Interferon-gamma Treatment of Human Umbilical Cord Mesenchymal Stem Cells can Significantly Reduce Damage Associated with Diabetic Peripheral Neuropathy in Mice


Cite item

Full Text

Abstract

Background:Diabetic peripheral neuropathy causes significant pain to patients. Umbilical cord mesenchymal stem cells have been shown to be useful in the treatment of diabetes and its complications. The aim of this study was to investigate whether human umbilical cord mesenchymal stem cells treated with interferon-gamma can ameliorate nerve injury associated with diabetes better than human umbilical cord mesenchymal stem cells without interferon-gamma treatment.

Methods:Human umbilical cord mesenchymal stem cells were assessed for adipogenic differentiation, osteogenic differentiation, and proliferation ability. Vonfry and a hot disc pain tester were used to evaluate tactile sensation and thermal pain sensation in mice. Hematoxylin-eosin and TUNEL staining were performed to visualize sciatic nerve fiber lesions and Schwann cell apoptosis in diabetic mice. Western blotting was used to detect expression of the apoptosis-related proteins Bax, B-cell lymphoma-2, and caspase-3 in mouse sciatic nerve fibers and Schwann cells. Real-Time Quantitative PCR was used to detect mRNA levels of the C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 2, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10 in mouse sciatic nerve fibers and Schwann cells. Enzyme-linked immunosorbent assay was used to detect levels of the inflammatory cytokines, interleukin- 1β, interleukin-6, and tumor necrosis factor-α in serum and Schwann cells.

Results:The adipogenic differentiation capacity, osteogenic differentiation capacity, and proliferation ability of human umbilical cord mesenchymal stem cells were enhanced after interferon-gamma treatment. Real-Time Quantitative PCR revealed that interferon-gamma promoted expression of the adipogenic markers, PPAR-γ and CEBP-α, as well as of the osteogenic markers secreted phosphoprotein 1, bone gamma-carboxyglutamate protein, collagen type I alpha1 chain, and Runt-related transcription factor 2. The results of hematoxylin-eosin and TUNEL staining showed that pathological nerve fiber damage and Schwann cell apoptosis were reduced after the injection of interferon-gamma-treated human umbilical cord mesenchymal stem cells. Expression of the apoptosis-related proteins, caspase-3 and Bax, was significantly reduced, while expression of the anti-apoptotic protein B-cell lymphoma-2 was significantly increased. mRNA levels of the cell chemokines, C-X-C motif chemokine ligand 1, C-X-C motif chemokine ligand 2, C-X-C motif chemokine ligand 9, and C-X-C motif chemokine ligand 10, were significantly reduced, and levels of the inflammatory cytokines, interleukin-1β, interleukin-6, and tumor necrosis factor-α, were decreased. Tactile and thermal pain sensations were improved in diabetic mice.

Conclusion:Interferon-gamma treatment of umbilical cord mesenchymal stem cells enhanced osteogenic differentiation, adipogenic differentiation, and proliferative potential. It can enhance the ability of human umbilical cord mesenchymal stem cells to alleviate damage to diabetic nerve fibers and Schwann cells, in addition to improving the neurological function of diabetic mice.

About the authors

Li-Fen Yang

Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province

Email: info@benthamscience.net

Jun-Dong He

Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province

Email: info@benthamscience.net

Wei-Qi Jiang

The First Clinical Medical collage, Kunming Medical University

Email: info@benthamscience.net

Xiao-Dan Wang

, Kunming Yan'an Hospital Kunming,

Email: info@benthamscience.net

Xiao-Chun Yang

Department of Ophthalmology, First People’s Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology)

Author for correspondence.
Email: info@benthamscience.net

Zhi Liang

Department of Information Center, First People's Hospital of Yunnan Province

Author for correspondence.
Email: info@benthamscience.net

Yi-Kun Zhou

Department of Endocrinology and Metabolism, First People's Hospital of Yunnan Province

