Thromb Haemost 2013; 110(02): 323-330
DOI: 10.1160/TH12-11-0875
Platelets and Blood Cells
Schattauer GmbH

Platelet lysates stimulate angiogenesis, neurogenesis and neuroprotection after stroke

Yael Hayon
1   Department of Neurology, Peritz and Chantal Scheinberg Cerebrovascular Research Laboratory, Hadassah Ein Kerem, Jerusalem, Israel
,
Olga Dashevsky
2   Department of Hematology, Coagulation Unit Hadassah University Hospital, Hadassah Ein Kerem, Jerusalem, Israel
,
Ela Shai
2   Department of Hematology, Coagulation Unit Hadassah University Hospital, Hadassah Ein Kerem, Jerusalem, Israel
,
David Varon
2   Department of Hematology, Coagulation Unit Hadassah University Hospital, Hadassah Ein Kerem, Jerusalem, Israel
,
Ronen R. Leker
1   Department of Neurology, Peritz and Chantal Scheinberg Cerebrovascular Research Laboratory, Hadassah Ein Kerem, Jerusalem, Israel
› Author Affiliations
Financial support: This study was funded by Ministry of Science, Israel.
Further Information

Publication History

Received: 28 November 2012

Accepted after major revision: 02 May 2013

Publication Date:
04 December 2017 (online)

Summary

Platelets contain chemo-attractants and mitogens that have a major role in tissue repair. Therefore we hypothesised that tissue regeneration secondary to activation of endogenous neural stem cells (eNSC) can be enhanced by delivering platelets to the ischaemic brain. To examine these potential therapeutic effects we injected platelet-poor plasma (PPP), fibroblast growth factor (FGF2) and platelet lysate (PLT) to the lateral ventricles after permanent middle cerebral artery occlusion (PMCAO) in rats. The animals were tested with the neurological severity score, and infarct volumes were measured at 90 days post–PMCAO. Immunohistochemistry was used to determine the fate of newborn cells and to count blood vessels in the ischaemic brain. Platelets significantly increased eNSC proliferation and angiogenesis in the subventricular zone (SVZ) and in the peri-lesion cortex. Functional outcome was significantly improved and injury size was significantly reduced in rats treated with PLT suggesting additional neuroprotective effects. In conclusion, local delivery of PLT to the lateral ventricles induces angiogenesis, neurogenesis and neuroprotection and reduces behavioural deficits after brain ischaemia.

