Chemokines and Proteolysis: Implications for Stem Cell Dynamics in Ischemic Stroke

  • Umadevi V. WesleyEmail author
  • Robert J. Dempsey
Part of the Springer Series in Translational Stroke Research book series (SSTSR)


Stroke still remains a significant clinical challenge, with only a small proportion of the ischemic patients benefiting from current treatments which are limited by a narrow therapeutic time window. Cerebral ischemic stroke results in severe neurological deficits due to massive loss of neurons and disruption of vasculature. Although our understanding of the stroke pathology has remarkably increased, further insight into the cellular and molecular mechanisms involved in the post-stroke brain repair is still required to identify more effective drug targets with wider time window. Cerebral ischemia and reperfusion injury alters the brain microenvironment including dysregulation of cytokines, chemokines and abnormal release of proteases leading to neuronal cell death, endothelial cell and stem/progenitor cell dysfunction, disruption of blood brain barrier and the vascular unit. Thus, delineating the timely and balanced regulation of proteases, cytokines, chemokines, and stem/progenitor cells is critical for enhancing post-stroke brain protection and repair, and neurological functional recovery. In this chapter, we will present the facts about interactions of chemokines, proteases and stem cells in the context of pathophysiology of stroke.


Stroke Ischemic brain injury Chemokines Proteases Stem cells Matrix metalloproteases Dipeptidyl peptidase IV Stromal derived factor 



Cerebro-vascular diseases


Dipeptidyl peptidase 4


Endothelial progenitor cells


Hypoxia-inducible factor-1α (HIF-1α)




Middle cerebral artery occlusion


Monocyte chemoattractant protein-1


Matrix metalloproteases


Mesenchymal stem cells


Neural progenitor cells


Stromal derived factor



Supported in part by National Institute of Health (R.J.D.) and American Heart Association (U.V.W.), and the department of Neurosurgery, UW Madison, WI 53792.


