering and Regenerative Medicine Society and Springer Science+Business Media Dordrecht 2016

Authors and Affiliations

  • James P. Chow
    • 1
  • Dan T. Simionescu
    • 2
    • 3
  • Anna L. Carter
    • 1
  • Agneta Simionescu
    • 1
    • 4
  1. 1.Cardiovascular Tissue Engineering and Regenerative Medicine Laboratory, Department of BioengineeringClemson UniversityClemsonUSA
  2. 2.Biocompatibility and Tissue Regeneration Laboratories, Department of BioengineeringClemson UniversityClemsonUSA
  3. 3.Tissue Engineering and Regenerative Medicine Laboratory, Department of AnatomyUniversity of Medicine and PharmacyTargu MuresRomania
  4. 4.Cardiovascular Tissue Engineering and Regenerative Medicine Laboratory, Department of BioengineeringClemson UniversityClemsonUSA

Personalised recommendations