Abstract
This study evaluated whether bone marrow-derived mesenchymal stem cells (BM-MSCs) combined with xenogeneic acellular nerve grafts (xANGs) would reduce the inflammation reaction of xANGs transplantation. BM-MSCs were extracted, separated, purified, and cultured from the bone marrow of rats. Then BM-MSCs were seeded into 5 mm xANGs as experimental group, while xANGs group was chosen as control. Subcutaneous implantation and nerve grafts transplantation were done in this study. Walking-track tests, electrophysiological tests, H&E staining, and immunostaining of CD4, CD8, and CD68 of subcutaneous implantations, cytokine concentrations of IL-2, IL-10, IFN-γ and TNF-α in lymphocytes supernatants and serum of the two groups were evaluated. Walking-track tests and electrophysiological tests suggested the group of BM-MSCs with xANGs obtained better results than xANGs group (P < 0.05). H&E staining and immunostaining of CD4, CD8, and CD68 of subcutaneous implantations showed there were less inflammatory cells in the group of BM-MSCs when compared with the xANGs group. The cytokine concentrations of IL-2, IFN-γ, and TNF-α in BM-MSCs group were lower than xANGs group in lymphocytes supernatants and serum (P < 0.05). However, IL-10 concentrations in BM-MSCs group were higher than xANGs group (P < 0.05). xANG with BM-MSCs showed better nerve repair function when compared with xANG group. Furthermore, xANG with BM-MSCs showed less inflammatory reaction which might indicate the reason of its better nerve regeneration.
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References
Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105(4):1815–1822
Allman AJ, McPherson TB, Badylak SF, Merrill LC, Kallakury B, Sheehan C, Raeder RH, Metzger DW (2001) Xenogeneic extracellular matrix grafts elicit a Th2-restricted immune response. Transplantation 71(11):1631–1640
Anderson JM, Rodriguez A, Chang DT (2008) Foreign body reaction to biomaterials. Semin Immunol 20(2):86–100
Badylak SF, Freytes DO, Gilbert TW (2009) Extracellular matrix as a biological scaffold material: structure and function. Acta Biomater 5(1):1–13
Baptista AF, de Souza Gomes JR, Oliveira JT, Garzedim Santos SM, Vannier-Santos MA, Blanco Martinez AM (2007) A new approach to assess function after sciatic nerve lesion in the mouse—adaptation of the sciatic static index. J Neurosci Methods 161(2):259–264
Bayrak A, Tyralla M, Ladhoff J, Schleicher M, Stock UA, Volk H-D, Seifert M (2010) Human immune responses to porcine xenogeneic matrices and their extracellular matrix constituents in vitro. Biomaterials 31(14):3793–3803
Bozkurt A, Tholl S, Wehner S, Tank J, Cortese M, Dm O’Dey, Deumens R, Lassner F, Schuegner F, Groeger A, Smeets R, Brook G, Pallua N (2008) Evaluation of functional nerve recovery with Visual-SSI—A novel computerized approach for the assessment of the static sciatic index (SSI). J Neurosci Methods 170(1):117–122
Briesemeister D, Sommermeyer D, Loddenkemper C, Loew R, Uckert W, Blankenstein T, Kammertoens T (2011) Tumor rejection by local interferon gamma induction in established tumors is associated with blood vessel destruction and necrosis. Int J Cancer 128(2):371–378
Cantrell DA, Smith KA (1984) The interleukin-2 T-cell system—a new cell-growth model. Science 224(4655):1312–1316
Chen X, Armstrong MA, Li G (2006) Mesenchymal stem cells in immunoregulation. Immunol Cell Biol 84(5):413–421
Chen C-J, Ou Y-C, Liao S-L, Chen W-Y, Chen S-Y, Wu C-W, Wang C-C, Wang W-Y, Huang Y-S, Hsu S-H (2007) Transplantation of bone marrow stromal cells for peripheral nerve repair. Exp Neurol 204(1):443–453
Chernoff AE, Granowitz EV, Shapiro L, Vannier E, Lonnemann G, Angel JB, Kennedy JS, Rabson AR, Wolff SM, Dinarello CA (1995) A randomized, controlled trial of IL-10 in humans—inhibition of inflammatory cytokine production and immune-responses. J Immunol 154(10):5492–5499
Dazzi F, Krampera M (2011) Mesenchymal stem cells and autoimmune diseases. Best Pract Res Clin Haematol 24(1):49–57
