G-CSF for mobilizing transplanted bone marrow stem cells in rat model of Parkinson's disease

Document Type: Original Article

Authors

1 Research Center of Nervous System Stem Cells, Department of Anatomy, Semnan University of Medical Sciences, Semnan, Iran

2 Department of Physiology, Semnan University of Medical Sciences, Semnan, Iran

3 Department of Anatomy, AJA University of Medical Sciences, Tehran, Iran

Abstract

Objective(s): Granulocyte-colony stimulating factor (G-CSF) is used in clinical practice for the treatment of neutropenia and to stimulate generation of hematopoietic stem cells in bone marrow donors. In the present study, the ability of G-CSF in mobilizing exogenous bone marrow stem cells (BMSCs) from peripheral blood into the brain was tested. We for the first time injected a small amount of BMSCs through the tail vein.
Materials and Methods: We choose 25 male Wistar rats (200–250 g) were lesioned by 6-OHDA injected into the left substantia nigra, pars compacta (SNpc). G-CSF (70 µg/kg/day) was given from the 7th day after lesion for five days. The BMSCs (2×105) were injected through the dorsal tail vein on the 7th day after lesion.
Results:The number of rotations was significantly lower in the stem cell therapy group than in the control group. In the third test in the received G-CSF and G-CSF+stem cells groups, animals displayed significant behavioral recovery compared with the control group (P<0.05). There was a significant difference in the average of dopaminergic neurons in SNpc between the control group and G-CSF and G-CS+stem cells groups. We didn't detect any labeling stem cells in SNpc.
Conclusion: G-CSF can't mobilize low amounts of exogenous BMSCs from the blood stream to injured SNpc. But G-CSF (70 µg/kg) is more neuroprotective than BMSCs (2×105 number of BMSCs). Results of our study suggest that G-CSF alone is more neuroprotective than BMSCs.

Keywords


1. Ali F, Stott SR, Barker RA. Stem cells and the treatment of Parkinson's disease. Exp Neurol 2014; 260:3-11.

2. Toulouse A, Sullivan AM. Progress in parkinson's disease-where do we stand? Prog Neurobiol 2008; 85:376-392.

3. Prakash N, Wurst W. Development of dopaminergic neurons in the mammalian brain. Cell Mol Life Sci 2006; 63:187-206.

4. Vernier P, Moret F, Callier S, Snapyan M, Wersinger C, Sidhu A. The degeneration of dopamine neurons in Parkinson's disease: insights from embryology and evolution of the mesostriatocortical system. Ann N Y Acad Sci 2004; 1035:231-249.

5. Badban L, Safari M, Sameni HR, Bandegi AR, Vafaei AA, Rashidy-Pour A, et al. Protective effects of water extract of propolis on dopaminergic neurons, brain derived neurotrophic factor and stress oxidative actors in the rat model of parkinson’s disease. Int J Pharmacol 2015; 11:300-308.

6. Sethi KD. Clinical aspects of Parkinson disease. Curr Opin Neurol 2002; 15:457-460.

7. Lindvall O, Kokaia Z. Prospects of stem cell therapy for replacing dopamine neurons in Parkinson's disease. Trends Pharmacol Sci 2009; 30:260-267.

8. Kadota T, Shingo T, Yasuhara T, Tajiri N, Kondo A, Morimoto T, et al. Continuous intraventricular infusion of erythropoietin exerts neuroprotective/rescue effects upon Parkinson's disease model of rats with enhanced neurogenesis. Brain Res 2009; 1254:120-127.

9.   Redmond DE, Jr., Sladek JR, Spencer DD. Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 2001; 345:146-147.

10. Dunnett SB. Transplantation of embryonic dopamine neurons: what we know from rats. J Neurol 1991;238:65-74.

11. Piccini P, Brooks DJ, Bjorklund A, Gunn RN, Grasby PM, Rimoldi O, et al. Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient. Nat Neurosci 1999; 22:1137-1140.

12. Kim HJ. Stem cell potential in Parkinson's disease and molecular factors for the generation of dopamine neurons. Biochim Biophys Acta 2011; 1812:1-11.

13. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284:143-147.

14. Priller J, Persons DA, Klett FF, Kempermann G, Kreutzberg GW, Dirnagl U. Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo.  J Cell Biol 2001; 155:733-738.

15. Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P. Bone marrow stem cells regenerate infarcted myocardium. Pediatr Transplant 2003; 3:86-88.

