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Cell Type Specific Signalling by Hematopoietic Growth Factors in Neural Cells

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Abstract

Correct timing and spatial location of growth factor expression is critical for undisturbed brain development and functioning. In terminally differentiated cells distinct biological responses to growth factors may depend on cell type specific activation of signalling cascades. We show that the hematopoietic growth factors thrombopoietin (TPO) and granulocyte colony-stimulating factor (GCSF) exert cell type specific effects on survival, proliferation and the degree of phosphorylation of Akt1, ERK1/2 and STAT3 in rat hippocampal neurons and cortical astrocytes. In neurons, TPO induced cell death and selectively activated ERK1/2. GCSF protected neurons from TPO- and hypoxia-induced cell death via selective activation of Akt1. In astrocytes, neither TPO nor GCSF had any effect on cell viability but inhibited proliferation. This effect was accompanied by activation of ERK1/2 and inhibition of STAT3 activity. A balance between growth factors, their receptors and signalling proteins may play an important role in regulation of neural cell survival.

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Abbreviations

ECL:

enhanced chemoluminescence

EPO:

erythropoietin

ERK:

extracellular signal-regulated kinase

FCS:

foetal calf serum

GCSF:

granulocyte colony-stimulating factor

GFAP:

glial fibrillary acidic protein

GH:

growth hormone

JAK:

Janus kinase

MAP:

microtubule-associated protein

OGD:

oxygen/glucose deprivation

NF-200:

neurofilament 200

PI3K:

phosphatidylinositol-3′ kinase

STAT:

signal transducer and activator of transcription

TPO:

thrombopoietin

References

  1. Huang EJ, Reichardt LF (2003) Trk receptors: roles in neuronal signal transduction. Annu Rev Biochem 72:609–642

    Article  PubMed  CAS  Google Scholar 

  2. Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M, Sasaki R (1998) In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci USA 95:4635–4640

    Article  PubMed  CAS  Google Scholar 

  3. Bernaudin M, Marti HH, Roussel S, Divoux D, Nouvelot A, MacKenzie ET, Petit E (1999) A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 19:643–651

    Article  PubMed  CAS  Google Scholar 

  4. Scheepens A, Sirimanne ES, Breier BH, Clark RG, Gluckman PD, Williams CE (2001) Growth hormone as a neuronal rescue factor during recovery from CNS injury. Neuroscience 104:677–687

    Article  PubMed  CAS  Google Scholar 

  5. Shingo T, Sorokan ST, Shimazaki T, Weiss S (2001) Erythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci 21:9733–9743

    PubMed  CAS  Google Scholar 

  6. Yu X, Shacka JJ, Eells JB, Suarez-Quian C, Przygodzki RM, Beleslin-Cokic B, Lin CS, Nikodem VM, Hempstead B, Flanders KC, Costantini F, Noguchi CT (2002) Erythropoietin receptor signalling is required for normal brain development. Development 129:505–516

    PubMed  CAS  Google Scholar 

  7. Dame C, Wolber EM, Freitag P, Hofmann D, Bartmann P, Fandrey J (2003) Thrombopoietin gene expression in the developing human central nervous system. Brain Res Dev Brain Res 143:217–223

    Article  PubMed  CAS  Google Scholar 

  8. Schabitz WR, Kollmar R, Schwaninger M, Juettler E, Bardutzky J, Scholzke MN, Sommer C, Schwab S (2003) Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia. Stroke 34:745–751

    Article  PubMed  CAS  Google Scholar 

  9. Kleinschnitz C, Schroeter M, Jander S, Stoll G (2004) Induction of granulocyte colony-stimulating factor mRNA by focal cerebral ischemia and cortical spreading depression. Brain Res Mol Brain Res 131:73–78

    Article  PubMed  CAS  Google Scholar 

  10. Knabe W, Knerlich F, Washausen S, Kietzmann T, Sirén AL, Brunnett G, Kuhn HJ, Ehrenreich H (2004) Expression patterns of erythropoietin and its receptor in the developing midbrain. Anat Embryol (Berl) 207:503–512

    Article  CAS  Google Scholar 

  11. Brines M, Cerami A (2005) Emerging biological roles for erythropoietin in the nervous system. Nat Rev Neurosci 6:484–494

    Article  PubMed  CAS  Google Scholar 

  12. Ehrenreich H, Hasselblatt M, Knerlich F, von Ahsen N, Jacob S, Sperling S, Woldt H, Vehmeyer K, Nave KA, Sirén AL (2005) A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain. Proc Natl Acad Sci USA 102:862–867