de Menezes Neves PDM, Machado JR, dos Reis MA, Faleiros ACG, de Lima Pereira SA, Rodrigues DBR (2013) Distinct expression of interleukin 17, tumor necrosis factor alpha, transforming growth factor beta, and forkhead box P3 in acute rejection after kidney transplantation. Ann Diagn Pathol 17(1):75–79
Di Nicola M, Carlo-Stella C, Magni M, Milanesi M, Longoni PD, Matteucci P, Grisanti S, Gianni AM (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99(10):3838–3843
Dominici 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(4):315–317
English K, Barry FP, Field-Corbett CP, Mahon BP (2007) IFN-gamma and TNF-alpha differentially regulate immunomodulation by murine mesenchymal stem cells. Immunol Lett 110(2):91–100
Friedens AJ, Deriglas UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luria EA, Rudakow IA (1974) Precursors for fibroblasts in different populations of hematopoietic cells as detected by invitro colony assay method. Exp Hematol 2(2):83–92
Glennie S, Soeiro I, Dyson PJ, Lam EWF, Dazzi F (2005) Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105(7):2821–2827
He B, Zhu QT, Chai YM, Ding XH, Tang JY, Gu LQ, Xiang JP, Yang YX, Zhu JK, Liu XL (2012) Outcomes with the use of human acellular nerve graft for repair of digital nerve defects: a prospective, multicenter, controlled clinical trial. J Tissue Eng Reg Med 6:76
Hu J, Zhu Q-T, Liu X-L, Y-b Xu, Zhu J-K (2007) Repair of extended peripheral nerve lesions in rhesus monkeys using acellular allogenic nerve grafts implanted with autologous mesenchymal stem cells. Exp Neurol 204(2):658–666
Hudson TW, Liu SY, Schmidt CE (2004) Engineering an improved acellular nerve graft via optimized chemical processing. Tissue Eng 10(9–10):1346–1358
Jesuraj NJ, Santosa KB, Newton P, Liu Z, Hunter DA, Mackinnon SE, Sakiyama-Elbert SE, Johnson PJ (2011) A systematic evaluation of Schwann cell injection into acellular cold-preserved nerve grafts. J Neurosci Methods 197(2):209–215
Kanaya F, Firrell JC, Breidenbach WC (1996) Sciatic function index, nerve conduction tests, muscle contraction, and axon morphometry as indicators of regeneration. Plast Reconstr Surg 98(7):1264–1271
Kang JW, Kang K-S, Koo HC, Park JR, Choi EW, Park YH (2008) Soluble factors-mediated immunomodulatory effects of canine adipose tissue-derived mesenchymal stem cells. Stem Cells Dev 17(4):681–693
Kim J, Hematti P (2009) Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Exp Hematol 37(12):1445–1453
Krampera M (2011) Mesenchymal stromal cells: more than inhibitory cells. Leukemia 25(4):565–566
Kubek T, Ghalib N, Dubovy P (2011) Endoneurial extracellular matrix influences regeneration and maturation of motor nerve axons—a model of acellular nerve graft. Neurosci Lett 496(2):75–79
Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O (2003) Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 57(1):11–20
Luz-Crawford P, Kurte M, Bravo-Alegria J, Contreras R, Nova-Lamperti E, Tejedor G, Noel D, Jorgensen C, Figueroa F, Djouad F, Carrion F (2013) Mesenchymal stem cells generate a CD4(+) CD25(+) Foxp3(+) regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther 4:65
Ma S, Xie N, Li W, Yuan B, Shi Y, Wang Y (2014) Immunobiology of mesenchymal stem cells. Cell Death Differ 21(2):216–225
Mandegary A, Azmandian J, Soleymani S, Pootari M, Habibzadeh S-D, Ebadzadeh M-R, Dehghani-Firouzabadi M-H (2013) Effect of donor tumor necrosis factor-alpha and interleukin-10 genotypes on delayed graft function and acute rejection in kidney transplantation. Iran J Kidney Dis 7(2):135–141
Mimura T, Dezawa M, Kanno H, Sawada H, Yamamoto I (2004) Peripheral nerve regeneration by transplantation of bone marrow stromal cell-derived Schwann cells in adult rats. J Neurosurg 101(5):806–812
Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Ann Rev Immunol 19:683–765
Nadri S, Soleimani M, Hosseni RH, Massumi M, Atashi A, Izadpanah R (2007) An efficient method for isolation of murine bone marrow mesenchymal stem cells. Int J Dev Biol 51(8):723–729
Nagao RJ, Lundy S, Khaing ZZ, Schmidt CE (2011) Functional characterization of optimized acellular peripheral nerve graft in a rat sciatic nerve injury model. Neurol Res 33(6):600–608