16. Jadidi M, Biat SM, Sameni HR, Safari M, Vafaei AA, Ghahari L. Mesenchymal stem cells that located in the electromagnetic fields improves rat model of Parkinson’s disease. Iran J Basic Med Sci 2016; 19:741.

17. Safari M, Jadidi M, Baghian A, Hasanzadeh H. Proliferation and differentiation of rat bone marrow stem cells by 400μT electromagnetic field. Neurosci Lett 2016; 612:1-6.

18. Park HC, Shim YS, Ha Y, Yoon SH, Park SR, Choi BH, et al. Treatment of complete spinal cord injury patients by autologous bone marrow cell transplantation and administration of granulocyte-macrophage colony stimulating factor. Tissue Engin 2005; 11:913-922.

19.  Grasso G, Sfacteria A, Passalacqua M, Morabito A, Buemi M, Macri B, et al. Erythropoietin and erythropoietin receptor expression after experimental spinal cord injury encourages therapy by exogenous erythropoietin. Neurosurgery 2005; 56:821-827; discussion -7.

20. Gibson CL, Jones NC, Prior MJ, Bath PM, Murphy SP. G-CSF suppresses edema formation and reduces interleukin-1beta expression after cerebral ischemia in mice. J Neuropathol Exp Neurol 2005; 64:763-769.

21. Brines M, Grasso G, Fiordaliso F, Sfacteria A, Ghezzi P, Fratelli M, et al. Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc Natl Acad Sci U S A 2004; 101:14907-14912.

22. Bouhy D, Malgrange B, Multon S, Poirrier AL, Scholtes F, Schoenen J, et al. Delayed GM-CSF treatment stimulates axonal regeneration and functional recovery in paraplegic rats via an increased BDNF expression by endogenous macrophages. FASEB J 2006; 20:1239-1241.

23. Ghahari L, Safari M, Joghataei MT, Mehdizadeh M, Soleimani M. Effect of combination therapy using hypothermia and granulocyte colony-stimulating factor in a rat transient middle cerebral artery occlusion model. Iran Biomed J 2014; 18:239.

24. Sprigg N, Bath PM, Zhao L, Willmot MR, Gray LJ, Walker MF, et al. Granulocyte-colony-stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the Stem cell Trial of recovery EnhanceMent after Stroke (STEMS) pilot randomized, controlled trial (ISRCTN 16784092). Stroke 2006; 37:2979-2983.

25. Schneider A, Kruger C, Steigleder T, Weber D, Pitzer C, Laage R, 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.

26. Schneider A, Kuhn HG, Schabitz WR. A role for G-CSF (granulocyte-colony stimulating factor) in the central nervous system. Cell Cycle 2005; 4:1753-1757.

27. Cao XQ, Arai H, Ren YR, Oizumi H, Zhang N, Seike S, et al. Recombinant human granulocyte colony-stimulating factor protects against MPTP-induced dopaminergic cell death in mice by altering Bcl-2/Bax expression levels. J Neurochem 2006; 99:861-867.

28. Meuer K, Pitzer C, Teismann P, Kruger C, Goricke B, Laage R, et al. Granulocyte-colony stimulating factor is neuroprotective in a model of Parkinson's disease. J Neurochem 2006; 97:675-686.

29. Lee ST, Park JE, Kim DH, Kim S, Im WS, Kang L, et al. Granulocyte-colony stimulating factor attenuates striatal degeneration with activating survival pathways in 3-nitropropionic acid model of Huntington's disease. Brain Res 2008; 1194:130-137.

30. Lu CZ, Xiao BG. Neuroprotection of G-CSF in cerebral ischemia. Front Biosci 2007; 12:2869-2875.

31. Ye M, Chen S, Wang X, Qi C, Lu G, Liang L, et al. Glial cell line-derived neurotrophic factor in bone marrow stromal cells of rat. Neuroreport 2005; 16:581-584.

32. Prakash A, Chopra K, Medhi B. Granulocyte-colony stimulating factor improves Parkinson's disease associated with co-morbid depression: an experimental exploratory study. Indian J Pharmacol 2013; 45:612-615.

33. Toledo-Aral JJ, Mendez-Ferrer S, Pardal R, Lopez-Barneo J. Dopaminergic cells of the carotid body: physiological significance and possible therapeutic applications in Parkinson's disease. Brain Res Bull 2002; 57:847-853.

34. Deng J, Zou ZM, Zhou TL, Su YP, Ai GP, Wang JP, et al. Bone marrow mesenchymal stem cells can be mobilized into peripheral blood by G-CSF in vivo and integrate into traumatically injured cerebral tissue. Neurol Sci 2011; 32:641-651.

35. Park HJ, Lee PH, Bang OY, Lee G, Ahn YH. Mesenchymal stem cells therapy exerts neuroprotection in a progressive animal model of Parkinson's disease. J Chem 2008; 107:141-151.

36. Karussis D, Kassis I, Kurkalli BG, Slavin S. Immunomodulation and neuroprotection with mesenchymal bone marrow stem cells (MSCs): a proposed treatment for multiple sclerosis and other neuroimmunological/neurodegenerative diseases. J Neurol Sci 2008; 265:131-135.

37. Krampera M, Pasini A, Pizzolo G, Cosmi L, Romagnani S, Annunziato F. Regenerative and immunomodulatory potential of mesenchymal stem cells. Curr Opin Pharmacol 2006; 6:435-441.

38. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007; 110:3499-3506.

39. Jin K, Sun Y, Xie L, Mao XO, Childs J, Peel A, et al. Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat. Neurobiol Dis 2005; 18:366-374.

40. Huang HY, Lin SZ, Kuo JS, Chen WF, Wang MJ. G-CSF protects dopaminergic neurons from 6-OHDA-induced toxicity via the ERK pathway. Neurobiol Aging 2007; 28:1258-1269.

41. Gorgen I, Hartung T, Leist M, Niehorster M, Tiegs G, Uhlig S, et al. Granulocyte colony-stimulating factor treatment protects rodents against lipopolysaccharide-induced toxicity via suppression of systemic tumor necrosis factor-alpha. J Immunol 1992; 149:918-924.

42. Kitabayashi A, Hirokawa M, Hatano Y, Lee M, Kuroki J, Niitsu H, et al. Granulocyte colony-stimulating factor downregulates allogeneic immune responses by posttranscriptional inhibition of tumor necrosis factor-alpha production. Blood 1995; 86:2220-2227.

43. Hebert JC, O'Reilly M, Barry B, Shatney L, Sartorelli K. Effects of exogenous cytokines on intravascular clearance of bacteria in normal and splenectomized mice. J Trauma 1997; 43:875-879.

44. Heard SO, Fink MP, Gamelli RL, Solomkin JS, Joshi M, Trask AL, et al. Effect of prophylactic administration of recombinant human granulocyte colony-stimulating factor (filgrastim) on the frequency of nosocomial infections in patients with acute traumatic brain injury or cerebral hemorrhage. The Filgrastim Study Group. Crit Care Med 1998; 26:748-754.

45. Heard SO, Fink MP. Counterregulatory control of the acute inflammatory response: granulocyte colony-stimulating factor has anti-inflammatory properties. Crit Care Med 1999; 27:1019-1021.

46. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 1995; 80:285-291.

47. Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 1996; 87:619-628.

48. Offen D, Beart PM, Cheung NS, Pascoe CJ, Hochman A, Gorodin S, et al. Transgenic mice expressing human Bcl-2 in their neurons are resistant to 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine neurotoxicity. Proc Natl Acad Sci U S Am 1998; 95:5789-5794.

49. Basu S, Dunn A, Ward A. G-CSF: function and modes of action (Review). Int J Mol Med 2002; 10:3-10.

50. Boneberg EM, Hartung T. Molecular aspects of anti-inflammatory action of G-CSF. Inflamm Res 2002; 51:119-128.

51. Hagg T, Varon S. Ciliary neurotrophic factor prevents degeneration of adult rat substantia nigra dopaminergic neurons in vivo. Proc Natl Acad Sci U S A 1993; 90:6315-6319.

52. Schulz JB, Bremen D, Reed JC, Lommatzsch J, Takayama S, Wullner U, et al. Cooperative interception of neuronal apoptosis by BCL-2 and BAG-1 expression: prevention of caspase activation and reduced production of reactive oxygen species. J Neurochem 1997; 69:2075-2086.

53. Cohen G, Heikkila RE. The generation of hydrogen peroxide, superoxide radical, and hydroxyl radical by 6-hydroxydopamine, dialuric acid, and related cytotoxic agents. J Biol Chem 1974; 249:2447-2452.

54. Stridh H, Kimland M, Jones DP, Orrenius S, Hampton MB. Cytochrome c release and caspase activation in hydrogen peroxide- and tributyltin-induced apoptosis. FEBS Lett 1998; 429:351-355.