Author for correspondence.
Email: info@benthamscience.net

References

  1. Xu Y, Wang L, He J, et al. Prevalence and control of diabetes in Chinese adults. JAMA 2013; 310(9): 948-59. doi: 10.1001/jama.2013.168118 PMID: 24002281
  2. Shiferaw WS, Akalu TY, Work Y, Aynalem YA. Prevalence of diabetic peripheral neuropathy in Africa: A systematic review and meta-analysis. BMC Endocr Disord 2020; 20(1): 49. doi: 10.1186/s12902-020-0534-5 PMID: 32293400
  3. Li C, Wang W, Ji Q, et al. Prevalence of painful diabetic peripheral neuropathy in type 2 diabetes mellitus and diabetic peripheral neuropathy: A nationwide cross-sectional study in mainland China. Diabetes Res Clin Pract 2023; 198: 110602. doi: 10.1016/j.diabres.2023.110602 PMID: 36871876
  4. Li L, Chen J, Wang J, Cai D. Prevalence and risk factors of diabetic peripheral neuropathy in Type 2 diabetes mellitus patients with overweight/obese in Guangdong province, China. Prim Care Diabetes 2015; 9(3): 191-5. doi: 10.1016/j.pcd.2014.07.006 PMID: 25163987
  5. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheral neuropathic pain: clinical and quality-of-life issues. Mayo Clin Proc 2006; 81(S4): S3-S11. doi: 10.1016/S0025-6196(11)61474-2 PMID: 16608048
  6. Han JW, Sin MY, Yoon Y. Cell therapy for diabetic neuropathy using adult stem or progenitor cells. Diabetes Metab J 2013; 37(2): 91-105. doi: 10.4093/dmj.2013.37.2.91 PMID: 23641349
  7. Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: Cellular mechanisms as therapeutic targets. Nat Rev Neurol 2011; 7(10): 573-83. doi: 10.1038/nrneurol.2011.137 PMID: 21912405
  8. Dominiczak MH. Obesity, glucose intolerance and diabetes and their links to cardiovascular disease. Implications for laboratory medicine. Clin Chem Lab Med 2003; 41(9): 1266-78. doi: 10.1515/CCLM.2003.194 PMID: 14598880
  9. Porada C, Zanjani E, Almeida-Porada G. Adult mesenchymal stem cells: A pluripotent population with multiple applications. Curr Stem Cell Res Ther 2006; 1(3): 365-9. doi: 10.2174/157488806778226821 PMID: 18220880
  10. Prockop DJ. Repair of tissues by adult stem/progenitor cells (MSCs): Controversies, myths, and changing paradigms. Mol Ther 2009; 17(6): 939-46. doi: 10.1038/mt.2009.62 PMID: 19337235
  11. Bunnell BA, Betancourt AM, Sullivan DE. New concepts on the immune modulation mediated by mesenchymal stem cells. Stem Cell Res Ther 2010; 1(5): 34. doi: 10.1186/scrt34 PMID: 21092149
  12. Salem HK, Thiemermann C. Mesenchymal stromal cells: Current understanding and clinical status. Stem Cells 2010; 28(3): 585-96. doi: 10.1002/stem.269 PMID: 19967788
  13. Singer NG, Caplan AI. Mesenchymal stem cells: Mechanisms of inflammation. Annu Rev Pathol 2011; 6(1): 457-78. doi: 10.1146/annurev-pathol-011110-130230 PMID: 21073342
  14. Zdravkovic N, Shahin A, Arsenijevic N, Lukic ML, Mensah-Brown EPK. Regulatory T cells and ST2 signaling control diabetes induction with multiple low doses of streptozotocin. Mol Immunol 2009; 47(1): 28-36. doi: 10.1016/j.molimm.2008.12.023 PMID: 19356801
  15. Volarevic V, Al-Qahtani A, Arsenijevic N, Pajovic S, Lukic ML. Interleukin-1 receptor antagonist (IL-1Ra) and IL-1Ra producing mesenchymal stem cells as modulators of diabetogenesis. Autoimmunity 2010; 43(4): 255-63. doi: 10.3109/08916930903305641 PMID: 19845478
  16. Omi M, Hata M, Nakamura N, et al. Transplantation of dental pulp stem cells suppressed inflammation in sciatic nerves by promoting macrophage polarization towards anti‐inflammation phenotypes and ameliorated diabetic polyneuropathy. J Diabetes Investig 2016; 7(4): 485-96. doi: 10.1111/jdi.12452 PMID: 27181261
  17. 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(4): e10088. doi: 10.1371/journal.pone.0010088 PMID: 20436665