Nagler A, Berger R, Ackerstein A, Czyz JA, Luis Diez-Martin J, Naparstek E, Or R, Gan S, Shimoni A, Slavin S (2010) A randomized controlled multicenter study comparing recombinant interleukin 2 (rIL-2) in conjunction with recombinant interferon alpha (IFN-alpha) versus no immunotherapy for patients with malignant lymphoma postautologous stem cell transplantation. J Immunother 33(3):326–333
Navarro X, Vivo M, Valero-Cabre A (2007) Neural plasticity after peripheral nerve injury and regeneration. Prog Neurobiol 82(4):163–201
Noble J, Munro CA, Prasad V, Midha R (1998) Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries. J Trauma 45(1):116–122
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284(5411):143–147
Polchert D, Sobinsky J, Douglas GW, Kidd M, Moadsiri A, Reina E, Genrich K, Mehrotra S, Setty S, Smith B, Bartholomew A (2008) IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol 38(6):1745–1755
Prasanna SJ, Gopalakrishnan D, Shankar SR, Vasandan AB (2010) Pro-inflammatory cytokines, IFN gamma and TNF alpha, influence immune properties of human bone marrow and Wharton jelly mesenchymal stem cells differentially. Plos One 5(2):e9016
Pulford KAF, Sipos A, Cordell JL, Stross WP, Mason DY (1990) Distribution of the CD68 macrophage myeloid associated antigen. Int Immunol 2(10):973–980
Rendina M, Castellaneta NM, Fagiuoli S, Ponziani FR, Vigano R, Iemmolo RM, Donato MF, Toniutto P, Pasulo L, Morelli MC, Burra P, Miglioresi L, Giannelli V, Di Paolo D, Di Leo A (2011) Acute and chronic rejection during interferon therapy in HCV recurrent liver transplant patients: results from the AISF-RECOLT-C group. Digest Liver Dis 43:S148–S149
Rosberg HE, Carlsson KS, Dahlin LB (2005) Prospective study of patients with injuries to the hand and forearm: costs, function, and general health. Scand J Plast Reconstr Surg Hand Surg 39(6):360–369
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunological self-tolerance maintained by activated t-cells expressing il-2 receptor alpha-chains (CD25)—breakdown of a single mechanism of self-tolerance causes various autoimmune-diseases. J Immunol 155(3):1151–1164
Sandor M, Xu H, Connor J, Lombardi J, Harper JR, Silverman RP, McQuillan DJ (2008) Host response to implanted porcine-derived biologic materials in a primate model of abdominal wall repair. Tissue Eng Part A 14(12):2021–2031
Wang J, Al-Lamki RS (2013) Tumor necrosis factor receptor 2: its contribution to acute cellular rejection and clear cell renal carcinoma. Biomed Res Int 2013:821310
Wang D, Liu X-L, Zhu J-K, Jiang L, Hu J, Zhang Y, Yang L-M, Wang H-G, Yi J-H (2008) Bridging small-gap peripheral nerve defects using acellular nerve allograft implanted with autologous bone marrow stromal cells in primates. Brain Res 1188:44–53
Xu H, Wan H, Sandor M, Qi S, Ervin F, Harper JR, Silverman RP, McQuillan DJ (2008) Host response to human acellular dermal matrix transplantation in a primate model of abdominal wall repair. Tissue Eng Part A 14(12):2009–2019
Zhang Y, Luo H, Zhang Z, Lu Y, Huang X, Yang L, Xu J, Yang W, Fan X, Du B, Gao P, Hu G, Jin Y (2010) A nerve graft constructed with xenogeneic acellular nerve matrix and autologous adipose-derived mesenchymal stem cells. Biomaterials 31(20):5312–5324
Zibar L, Wagner J, Pavlinic D, Galic J, Pasini J, Juras K, Barbic J (2011) The relationship between interferon-gamma gene polymorphism and acute kidney allograft rejection. Scand J Immunol 73(4):319–324
Acknowledgments
We would like to thank the National Natural Science Foundation of China (Grant Nos. 81101363 and 81371944) for financially supporting this study.
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Fan, L., Yu, Z., Li, J. et al. Immunoregulation Effects of Bone Marrow-Derived Mesenchymal Stem Cells in Xenogeneic Acellular Nerve Grafts Transplant. Cell Mol Neurobiol 34, 999–1010 (2014). https://doi.org/10.1007/s10571-014-0076-3
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DOI: https://doi.org/10.1007/s10571-014-0076-3