  1. 1.
    Nagy Z, Nardai S. Cerebral ischemia/repefusion injury: from bench space to bedside. Brain Res Bull. 2017;pii:S0361-9230(16)30227-1.Google Scholar
  2. 2.
    Lo EH, Ning M. Mechanisms and challenges in translational stroke research. J Investig Med. 2016;64(4):827–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 2003;4:2123–6.CrossRefGoogle Scholar
  4. 4.
    Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67:181–98.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Hossmann KA. Pathophysiology and therapy of experimental stroke. Cell Mol Neurobiol. 2006;26:1057–84.PubMedCrossRefGoogle Scholar
  6. 6.
    Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 1999;22:391–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Pappachan J, Kirkham FJ. Cerebrovascular disease and stroke. Arch Dis Child. 2008;93:890–8.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Borlongan CV, Rodrigues AA Jr, Oliveira MC. Breaking the barrier in stroke: what should we know? Curr Pharm Des. 2012;18(25):3615–23.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Amantea D, Nappi G, Bernardi G, Bagetta G, Corasaniti MT. Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. FEBS J. 2009;276:13–26.PubMedCrossRefGoogle Scholar
  10. 10.
    Arai K, Lok J, Guo S, Hayakawa K, Xing C, Lo EH. Cellular mechanisms of neurovascular damage and repair after stroke. J Child Neurol. 2011;26:1193–8.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Lo EH. A new penumbra: transitioning from injury into repair after stroke. Nat Med. 2008;14:497–500.PubMedCrossRefGoogle Scholar
  12. 12.
    Xiong Y, Mahmood A, Chopp M. Angiogenesis, neurogenesis and brain recovery of function following injury. Curr Opin Investig Drugs. 2010;11:298–308.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Love S. Apoptosis and brain ischaemia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2003;27:267–82.CrossRefGoogle Scholar
  14. 14.
    Kalluri HS, Dempsey RJ. Growth factors, stem cells, and stroke. Neurosurg Focus. 2008;24:E14.PubMedCrossRefGoogle Scholar
  15. 15.
    Iadecola C, Ross ME. Molecular pathology of cerebral ischemia: delayed gene expression and strategies for neuroprotection. Ann N Y Acad Sci. 1997;835:203–17.PubMedCrossRefGoogle Scholar
  16. 16.
    Mergenthaler P, Dirnagl U, Meisel A. Pathophysiology of stroke: lessons from animal models. Metab Brain Dis. 2004;19(3–4):151–67.PubMedCrossRefGoogle Scholar
  17. 17.
    Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002;8:963–70.PubMedCrossRefGoogle Scholar
  18. 18.
    Yamashita T, Abe K. Mechanisms of endogenous endothelial repair in stroke. Curr Pharm Des. 2012;18:3649–52.PubMedCrossRefGoogle Scholar
  19. 19.
    Del Zoppo GJ, Becker KJ, Hallenbeck JM. Inflammation after stroke: is it harmful? Arch Neurol. 2001;58:669–72.PubMedGoogle Scholar
  20. 20.
    Kriz J. Inflammation in ischemic brain injury: timing is important. Crit Rev Neurobiol. 2006;18:145–57.PubMedCrossRefGoogle Scholar
  21. 21.
    Bosisio D, Salvi V, Gagliostro V, Sozzani S. Angiogenic and antiangiogenic chemokines. Chem Immunol Allergy. 2014;99:89–104.PubMedCrossRefGoogle Scholar
  22. 22.
    Ahmed S, Malemud CJ, Koch AE, Athar M, Taub DD. Cytokines and chemokines: disease models, mechanisms, and therapies. Mediat Inflamm. 2014;2014:296356. Scholar
  23. 23.
    Goazigo AR-L. Current status of chemokines in the adult CNS. Prog Neurobiol. 2013;104:67–92.CrossRefGoogle Scholar
  24. 24.
    Stone MJ, Hayward JA, Huang C, Huma Z, Sanchez J. Mechanisms of regulation of the chemokine-receptor network. Int J Mol Sci. 2017;18(2):pii:E342. Scholar
  25. 25.
    Minami M, Satoh M. Chemokines and their receptors in the brain: pathophysiological roles in ischemic brain injury. Life Sci. 2003;74(2–3):321–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Bajetto A, Bonavia R, Barbero S, Florio T, Schettini G. Chemokines and their receptors in the central nervous system. Front Neuroendocrinol. 2001;22(3):147–84.PubMedCrossRefGoogle Scholar
  27. 27.
    Du Y, Deng W, Wang Z, Ning M, Zhang W, Zhou Y, Lo EH, Xing C. Differential subnetwork of chemokines/cytokines in human, mouse, and rat brain cells after oxygen-glucose deprivation. J Cereb Blood Flow Metab. 2017;37(4):1425–34.PubMedCrossRefGoogle Scholar
  28. 28.
    Mortier A, Van Damme J, Proost P. Regulation of chemokine activity by posttranslational modifcation. Pharmacol Ther. 2008;120:197–217.PubMedCrossRefGoogle Scholar
  29. 29.
    Newton RC, Vaddi K. Biological responses to C-C chemokines. Methods Enzymol. 1997;287:174–86.PubMedCrossRefGoogle Scholar
  30. 30.
    Mirabelli-Badenier M, Braunersreuther V, Viviani GL, Dallegri F, Quercioli A, Veneselli E, Mach F, Montecucco F. CC and CXC chemokines are pivotal mediators of cerebral injury in ischaemic stroke. Thromb Haemost. 2011;105(3):409–20.PubMedCrossRefGoogle Scholar
  31. 31.
    Réaux-Le Goazigo A, Van Steenwinckel J, Rostène W, Mélik Parsadaniantz S. Current status of chemokines in the adult CNS. Prog Neurobiol. 2013;104:67–92.PubMedCrossRefGoogle Scholar
  32. 32.
    Graves DT, Jiang Y. Chemokines, a family of chemotactic cytokines. Crit Rev Oral Biol Med. 1995;6(2):109–18.PubMedCrossRefGoogle Scholar
  33. 33.
    Metzemaekers M, Van Damme J, Mortier A, Proost P. Regulation of chemokine activity – a focus on the role of dipeptidyl peptidase IV/CD26. Front Immunol. 2016;7(483):1–23.Google Scholar
  34. 34.
    Zlotnik A, Yoshie O. The chemokine superfamily revisited. Immunity. 2012;36(5):705–16.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Ahuja SK, Gao JL, Murphy PM. Chemokine receptors and molecular mimicry. Immunol Today. 1994;15(6):281–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Motaln H, Turnsek TL. Cytokines play a key role in communication between mesenchymal stem cells and brain cancer cells. Protein Pept Lett. 2015;22(4):322–31.PubMedCrossRefGoogle Scholar
  37. 37.
    Sullivan R, Duncan K, Dailey T, Kaneko Y, Tajiri N, Borlongan CV. A possible new focus for stroke treatment – migrating stem cells. Expert Opin Biol Ther. 2015;15(7):949–58.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Pelus LM, Fukuda S. Chemokine-mobilized adult stem cells; defining a better hematopoietic graft. Leukemia. 2008;22(3):466–73.PubMedCrossRefGoogle Scholar
  39. 39.
    Nagasawa T. CXCL12/SDF-1 and CXCR4. Front Immunol. 2015;6:301. Scholar
  40. 40.
    Wang Y, Huang J, Li Y, Yang GY. Roles of chemokine CXCL12 and its receptors in ischemic stroke. Curr Drug Targets. 2012;13(2):166–72.PubMedCrossRefGoogle Scholar
  41. 41.
    Richter R, Jochheim-Richter A, Ciuculescu F, et al. Identification and characterization of circulating variants of CXCL12 from human plasma: effects on chemotaxis and mobilization of hematopoietic stem and progenitor cells. Stem Cells Dev. 2014;23(16):1959–74.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Hill WD, Hess DC, Martin-Studdard A, et al. SDF-1 (CXCL12) is upregulated in the ischemic penumbra following stroke: association with bone marrow cell homing to injury. J Neuropathol Exp Neurol. 2004;63(1):84–96.PubMedCrossRefGoogle Scholar
  43. 43.
    Cui L, Qu H, Xiao T, Zhao M, Jolkkonen J, Zhao C. Stromal cell-derived factor-1 and its receptor CXCR4 in adult neurogenesis after cerebral ischemia. Restor Neurol Neurosci. 2013;31(3):239–51.PubMedGoogle Scholar
  44. 44.
    Robin AM, Zhang ZG, Wang L, et al. Stromal cell-derived factor 1alpha mediates neural progenitor cell motility after focal cerebral ischemia. J Cereb Blood Flow Metab. 2006;26(1):125–34.PubMedCrossRefGoogle Scholar
  45. 45.
    Bakondi B, Shimada IS, Peterson BM, Spees JL. SDF-1alpha secreted by human CD133-derived multipotent stromal cells promotes neural progenitor cell survival through CXCR7. Stem Cells Dev. 2011;20:1021–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004;10:858–64.PubMedCrossRefGoogle Scholar
  47. 47.
    Filippo TR, Galindo LT, Barnabe GF, et al. CXCL12 N-terminal end is sufficient to induce chemotaxis and proliferation of neural stem/progenitor cells. Stem Cell Res. 2013;11:913–25.PubMedCrossRefGoogle Scholar
  48. 48.
    Imitola J, Raddassi K, Park KI, et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci. 2004;101:18117–22.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Merino JJ, Bellver-Landete V, Oset-Gasque MJ, Cubelos B. CXCR4/CXCR7 molecular involvement in neuronal and neural progenitor migration: focus in CNS repair. J Cell Physiol. 2015;230:27–42.PubMedCrossRefGoogle Scholar
  50. 50.
    Yin W, Ma L, Zhang J, et al. The migration of neural progenitor cell mediated by SDF-1 is NF-kappaB/HIF-1alpha dependent upon hypoxia. CNS Neurosci Ther. 2013;19:145–53.PubMedCrossRefGoogle Scholar
  51. 51.
    Zheng H, Fu G, Dai T, Huang H. Migration of endothelial progenitor cells mediated by stromal cell-derived factor-1alpha/CXCR4 via PI3K/Akt/eNOS signal transduction pathway. J Cardiovasc Pharmacol. 2007;50:274–80.PubMedCrossRefGoogle Scholar
  52. 52.
    Kuhlmann CR, Schaefer CA, Reinhold L, Tillmanns H, Erdogan A. Signalling mechanisms of SDF-induced endothelial cell proliferation and migration. Biochem Biophys Res Commun. 2005;335(4):1107–14.PubMedCrossRefGoogle Scholar
  53. 53.
    Salcedo R, Wasserman K, Young HA, et al. Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: In vivo neovascularization induced by stromal-derived factor-1alpha. Am J Pathol. 1999;154(4):1125–35.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Bajetto A, Barbero S, Bonavia R, et al. Stromal cell-derived factor-1alpha induces astrocyte proliferation through the activation of extracellular signal-regulated kinases 1/2 pathway. J Neurochem. 2001;77:1226–36.PubMedCrossRefGoogle Scholar
  55. 55.
    Deshmane SL, Kremlev S, Amini S, Bassel E, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interf Cytokine Res. 2009;29(6):313–26.CrossRefGoogle Scholar
  56. 56.
    Chen Y, Hallenbeck JM, Ruetzler C, et al. Overexpression of monocyte chemoattractant protein 1 in the brain exacerbates ischemic brain injury and is associated with recruitment of inflammatory cells. J Cereb Blood Flow Metab. 2003;23:748–55.PubMedCrossRefGoogle Scholar
  57. 57.
    Yan YP, Sailor KA, Lang BT, Park SW, Vemuganti R, Dempsey RJ. Monocyte chemoattractant protein-1 plays a critical role in neuroblast migration after focal cerebral ischemia. J Cereb Blood Flow Metab. 2007;27(6):1213–24.PubMedCrossRefGoogle Scholar
  58. 58.
    He X, Li DR, Cui C, Wen LJ. Clinical significance of serum MCP-1 and VE-cadherin levels in patients with acute cerebral infarction. Eur Rev Med Pharmacol Sci. 2017;21(4):804–8.PubMedGoogle Scholar
  59. 59.
    Lauro C, Catalano M, Di Paolo E, et al. Fractalkine/CX3CL1 engages different neuroprotective responses upon selective glutamate receptor overactivation. Front Cell Neurosci. 2015;21(8):472. Scholar
  60. 60.
    Lauro C, Catalano M, Trettel F, Limatola C. Fractalkine in the nervous system: neuroprotective or neurotoxic molecule? Ann N Y Acad Sci. 2015;1351:141–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Mizuno T, Kawanokuchi J, Numata K, Suzumura A. Production and neuroprotective functions of fractalkine in the central nervous system. Brain Res. 2003;979(1–2):65–70.PubMedCrossRefGoogle Scholar
  62. 62.
    Zhang Y, Zheng J, Zhou Z, et al. Fractalkine promotes chemotaxis of bone marrow-derived mesenchymal stem cells towards ischemic brain lesions through Jak2 signaling and cytoskeletal reorganization. FEBS J. 2015;282(5):891–903.PubMedCrossRefGoogle Scholar
  63. 63.
    Qin W, Li Z, Luo S, Wu R, Pei Z, Huang R. Exogenous fractalkine enhances proliferation of endothelial cells, promotes migration of endothelial progenitor cells and improves neurological deficits in a rat model of ischemic stroke. Neurosci Lett. 2014;569:80–4.PubMedCrossRefGoogle Scholar
  64. 64.
    R C, Villa P, Chece G, et al. CX3CL1 is neuroprotective in permanent focal cerebral ischemia in rodents. J Neurosci. 2011;31(45):16327–35.CrossRefGoogle Scholar
  65. 65.
    Liu Y, Wu XM, Luo QQ, et al. CX3CL1/CX3CR1-mediated microglia activation plays a detrimental role in ischemic mice brain via p38MAPK/PKC pathway. J Cereb Blood Flow Metab. 2015;35(10):1623–31.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Tang Z, Gan Y, Liu Q, et al. CX3CR1 deficiency suppresses activation and neurotoxicity of microglia/macrophage in experimental ischemic stroke. J Neuroinflammation. 2014;11:26. Scholar
  67. 67.
    D'Haese JG, Friess H, Ceyhan GO. Therapeutic potential of the chemokine-receptor duo Fractalkine/CX3CR1: an update. Expert Opin Ther Targets. 2012;16(6):613–8.PubMedCrossRefGoogle Scholar
  68. 68.
    Chapman GA, Moores K, Harrison D, Campbell CA, Stewart BR, Strijbos PJ. Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to excitotoxic brain damage. J Neurosci. 2000;20:RC87(1–5).Google Scholar
  69. 69.
    Davis M, Mantle D, Mendelow AD. The role of proteolytic enzymes in focal ischaemic brain damage. Acta Neurochir Suppl. 2000;76:261–4.PubMedGoogle Scholar
  70. 70.
    Lee SR, Wang X, Tsuji K, Lo EH. Extracellular proteolytic pathophysiology in the neurovascular unit after stroke. Neurol Res. 2004;26:854–61.PubMedCrossRefGoogle Scholar
  71. 71.
    Zhao BQ, Tejima E, Lo EH. Neurovascular proteases in brain injury, hemorrhage and remodeling after stroke. Stroke. 2007;38(2 Suppl):748–52.PubMedCrossRefGoogle Scholar
  72. 72.
    Wolf M, Albrecht S, Marki C. Proteolytic processing of chemokines: implications in physiological and pathological conditions. Int J Biochem Cell Biol. 2008;40:1185–98.PubMedCrossRefGoogle Scholar
  73. 73.
    Kryczka J, Boncela J. Proteases revisited: roles and therapeutic implications in fibrosis. Mediat Inflamm. 2017;2017:2570154. Scholar
  74. 74.
    Vivien D, Buisson A. Serine protease inhibitors: novel therapeutic targets for stroke? J Cereb Blood Flow Metab. 2000;20:755–64.PubMedCrossRefGoogle Scholar
  75. 75.
    Wang X, Li X, Xu L, et al. Up-regulation of secretory leukocyte protease inhibitor (SLPI) in the brain after ischemic stroke: adenoviral expression of SLPI protects brain from ischemic injury. Mol Pharmacol. 2003;64:833–40.PubMedCrossRefGoogle Scholar
  76. 76.
    Apte SS, Parks WC. Metalloproteinases: a parade of functions in matrix biology and an outlook for the future. Matrix Biol. 2015;44-46:1–6.PubMedCrossRefGoogle Scholar
  77. 77.
    Yang Y, Rosenberg GA. Matrix metalloproteinases as therapeutic targets for stroke. Brain Res. 2015;1623:30–8.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Kurzepa J, Kurzepa J, Golab P, Czerska S, Bielewicz J. The significance of matrix metalloproteinase (MMP)-2 and MMP-9 in the ischemic stroke. Int J Neurosci. 2014;124:707–16.PubMedCrossRefGoogle Scholar
  79. 79.
    Song J, Wu C, Korpos E, et al. Focal MMP-2 and MMP-9 activity at the blood-brain barrier promotes chemokine-induced leukocyte migration. Cell Rep. 2015;10(7):1040–54.PubMedCrossRefGoogle Scholar
  80. 80.
    Zhao BQ, Wang S, Kim HY, et al. Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med. 2006;12:441–5.PubMedCrossRefGoogle Scholar
  81. 81.
    Siwetz M, Blaschitz A, Kremshofer J, et al. Metalloprotease dependent release of placenta derived fractalkine. Mediat Inflamm. 2014;2014:839290. Scholar