  18. Jorgovanovic D, Song M, Wang L, Zhang Y. Roles of IFN-γ in tumor progression and regression: A review. Biomark Res 2020; 8(1): 49. doi: 10.1186/s40364-020-00228-x PMID: 33005420
  19. Li X, Du W, Ma FX, Feng X, Bayard F, Han ZC. High concentrations of TNF-α induce cell death during interactions between human umbilical cord mesenchymal stem cells and peripheral blood mononuclear cells. PLoS One 2015; 10(5): e0128647. doi: 10.1371/journal.pone.0128647 PMID: 26023782
  20. Mounayar M, Kefaloyianni E, Smith B, et al. PI3kα and STAT1 interplay regulates human mesenchymal stem cell immune polarization. Stem Cells 2015; 33(6): 1892-901. doi: 10.1002/stem.1986 PMID: 25753288
  21. Meirelles LS, Chagastelles PC, Nardi NB. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 2006; 119(11): 2204-13. doi: 10.1242/jcs.02932 PMID: 16684817
  22. Lu LL, Liu YJ, Yang SG, et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica 2006; 91(8): 1017-26. PMID: 16870554
  23. Carrade Holt DD, Wood JA, Granick JL, Walker NJ, Clark KC, Borjesson DL. Equine mesenchymal stem cells inhibit T cell proliferation through different mechanisms depending on tissue source. Stem Cells Dev 2014; 23(11): 1258-65. doi: 10.1089/scd.2013.0537 PMID: 24438346
  24. Cheng YC, Chu LW, Chen JY, et al. Loganin attenuates high glucose-induced schwann cells pyroptosis by inhibiting ROS generation and NLRP3 inflammasome activation. Cells 2020; 9(9): 1948. doi: 10.3390/cells9091948 PMID: 32842536
  25. Zhang C, Huang L, Wang X, et al. Topical and intravenous administration of human umbilical cord mesenchymal stem cells in patients with diabetic foot ulcer and peripheral arterial disease: A phase I pilot study with a 3-year follow-up. Stem Cell Res Ther 2022; 13(1): 451. doi: 10.1186/s13287-022-03143-0 PMID: 36064461
  26. Xue J, Sun N, Liu Y. Self-assembled nano-peptide hydrogels with human umbilical cord mesenchymal stem cell spheroids accelerate diabetic skin wound healing by inhibiting inflammation and promoting angiogenesis. Int J Nanomedicine 2022; 17: 2459-74. doi: 10.2147/IJN.S363777 PMID: 35669002
  27. Shi R, Lian W, Jin Y, et al. Role and effect of vein-transplanted human umbilical cord mesenchymal stem cells in the repair of diabetic foot ulcers in rats. Acta Biochim Biophys Sin 2020; 52(6): 620-30. doi: 10.1093/abbs/gmaa039 PMID: 32484226
  28. Bailey CJ. Treating insulin resistance: Future prospects. Diab Vasc Dis Res 2007; 4(1): 20-31. doi: 10.3132/dvdr.2007.002 PMID: 17469040
  29. Kampoli AM, Tousoulis D, Briasoulis A, Latsios G, Papageorgiou N, Stefanadis C. Potential pathogenic inflammatory mechanisms of endothelial dysfunction induced by type 2 diabetes mellitus. Curr Pharm Des 2011; 17(37): 4147-58. doi: 10.2174/138161211798764825 PMID: 22204375
  30. Sjöholm A, Nyström T. Endothelial inflammation in insulin resistance. Lancet 2005; 365(9459): 610-2. doi: 10.1016/S0140-6736(05)70804-7 PMID: 15708106
  31. Purwata T. High TNF-alpha plasma levels and macrophages iNOS and TNF-alpha expression as risk factors for painful diabetic neuropathy. J Pain Res 2011; 4: 169-75. doi: 10.2147/JPR.S21751 PMID: 21811392
  32. Uçeyler N, Rogausch JP, Toyka KV, Sommer C. Differential expression of cytokines in painful and painless neuropathies. Neurology 2007; 69(1): 42-9. doi: 10.1212/01.wnl.0000265062.92340.a5 PMID: 17606879
  33. Doupis J, Lyons TE, Wu S, Gnardellis C, Dinh T, Veves A. Microvascular reactivity and inflammatory cytokines in painful and painless peripheral diabetic neuropathy. J Clin Endocrinol Metab 2009; 94(6): 2157-63. doi: 10.1210/jc.2008-2385 PMID: 19276232