 
  • References

  • 1 Nakagomi T, Taguchi A, Fujimori Y. et al. Isolation and characterisation of neural stem/progenitor cells from post-stroke cerebral cortex in mice. Eur J Neurosci 2009; 29: 1842-1852.
  • 2 Nakatomi H, Kuriu T, Okabe S. et al. Regeneration of hippocampal pyramidal neurons after ischaemic brain injury by recruitment of endogenous neural progenitors. Cell 2002; 110: 429-441.
  • 3 Leker RR, Soldner F, Velasco I. et al. Long-lasting regeneration after ischaemia in the cerebral cortex. Stroke 2007; 38: 153-161.
  • 4 Mazzucco L, Borzini P, Gope R. Platelet-derived factors involved in tissue repair-from signal to function. Transfus Med Rev 2010; 24: 218-234.
  • 5 Nocito A, Georgiev P, Dahm F. et al. Platelets and platelet-derived serotonin promote tissue repair after normothermic hepatic ischaemia in mice. Hepatology 2007; 45: 369-376.
  • 6 Rautou PE, Vion AC, Amabile N. et al. Microparticles, vascular function, and atherothrombosis. Circ Res 2011; 109: 593-606.
  • 7 Arvidsson A, Collin T, Kirik D. et al. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 2002; 08: 963-970.
  • 8 Androutsellis-Theotokis A, Leker RR, Soldner F. et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 2006; 442: 823-826.
  • 9 Parent JM, Vexler ZS, Gong C. et al. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 2002; 52: 802-813.
  • 10 Hayon Y, Dashevsky O, Shai E. et al. Platelet Microparticles Induce Angiogenesis and Neurogenesis after Cerebral Ischaemia. Curr Neurovasc Res 2012; 09: 185-192.
  • 11 Brill A, Dashevsky O, Rivo J. et al. Platelet-derived microparticles induce angiogenesis and stimulate post-ischaemic revascularisation. Cardiovasc Res 2005; 67: 30-38.
  • 12 Mause SF, Ritzel E, Liehn EA. et al. Platelet microparticles enhance the vasoregenerative potential of angiogenic early outgrowth cells after vascular injury. Circulation 2010; 122: 495-506.
  • 13 Hayon Y, Dashevsky O, Shai E. et al. Platelet Microparticles Promote Neural Stem Cell Proliferation, Survival and Differentiation. J Mol Neurosci 2012; 47: 659-665.
  • 14 Mack M, Kleinschmidt A, Bruhl H. et al. Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodeficiency virus 1 infection. Nat Med 2000; 06: 769-775.
  • 15 Beni-Adani L, Gozes I, Cohen Y. et al. A peptide derived from activity-dependent neuroprotective protein (ADNP) ameliorates injury response in closed head injury in mice. J Pharmacol Exp Ther 2001; 296: 57-63.
  • 16 Swanson RA, Morton MT, Tsao-Wu G. et al. A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab 1990; 10: 290-293.
  • 17 Shetty AK, Rao MS, Hattiangady B. et al. Hippocampal neurotrophin levels after injury: Relationship to the age of the hippocampus at the time of injury. J Neurosci Res 2004; 78: 520-532.
  • 18 Cheng K, Malliaras K, Shen D. et al. Intramyocardial injection of platelet gel promotes endogenous repair and augments cardiac function in rats with myocardial infarction. J Am Coll Cardiol 2012; 59: 256-264.
  • 19 Rozman P, Bolta Z. Use of platelet growth factors in treating wounds and softtissue injuries. Acta Dermatovenerol Alp Panonica Adriat 2007; 16: 156-165.
  • 20 Stellos K, Gnerlich S, Kraemer B. et al. Platelet interaction with progenitor cells: vascular regeneration or inquiry?. Pharmacol Rep 2008; 60: 101-108.
  • 21 de Boer HC, Verseyden C, Ulfman LH. et al. Fibrin and activated platelets cooperatively guide stem cells to a vascular injury and promote differentiation towards an endothelial cell phenotype. Arterioscler Thromb Vasc Biol 2006; 26: 1653-1659.
  • 22 English D, Garcia JG, Brindley DN. Platelet-released phospholipids link haemostasis and angiogenesis. Cardiovasc Res 2001; 49: 588-599.
  • 23 Fujimura H, Altar CA, Chen R. et al. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost 2002; 87: 728-734.
  • 24 Ventimiglia R, Jones BE, Moller A. A quantitative method for morphometric analysis in neuronal cell culture: unbiased estimation of neuron area and number of branch points. J Neurosci Methods 1995; 57: 63-66.
  • 25 Stellos K, Gawaz M. Platelet interaction with progenitor cells: potential implications for regenerative medicine. Thromb Haemost 2007; 98: 922-929.
  • 26 Schneider A, Kruger C, Steigleder T. et al. The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 2005; 115: 2083-2098.
  • 27 Prévost N, Woulfe DS, Jiang H, Stalker TJ, Marchese P, Ruggeri ZM, Brass LF. Eph kinases and ephrins support thrombus growth and stability by regulating integrin outside-in signalling in platelets. Proc Natl Acad Sci. 2005 102. 9820-9825.
  • 28 Palmer A, Klein R. Multiple roles of ephrins in morphogenesis, neuronal networking, and brain function. Genes Dev. 2003 17. 1429-1450.
  • 29 Parent JM. Injury-induced neurogenesis in the adult mammalian brain. Neuroscientist 2003; 09: 261-272.
  • 30 Thored P, Arvidsson A, Cacci E. et al. Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells 2006; 24: 739-747.
  • 31 Palmer TD, Willhoite AR, Gage FH. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 2000; 425: 479-494.
  • 32 Ohab JJ, Fleming S, Blesch A. et al. A neurovascular niche for neurogenesis after stroke. J Neurosci 2006; 26: 13007-13016.
  • 33 Nakagomi N, Nakagomi T, Kubo S. et al. Endothelial cells support survival, proliferation, and neuronal differentiation of transplanted adult ischaemia-induced neural stem/progenitor cells after cerebral infarction. Stem Cells 2209 27: 2185-2195.
  • 34 Blackshear PJ. Implantable drug-delivery systems. Sci Am 1979; 241: 66-73.