  82. 82.
    Lucivero V, Prontera M, Mezzapesa DM, et al. Different roles of matrix metalloproteinases-2 and -9 after human ischaemic stroke. Neurol Sci. 2007;28:165–70.PubMedCrossRefGoogle Scholar
  83. 83.
    Rosenberg GA, Cunningham LA, Wallace J, et al. Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res. 2001;893(1–2):104–12.PubMedCrossRefGoogle Scholar
  84. 84.
    Seo JH, Guo S, Lok J, et al. Neurovascular matrix metalloproteinases and the blood-brain barrier. Curr Pharm Des. 2012;18(25):3645–8.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Park KP, Rosell A, Foerch C, et al. Plasma and brain matrix metalloproteinase-9 after acute focal cerebral ischemia in rats. Stroke. 2009;40(8):2836–42.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Lenglet S, Montecucco F, Mach F. Role of matrix metalloproteinases in animal models of ischemic stroke. Curr Vasc Pharmacol. 2015;13(2):161–6.PubMedCrossRefGoogle Scholar
  87. 87.
    McQuibban GA, Gong JH, Wong JP, Wallace JL, Clark-Lewis I, Overall CM. Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood. 2002;100:1160–7.PubMedGoogle Scholar
  88. 88.
    Le NT, Xue M, Castelnoble LA, Jackson CJ. The dual personalities of matrix metalloproteinases in inflammation. Front Biosci. 2007;12:1475–87.PubMedCrossRefGoogle Scholar
  89. 89.
    Hopsu-Havu VK, Glenner GG. A new dipeptide naphthylamidase hydrolyzing glycyl-prolyl-β-naphthylamide. Histochemie. 1966;7:197–201.PubMedCrossRefGoogle Scholar
  90. 90.
    Koivisto V. Discovery of dipeptidyl-peptidase IV – a 40 year journey from bench to patient. Diabetologia. 2008;51:1088–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Waumans Y, Baerts L, Kehoe K, Lambeir AM, De Meester I. The dipeptidyl peptidase family, prolyl oligopeptidase, and prolyl carboxypeptidase in the immune system and inflammatory disease, including atherosclerosis. Front Immunol. 2015;6:387. Scholar
  92. 92.
    Mortier A, Gouwy M, Van Damme J, Proost P, Struyf S. CD26/dipeptidylpeptidase IV-chemokine interactions: double-edged regulation of inflammation and tumor biology. J Leukoc Biol. 2016;99(6):955–69.PubMedCrossRefGoogle Scholar
  93. 93.
    Klemann C, Wagner L, Stephan M, von Hörsten S. Cut to the chase: a review of CD26/dipeptidyl peptidase-4’s (DPP4) entanglement in the immune system. Clin Exp Immunol. 2016;185:1–21.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Scharpé S, De Meester I. Peptide truncation by dipeptidyl peptidase IV: a new pathway for drug discovery? Verh K Acad Geneeskd Belg. 2001;63(1):5–32.PubMedGoogle Scholar
  95. 95.
    Proost P, De Meester I, Schols D, et al. Amino-terminal truncation of chemokines by CD26/dipeptidyl-peptidase IV. Conversion of RANTES into a potent inhibitor of monocyte chemotaxis and HIV-1-infection. J Biol Chem. 1998;273(13):7222–7.PubMedCrossRefGoogle Scholar
  96. 96.
    Lambeir AM, Proost P, Durinx C, et al. Kinetic investigation of chemokine truncation by CD26/dipeptidyl peptidase IV reveals a striking selectivity within the chemokine family. J Biol Chem. 2001;276(32):29839–45.PubMedCrossRefGoogle Scholar
  97. 97.
    Shibuya-Saruta H, Kasahara Y, Hashimoto Y. Human serum dipeptidyl peptidase IV (DPPIV) and its unique properties. J Clin Lab Anal. 1996;10(6):435–40.PubMedCrossRefGoogle Scholar
  98. 98.
    Wesley UV, Hatcher JF, Ayvaci ER, Klemp A, Dempsey RJ. Regulation of dipeptidyl peptidase IV in the post-stroke rat brain and in vitro ischemia: Implications for chemokine-mediated neural progenitor cell migration and angiogenesis. Mol Neurobiol. 2016.
  99. 99.
    Arscott WT, LaBauve AE, May V, Wesley UV. Suppression of neuroblastoma growth by dipeptidyl peptidase IV: relevance of chemokine regulation and caspase activation. Oncogene. 2009;28(4):479–91.PubMedCrossRefGoogle Scholar