  34. Bharti D, Shivakumar SB, Park JK, et al. Comparative analysis of human Wharton’s jelly mesenchymal stem cells derived from different parts of the same umbilical cord. Cell Tissue Res 2018; 372(1): 51-65. doi: 10.1007/s00441-017-2699-4 PMID: 29204746
  35. Dabrowski FA, Burdzinska A, Kulesza A, et al. Comparison of the paracrine activity of mesenchymal stem cells derived from human umbilical cord, amniotic membrane and adipose tissue. J Obstet Gynaecol Res 2017; 43(11): 1758-68. doi: 10.1111/jog.13432 PMID: 28707770
  36. Liu Q, Chen X, Liu C, et al. Mesenchymal stem cells alleviate experimental immune-mediated liver injury via chitinase 3-like protein 1-mediated T cell suppression. Cell Death Dis 2021; 12(3): 240. doi: 10.1038/s41419-021-03524-y PMID: 33664231
  37. Yin Y, Hao H, Cheng Y, et al. Human umbilical cord-derived mesenchymal stem cells direct macrophage polarization to alleviate pancreatic islets dysfunction in type 2 diabetic mice. Cell Death Dis 2018; 9(7): 760. doi: 10.1038/s41419-018-0801-9 PMID: 29988034
  38. Inoue SI, Niikura M, Mineo S, Kobayashi F. Roles of IFN-γ and γδ T cells in protective immunity against blood-stage malaria. Front Immunol 2013; 4: 258. doi: 10.3389/fimmu.2013.00258 PMID: 24009610
  39. Xia N, Xu JM, Zhao N, Zhao QS, Li M, Cheng ZF. Human mesenchymal stem cells improve the neurodegeneration of femoral nerve in a diabetic foot ulceration rats. Neurosci Lett 2015; 597: 84-9. doi: 10.1016/j.neulet.2015.04.038 PMID: 25916880
  40. WenBo W, Fei Z, YiHeng D, et al. Human umbilical cord mesenchymal stem cells overexpressing nerve growth factor ameliorate diabetic cystopathy in rats. Neurochem Res 2017; 42(12): 3537-47. doi: 10.1007/s11064-017-2401-y PMID: 28952006
  41. Chen G, Fan X, Zheng X, Jin Y, Liu Y, Liu S. Human umbilical cord-derived mesenchymal stem cells ameliorate insulin resistance via PTEN-mediated crosstalk between the PI3K/Akt and Erk/MAPKs signaling pathways in the skeletal muscles of db/db mice. Stem Cell Res Ther 2020; 11(1): 401. doi: 10.1186/s13287-020-01865-7 PMID: 32938466
  42. Kong D, Zhuang X, Wang D, et al. Umbilical cord mesenchymal stem cell transfusion ameliorated hyperglycemia in patients with type 2 diabetes mellitus. Clin Lab 2014; 60(12/2014): 1969-76.2014; doi: 10.7754/Clin.Lab.2014.140305 PMID: 25651730
  43. Cai J, Wu Z, Xu X, et al. Umbilical cord mesenchymal stromal cell with autologous bone marrow cell transplantation in established type 1 diabetes: A pilot randomized controlled open-label clinical study to assess safety and impact on insulin secretion. Diabetes Care 2016; 39(1): 149-57. doi: 10.2337/dc15-0171 PMID: 26628416
  44. Waterman RS, Morgenweck J, Nossaman BD, Scandurro AE, Scandurro SA, Betancourt AM. Anti-inflammatory mesenchymal stem cells (MSC2) attenuate symptoms of painful diabetic peripheral neuropathy. Stem Cells Transl Med 2012; 1(7): 557-65. doi: 10.5966/sctm.2012-0025 PMID: 23197860
  45. Keating A. Mesenchymal stromal cells: New directions. Cell Stem Cell 2012; 10(6): 709-16. doi: 10.1016/j.stem.2012.05.015 PMID: 22704511
  46. Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol 2012; 12(5): 383-96. doi: 10.1038/nri3209 PMID: 22531326
  47. Prockop DJ, Youn Oh J. Mesenchymal stem/stromal cells (MSCs): Role as guardians of inflammation. Mol Ther 2012; 20(1): 14-20. doi: 10.1038/mt.2011.211 PMID: 22008910
  48. Li W, Ren G, Huang Y, et al. Mesenchymal stem cells: A double-edged sword in regulating immune responses. Cell Death Differ 2012; 19(9): 1505-13. doi: 10.1038/cdd.2012.26 PMID: 22421969
  49. Ren G, Zhang L, Zhao X, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2008; 2(2): 141-50. doi: 10.1016/j.stem.2007.11.014 PMID: 18371435