    Article  PubMed  CAS  Google Scholar 

  13. Schneider A, Kruger C, Steigleder T, Weber D, Pitzer C, Laage R, Aronowski J, Maurer MH, Gassler N, Mier W, Hasselblatt M, Kollmar R, Schwab S, Sommer C, Bach A, Kuhn HG, Schabitz WR (2005) The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 115:2083–2098

    Article  PubMed  CAS  Google Scholar 

  14. Geddis AE, Linden HM, Kaushansky K (2002) Thrombopoietin: a pan-hematopoietic cytokine. Cytokine Growth Factor Rev 13:61–73

    Article  PubMed  CAS  Google Scholar 

  15. Schindler C, Strehlow I (2000) Cytokines and STAT signaling. Adv Pharmacol 47:113–174

    Article  PubMed  CAS  Google Scholar 

  16. Dong F, Qiu Y, Yi T, Touw IP, Larner AC (2001) The carboxyl terminus of the granulocyte colony-stimulating factor receptor, truncated in patients with severe congenital neutropenia/acute myeloid leukemia, is required for SH2-containing phosphatase-1 suppression of Stat activation. J Immunol 167:6447–6452

    PubMed  CAS  Google Scholar 

  17. Zhang Y, Sun S, Wang Z, Thompson A, Kaluzhny Y, Zimmet J, Ravid K (2002) Signaling by the Mpl receptor involves IKK and NF-kappaB. J Cell Biochem 85:523–535

    Article  PubMed  CAS  Google Scholar 

  18. Ferrari G, Greene LA (1994) Proliferative inhibition by dominant-negative Ras rescues naive and neuronally differentiated PC12 cells from apoptotic death. Embo J 13:5922–5928

    PubMed  CAS  Google Scholar 

  19. Yao R, Cooper GM (1995) Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science 267:2003–2006

    Article  PubMed  CAS  Google Scholar 

  20. Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME (1997) Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 275:661–665

    Article  PubMed  CAS  Google Scholar 

  21. Hetman M, Kanning K, Cavanaugh JE, Xia Z (1999) Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J Biol Chem 274:22569–22580

    Article  PubMed  CAS  Google Scholar 

  22. Susen K, Heumann R, Blochl A (1999) Nerve growth factor stimulates MAPK via the low affinity receptor p75(LNTR). FEBS Lett 463:231–234

    Article  PubMed  CAS  Google Scholar 

  23. Sirén AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A, Mennini T, Heumann R, Cerami A, Ehrenreich H, Ghezzi P (2001) Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci USA 98:4044–4049

    Article  PubMed  Google Scholar 

  24. Ruscher K, Freyer D, Karsch M, Isaev N, Megow D, Sawitzki B, Priller J, Dirnagl U, Meisel A (2002) Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J Neurosci 22:10291–10301

    PubMed  CAS  Google Scholar 

  25. Um M, Lodish HF (2006) Antiapoptotic effects of erythropoietin in differentiated neuroblastoma SH-SY5Y cells require activation of both the STAT5 and AKT signaling pathways. J Biol Chem 281:5648–5656

    Article  PubMed  CAS  Google Scholar 

  26. Brewer GJ (1997) Isolation and culture of adult rat hippocampal neurons. J Neurosci Methods 71:143–155

    Article  PubMed  CAS  Google Scholar 

  27. Lewczuk P, Hasselblatt M, Kamrowski-Kruck H, Heyer A, Unzicker C, Sirén AL, Ehrenreich H (2000) Survival of hippocampal neurons in culture upon hypoxia: effect of erythropoietin. Neuroreport 11:3485–3488

    PubMed  CAS  Google Scholar 

  28. Heyer A, Hasselblatt M, von Ahsen N, Hafner H, Sirén AL, Ehrenreich H (2005) In vitro gender differences in neuronal survival on hypoxia and in 17beta-estradiol-mediated neuroprotection. J Cereb Blood Flow Metab 25:427–430

    Article  PubMed  CAS  Google Scholar 

  29. Unzicker C, Erberich H, Moldrich G, Woldt H, Bulla J, Mechoulam R, Ehrenreich H, Sirén AL (2005) Hippocampal cannabinoid-1 receptor upregulation upon endothelin-B receptor deficiency: a neuroprotective substitution effect? Neurochem Res 30:1305–1309

    Article  PubMed  CAS  Google Scholar 

  30. Ehrenreich H, Kehrl JH, Anderson RW, Rieckmann P, Vitkovic L, Coligan JE, Fauci AS (1991) A vasoactive peptide, endothelin-3, is produced by and specifically binds to primary astrocytes. Brain Res 538:54–58

    Article  PubMed  CAS  Google Scholar 

  31. Hasselblatt M, Lewczuk P, Loffler BM, Kamrowski-Kruck H, von Ahsen N, Sirén AL, Ehrenreich H (2001) Role of the astrocytic ET(B) receptor in the regulation of extracellular endothelin-1 during hypoxia. Glia 34:18–26

    Article  PubMed  CAS  Google Scholar 

  32. Haas R, Murea S (1995) The role of granulocyte colony-stimulating factor in mobilization and transplantation of peripheral blood progenitor and stem cells. Cytokines Mol Ther 1:249–270

    PubMed  CAS  Google Scholar 

  33. Jacobsen SE, Borge OJ, Ramsfjell V, Cui L, Cardier JE, Veiby OP, Murphy MJ Jr, Lok S (1996) Thrombopoietin, a direct stimulator of viability and multilineage growth of primitive bone marrow progenitor cells. Stem Cells 14(Suppl 1):173–180

    Article  PubMed  Google Scholar 

  34. Sirotkin AV, Sanislo P, Schaeffer HJ, Florkovicova I, Kotwica J, Bulla J, Hetenyi L (2004) Thrombopoietin regulates proliferation, apoptosis, secretory activity and intracellular messengers in porcine ovarian follicular cells: involvement of protein kinase A. J Endocrinol 183:595–604

    Article  PubMed  CAS  Google Scholar 

  35. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326–1331

    Article  PubMed  CAS  Google Scholar 

  36. Alessandrini A, Namura S, Moskowitz MA, Bonventre JV (1999) MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc Natl Acad Sci USA 96:12866–12869

    Article  PubMed  CAS  Google Scholar 

  37. Mori T, Wang X, Jung JC, Sumii T, Singhal AB, Fini ME, Dixon CE, Alessandrini A, Lo EH (2002) Mitogen-activated protein kinase inhibition in traumatic brain injury: in vitro and in vivo effects. J Cereb Blood Flow Metab 22:444–452

    Article  PubMed  CAS  Google Scholar 

  38. Subramaniam S, Zirrgiebel U, von Bohlen Und Halbach O, Strelau J, Laliberte C, Kaplan DR, Unsicker K (2004) ERK activation promotes neuronal degeneration predominantly through plasma membrane damage and independently of caspase-3. J Cell Biol 165:357–369

    Article  PubMed  CAS  Google Scholar 

  39. Stanciu M, Wang Y, Kentor R, Burke N, Watkins S, Kress G, Reynolds I, Klann E, Angiolieri MR, Johnson JW, DeFranco DB (2000) Persistent activation of ERK contributes to glutamate-induced oxidative toxicity in a neuronal cell line and primary cortical neuron cultures. J Biol Chem 275:12200–12206

    Article  PubMed  CAS  Google Scholar 

  40. Stanciu M, DeFranco DB (2002) Prolonged nuclear retention of activated extracellular signal-regulated protein kinase promotes cell death generated by oxidative toxicity or proteasome inhibition in a neuronal cell line. J Biol Chem 277:4010–4017

    Article  PubMed  CAS  Google Scholar 

  41. Raghupathi R (2004) Cell death mechanisms following traumatic brain injury. Brain Pathol 14:215–222

    Article  PubMed  Google Scholar 

  42. Six I, Gasan G, Mura E, Bordet R (2003) Beneficial effect of pharmacological mobilization of bone marrow in experimental cerebral ischemia. Eur J Pharmacol 458:327–328

    Article  PubMed  CAS  Google Scholar 

  43. Shyu WC, Lin SZ, Yang HI, Tzeng YS, Pang CY, Yen PS, Li H (2004) Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation 110:1847–1854

    Article  PubMed  CAS  Google Scholar 

  44. Teixeira A, Chaverot N, Strosberg AD, Cazaubon S (2000) Differential regulation of cyclin D1 and D3 expression in the control of astrocyte proliferation induced by endothelin-1. J Neurochem 74:1034–1040

    Article  PubMed  CAS  Google Scholar 

  45. Pebay A, Toutant M, Premont J, Calvo CF, Venance L, Cordier J, Glowinski J, Tence M (2001) Sphingosine-1-phosphate induces proliferation of astrocytes: regulation by intracellular signalling cascades. Eur J Neurosci 13:2067–2076

    Article  Google Scholar 

  46. Wang H, Ubl JJ, Stricker R, Reiser G (2002) Thrombin (PAR-1)-induced proliferation in astrocytes via MAPK involves multiple signaling pathways. Am J Physiol Cell Physiol 283:C1351–1364

    PubMed  CAS  Google Scholar 

  47. Fanton CP, McMahon M, Pieper RO (2001) Dual growth arrest pathways in astrocytes and astrocytic tumors in response to Raf-1 activation. J Biol Chem 276:18871–18877

    Article  PubMed  CAS  Google Scholar 

  48. Pascual M, Valles SL, Renau-Piqueras J, Guerri C (2003) Ceramide pathways modulate ethanol-induced cell death in astrocytes. J Neurochem 87:1535–1545

    Article  PubMed  CAS  Google Scholar 

  49. Isobe I, Maeno Y, Nagao M, Iwasa M, Koyama H, Seko-Nakamura Y, Monma-Ohtaki J (2003) Cytoplasmic vacuolation in cultured rat astrocytes induced by an organophosphorus agent requires extracellular signal-regulated kinase activation. Toxicol Appl Pharmacol 193:383–392

    Article  PubMed  CAS  Google Scholar 

  50. Abe K, Saito H (2000) The p44/42 mitogen-activated protein kinase cascade is involved in the induction and maintenance of astrocyte stellation mediated by protein kinase C. Neurosci Res 36:251–257

    Article  PubMed  CAS  Google Scholar 

  51. Lee SM, Nguyen TH, Park MH, Kim KS, Cho KJ, Moon DC, Kim HY, Yoon do Y, Hong JT (2004) EPO receptor-mediated ERK kinase and NF-kappaB activation in erythropoietin-promoted differentiation of astrocytes. Biochem Biophys Res Commun 320:1087–1095

    Article  PubMed  CAS  Google Scholar 

  52. Choi JS, Kim SY, Park HJ, Cha JH, Choi YS, Kang JE, Chung JW, Chun MH, Lee MY (2003) Upregulation of gp130 and differential activation of STAT and p42/44 MAPK in the rat hippocampus following kainic acid-induced seizures. Brain Res Mol Brain Res 119:10–18

    Article  PubMed  CAS  Google Scholar 

  53. Sriram K, Benkovic SA, Hebert MA, Miller DB, O’Callaghan JP (2004) Induction of gp130-related cytokines and activation of JAK2/STAT3 pathway in astrocytes precedes up-regulation of glial fibrillary acidic protein in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of neurodegeneration: key signaling pathway for astrogliosis in vivo? J Biol Chem 279:19936–19947

    Article  PubMed  CAS  Google Scholar 

  54. Bowman T, Garcia R, Turkson J, Jove R (2000) STATs in oncogenesis. Oncogene 19:2474–2488

    Article  PubMed  CAS  Google Scholar 

  55. Bromberg J (2002) Stat proteins and oncogenesis. J Clin Invest 109:1139–1142

    Article  PubMed  CAS  Google Scholar 

  56. Rahaman SO, Harbor PC, Chernova O, Barnett GH, Vogelbaum MA, Haque SJ (2002) Inhibition of constitutively active Stat3 suppresses proliferation and induces apoptosis in glioblastoma multiforme cells. Oncogene 21:8404–8413

    Article  PubMed  CAS  Google Scholar 

  57. Konnikova L, Kotecki M, Kruger MM, Cochran BH (2003) Knockdown of STAT3 expression by RNAi induces apoptosis in astrocytoma cells. BMC Cancer 3:23

    Article  PubMed  Google Scholar 

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Acknowledgments

This work has been supported by the DFG European Graduate Programme “Neuroplasticity: From Molecules to Systems” and by the DFG Research Center for Molecular Physiology of the Brain (CMPB, Göttingen).

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Authors and Affiliations

  1. Division of Clinical Neuroscience, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, Göttingen, D-37075, Germany

    Nadiya Byts, Helge Woldt, Hannelore Ehrenreich & Anna-Leena Sirén

  2. Department of Neurosurgery, Section of Experimental Neurosurgery, University of Würzburg, Josef-Schneider-St. 11, Würzburg, 97080, Germany

    Anatoly Samoylenko & Anna-Leena Sirén

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  1. Nadiya Byts
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  2. Anatoly Samoylenko
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Correspondence to Hannelore Ehrenreich.

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Byts, N., Samoylenko, A., Woldt, H. et al. Cell Type Specific Signalling by Hematopoietic Growth Factors in Neural Cells. Neurochem Res 31, 1219–1230 (2006). https://doi.org/10.1007/s11064-006-9149-0

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  • DOI: https://doi.org/10.1007/s11064-006-9149-0

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