  100. 100.
    Christopherson KW II, Hangoc G, Broxmeyer HE. Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells. J Immunol. 2002;169:7000–8.PubMedCrossRefGoogle Scholar
  101. 101.
    Wesley UV, Albino AP, Tiwari S, Houghton AN. A role for dipeptidyl peptidase IV in suppressing the malignant phenotype of melanocytic cells. J Exp Med. 1999;190:311–22.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Wesley UV, McGroarty M, Homoyouni A. Dipeptidyl peptidase inhibits malignant phenotype of prostate cancer cells by blocking basic fibroblast growth factor signaling pathway. Cancer Res. 2005;65:1325–34.PubMedCrossRefGoogle Scholar
  103. 103.
    Wesley UV, Tiwari S, Houghton AN. Role for dipeptidyl peptidase IV in tumor suppression of human non small cell lung carcinoma cells. Int J Cancer. 2004;1099(6):855–66.CrossRefGoogle Scholar
  104. 104.
    Sun YX, Pedersen EA, Shiozawa Y, et al. CD26/dipeptidyl peptidase IV regulates prostate cancer metastasis by degrading SDF-1/CXCL12. Clin Exp Metastasis. 2008;25:765–76.PubMedCrossRefGoogle Scholar
  105. 105.
    Jungraithmayr W, De Meester I, Matheeussen V, Baerts L, Arni S, Weder W. CD26/DPP-4 inhibition recruits regenerative stem cells via stromal cell-derived factor-1 and beneficially influences ischaemia-reperfusion injury in mouse lung transplantation. Eur J Cardiothorac Surg. 2012;41:1166–73.PubMedCrossRefGoogle Scholar
  106. 106.
    Rohnert P, Schmidt W, Emmerlich P, et al. Dipeptidyl peptidase IV, aminopeptidase N and DPIV/APN-like proteases in cerebral ischemia. J Neuroinflammation. 2012;9:44. Scholar
  107. 107.
    Chua S, Sheu JJ, Chen YL, et al. Sitagliptin therapy enhances the number of circulating angiogenic cells and angiogenesis-evaluations in vitro and in the rat critical limb ischemia model. Cytotherapy. 2013;15:1148–63.PubMedCrossRefGoogle Scholar
  108. 108.
    Vaghasiya J, Sheth N, Bhalodia Y, Manek R. Sitagliptin protects renal ischemia reperfusion induced renal damage in diabetes. Regul Pept. 2011;166:48–54.PubMedCrossRefGoogle Scholar
  109. 109.
    Chua S, Lee FY, Tsai TH, et al. Inhibition of dipeptidyl peptidase-IV enzyme activity protects against myocardial ischemia-reperfusion injury in rats. J Transl Med. 2014;12:357. Scholar
  110. 110.
    Boonacker E, Van Noordan CJ. The multifunctional or moonlighting protein CD26/DPPIV. Eur J Cell Biol. 2003;82:53–73.PubMedCrossRefGoogle Scholar
  111. 111.
    Havre PA, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang NH. The role of CD26/dipeptidyl peptidase IV in cancer. Front Biosci. 2008;13:1634–45.PubMedCrossRefGoogle Scholar
  112. 112.
    Dang DT, Chun SY, Burkitt K, et al. Hypoxia- inducible factor-1 target genes as indicators of tumor vessel response to vascular endothelial growth factor inhibition. Cancer Res. 2008;68:1872–80.PubMedCrossRefGoogle Scholar
  113. 113.
    Bauvois B, Djavaheri-Mergny M, Rouillard D, Dumont J, Wietzerbin J. Regulation of CD26/DPPIV gene expression by interferons and retinoic acid in tumor B cells. Oncogene. 2000;19:265–72.PubMedCrossRefGoogle Scholar
  114. 114.
    Gu N, Tsuda M, Matsunaga T, et al. Glucose regulation of dipeptidyl peptidase IV gene expression is mediated by hepato- cyte nuclear factor-1alpha in epithelial intestinal cells. Clin Exp Pharmacol Physiol. 2008;35:1433–9.PubMedGoogle Scholar
  115. 115.
    Proost P, Struyf S, Loos T, et al. Coexpression and interaction of CXCL10 and CD26 in mesenchymal cells by synergising inflammatory cytokines: CXCL8 and CXCL10 are discriminative markers for autoimmune arthropathies. Arthritis Res Ther. 2006;8:1–14.CrossRefGoogle Scholar
  116. 116.
    Kim NH, Yu T, Lee DH. The nonglycemic actions of dipeptidyl peptidase-4 inhibitors. Biomed Res Int. 2014;2014:368703. Scholar
  117. 117.
    El-Sahar AE, Safar MM, Zaki HF, Attia AS, Ain-Shoka AA. Sitagliptin attenuates transient cerebral ischemia/reperfusion injury in diabetic rats: implication of the oxidative-inflammatory-apoptotic pathway. Life Sci. 2015;126:81–6.PubMedCrossRefGoogle Scholar
  118. 118.
    Inthachai T, Lekawanvijit S, Kumfu S, Apaijai N, Pongkan W, Chattipakorn SC, Chattipakorn N. Dipeptidyl peptidase-4 inhibitor improves cardiac function by attenuating adverse cardiac remodelling in rats with chronic myocardial infarction. Exp Physiol. 2015;100(6):667–79.PubMedCrossRefGoogle Scholar
  119. 119.
    Tang YH, Ma YY, Zhang ZJ, Wang YT, Yang GY. Opportunities and challenges: stem cell-based therapy for the treatment of ischemic stroke. CNS Neurosci Ther. 2015;21(4):337–47.PubMedCrossRefGoogle Scholar
  120. 120.
    Burns TC, Steinberg GK. Stem cells and stroke: opportunities, challenges and strategies. Expert Opin Biol Ther. 2011;11(4):447–61.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Chang YC, Shyu WC, Lin SZ, Li H. Regenerative therapy for stroke. Cell Transplant. 2007;16:171–81.PubMedGoogle Scholar
  122. 122.
    Shyu WC, Lee YJ, Liu DD, Lin SZ, Li H. Homing genes, cell therapy and stroke. Front Biosci. 2006;11:899–907.PubMedCrossRefGoogle Scholar
  123. 123.
    Meamar R, Nikyar H, Dehghani L, et al. The role of endothelial progenitor cells in transient ischemic attack patients for future cerebrovascular events. J Res Med Sci. 2016;21:47. Scholar
  124. 124.
    Li Y-F, Ren L-N, Guo G, et al. Endothelial progenitor cells in ischemic stroke: an exploration from hypothesis to therapy. J Hematol Oncol. 2015;8:33. Scholar
  125. 125.
    Farag SS, Srivastava S, Messina-Graham S, et al. In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies. Stem Cells Dev. 2013;22:1007–15.PubMedCrossRefGoogle Scholar
  126. 126.
    Urbich C, De Souza AI, Rossig L, et al. Proteomic characterization of human early pro-angiogenic cells. J Mol Cell Cardiol. 2011;50(2):333–6.PubMedCrossRefGoogle Scholar
  127. 127.
    Jin K, Sun Y, Xie L, et al. Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol Cell Neurosci. 2003;24:171–89.PubMedCrossRefGoogle Scholar
  128. 128.
    Yamashita T, Ninomiya M, Hernandez Acosta P, et al. Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. J Neurosci. 2006;26:6627–36.PubMedCrossRefGoogle Scholar
  129. 129.
    Dempsey RJ, Sailor KA, Bowen KK, Tureyen K, Vemuganti R. Stroke-induced progenitor cell proliferation in adult spontaneously hypertensive rat brain: effect of exogenous IGF-1 and GDNF. J Neurochem. 2003;87:586–97.PubMedCrossRefGoogle Scholar
  130. 130.
    Maria Ferri AL, Bersano A, Lisini D, Boncoraglio G, Frigerio S, Parati E. Mesenchymal stem cells for ischemic stroke: progress and possibilities. Curr Med Chem. 2016;23(16):1598–608.PubMedCrossRefGoogle Scholar
  131. 131.
    Bang OY, Kim EH, Cha JM, Moon GJ. Adult stem cell therapy for stroke: challenges and progress. J Stroke. 2016;18(3):256–66.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Nurkovic J, Dolicanin Z, Mustafic F, Mujanovic R, Memic M, Grbovic V, Skevin AJ, Nurkovic S. Mesenchymal stem cells in regenerative rehabilitation. J Phys Ther Sci. 2016;28(6):1943–8.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Ou X, O'Leary HA, Broxmeyer HE. Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types. Blood. 2013;122:161–9.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Fadini GP, Avogaro A. Dipeptidyl peptidase-4 inhibition and vascular repair by mobilization of endogenous stem cells in diabetes and beyond. Atherosclerosis. 2013;229:23–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Neurosurgery, School of Medicine and Public HealthUniversity of WisconsinMadisonUSA

Personalised recommendations