  50. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol 2008; 8(9): 726-36. doi: 10.1038/nri2395 PMID: 19172693
  51. Ren G, Su J, Zhang L, et al. Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells 2009; 27(8): 1954-62. doi: 10.1002/stem.118 PMID: 19544427
  52. Mellor AL, Munn DH. Ido expression by dendritic cells: Tolerance and tryptophan catabolism. Nat Rev Immunol 2004; 4(10): 762-74. doi: 10.1038/nri1457 PMID: 15459668
  53. Polchert D, Sobinsky J, Douglas GW, et al. IFN-γ activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol 2008; 38(6): 1745-55. doi: 10.1002/eji.200738129 PMID: 18493986
  54. Li H, Liu Q, Gao X, zhang D, Mao S, Jia Y. IFN-γ gene loaded human umbilical mesenchymal stromal cells targeting therapy for Graft-versus-host disease. Int J Pharm 2021; 592: 120058. doi: 10.1016/j.ijpharm.2020.120058 PMID: 33220383
  55. Duijvestein M, Wildenberg ME, Welling MM, et al. Pretreatment with interferon-γ enhances the therapeutic activity of mesenchymal stromal cells in animal models of colitis. Stem Cells 2011; 29(10): 1549-58. doi: 10.1002/stem.698 PMID: 21898680
  56. Kizil C, Kyritsis N, Brand M. Effects of inflammation on stem cells: Together they strive? EMBO Rep 2015; 16(4): 416-26. doi: 10.15252/embr.201439702 PMID: 25739812
  57. Yang C, Chen Y, Li F, et al. The biological changes of umbilical cord mesenchymal stem cells in inflammatory environment induced by different cytokines. Mol Cell Biochem 2018; 446(1-2): 171-84. doi: 10.1007/s11010-018-3284-1 PMID: 29356988
  58. Ahmed M, Gaffen SL. IL-17 inhibits adipogenesis in part via C/EBPα, PPARγ and Krüppel-like factors. Cytokine 2013; 61(3): 898-905. doi: 10.1016/j.cyto.2012.12.007 PMID: 23332504
  59. Wei H, Shen G, Deng X, et al. The role of IL-6 in bone marrow (BM)-derived mesenchymal stem cells (MSCs) proliferation and chondrogenesis. Cell Tissue Bank 2013; 14(4): 699-706. doi: 10.1007/s10561-012-9354-9 PMID: 23322270
  60. Li C, Li G, Liu M, Zhou T, Zhou H. Paracrine effect of inflammatory cytokine-activated bone marrow mesenchymal stem cells and its role in osteoblast function. J Biosci Bioeng 2016; 121(2): 213-9. doi: 10.1016/j.jbiosc.2015.05.017 PMID: 26315505
  61. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringdén O. HLA expression and immunologic propertiesof differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003; 31(10): 890-6. doi: 10.1016/S0301-472X(03)00110-3 PMID: 14550804
  62. Pourgholaminejad A, Aghdami N, Baharvand H, Moazzeni SM. The effect of pro-inflammatory cytokines on immunophenotype, differentiation capacity and immunomodulatory functions of human mesenchymal stem cells. Cytokine 2016; 85: 51-60. doi: 10.1016/j.cyto.2016.06.003 PMID: 27288632
  63. Croitoru-Lamoury J, Lamoury FMJ, Caristo M, et al. Interferon-γ regulates the proliferation and differentiation of mesenchymal stem cells via activation of indoleamine 2,3 dioxygenase (IDO). PLoS One 2011; 6(2): e14698. doi: 10.1371/journal.pone.0014698 PMID: 21359206
  64. Vigo T, Procaccini C, Ferrara G, et al. IFN-γ orchestrates mesenchymal stem cell plasticity through the signal transducer and activator of transcription 1 and 3 and mammalian target of rapamycin pathways. J Allergy Clin Immunol 2017; 139(5): 1667-76. doi: 10.1016/j.jaci.2016.09.004 PMID: 27670240
  65. Takeshita K, Motoike S, Kajiya M, et al. Xenotransplantation of interferon-gamma-pretreated clumps of a human mesenchymal stem cell/extracellular matrix complex induces mouse calvarial bone regeneration. Stem Cell Res Ther 2017; 8(1): 101. doi: 10.1186/s13287-017-0550-1 PMID: 28446226

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers