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Published in: European Radiology 5/2015

01-05-2015 | Nuclear Medicine

Improved dopamine transporter binding activity after bone marrow mesenchymal stem cell transplantation in a rat model of Parkinson’s disease: small animal positron emission tomography study with F-18 FP-CIT

Authors: Bok-Nam Park, Jang-Hee Kim, Kwanjae Lee, So Hyun Park, Young-Sil An

Published in: European Radiology | Issue 5/2015

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Abstract

Objectives

We evaluated the effects of bone marrow-derived mesenchymal stem cells (BMSCs) in a model of Parkinson’s disease (PD) using serial F-18 fluoropropylcarbomethoxyiodophenylnortropane (FP-CIT) PET.

Methods

Hemiparkinsonian rats were treated with intravenously injected BMSCs, and animals without stem cell therapy were used as the controls. Serial FP-CIT PET was performed after therapy. The ratio of FP-CIT uptake in the lesion side to uptake in the normal side was measured. The changes in FP-CIT uptake were also analyzed using SPM. Behavioural and histological changes were observed using the rotational test and tyrosine hydroxylase (TH)-reactive cells.

Results

FP-CIT uptake ratio was significantly different in the BMSCs treated group (n = 28) at each time point. In contrast, there was no difference in the ratio in control rats (n = 25) at any time point. SPM analysis also revealed that dopamine transporter binding activity was enhanced in the right basal ganglia area in only the BMSC therapy group. In addition, rats that received BMSC therapy also exhibited significantly improved rotational behaviour and preservation of TH-positive neurons compared to controls.

Conclusions

The therapeutic effect of intravenously injected BMSCs in a rat model of PD was confirmed by dopamine transporter PET imaging, rotational functional studies, and histopathological evaluation.

Key Points

Mesenchymal stem cells were intravenously injected to treat the PD rats
Dopamine transporter binding activity was improved after stem cell therapy
Stem cell therapy induced functional recovery and preservation of dopaminergic neurons
The effect of stem cells was confirmed by FP-CIT PET
Literature
1.
go back to reference Beitz JM (2014) Parkinson’s disease: a review. Front Biosci (Schol Ed) 6:65–74CrossRef Beitz JM (2014) Parkinson’s disease: a review. Front Biosci (Schol Ed) 6:65–74CrossRef
2.
go back to reference Toulouse A, Sullivan AM (2008) Progress in Parkinson’s disease-where do we stand? Prog Neurobiol 85:376–392CrossRefPubMed Toulouse A, Sullivan AM (2008) Progress in Parkinson’s disease-where do we stand? Prog Neurobiol 85:376–392CrossRefPubMed
3.
go back to reference Glavaski-Joksimovic A, Bohn MC (2013) Mesenchymal stem cells and neuroregeneration in Parkinson’s disease. Exp Neurol 247:25–38CrossRefPubMed Glavaski-Joksimovic A, Bohn MC (2013) Mesenchymal stem cells and neuroregeneration in Parkinson’s disease. Exp Neurol 247:25–38CrossRefPubMed
4.
go back to reference Ali F, Stott SR, Barker RA (2014) Stem cells and the treatment of Parkinson’s disease. Exp Neurol 260:3–11CrossRefPubMed Ali F, Stott SR, Barker RA (2014) Stem cells and the treatment of Parkinson’s disease. Exp Neurol 260:3–11CrossRefPubMed
5.
go back to reference Yang M, Donaldson AE, Jiang Y, Iacovitti L (2003) Factors influencing the differentiation of dopaminergic traits in transplanted neural stem cells. Cell Mol Neurobiol 23:851–864CrossRefPubMedCentralPubMed Yang M, Donaldson AE, Jiang Y, Iacovitti L (2003) Factors influencing the differentiation of dopaminergic traits in transplanted neural stem cells. Cell Mol Neurobiol 23:851–864CrossRefPubMedCentralPubMed
6.
go back to reference Bjorklund LM, Sanchez-Pernaute R, Chung S et al (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci U S A 99:2344–2349CrossRefPubMedCentralPubMed Bjorklund LM, Sanchez-Pernaute R, Chung S et al (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci U S A 99:2344–2349CrossRefPubMedCentralPubMed
7.
go back to reference Bouchez G, Sensebe L, Vourc’h P et al (2008) Partial recovery of dopaminergic pathway after graft of adult mesenchymal stem cells in a rat model of Parkinson’s disease. Neurochem Int 52:1332–1342CrossRefPubMed Bouchez G, Sensebe L, Vourc’h P et al (2008) Partial recovery of dopaminergic pathway after graft of adult mesenchymal stem cells in a rat model of Parkinson’s disease. Neurochem Int 52:1332–1342CrossRefPubMed
8.
go back to reference Clarkson ED (2001) Fetal tissue transplantation for patients with Parkinson’s disease: a database of published clinical results. Drugs Aging 18:773–785CrossRefPubMed Clarkson ED (2001) Fetal tissue transplantation for patients with Parkinson’s disease: a database of published clinical results. Drugs Aging 18:773–785CrossRefPubMed
9.
go back to reference Wang F, Yasuhara T, Shingo T et al (2010) Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: focusing on neuroprotective effects of stromal cell-derived factor-1alpha. BMC Neurosci 11:52CrossRefPubMedCentralPubMed Wang F, Yasuhara T, Shingo T et al (2010) Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: focusing on neuroprotective effects of stromal cell-derived factor-1alpha. BMC Neurosci 11:52CrossRefPubMedCentralPubMed
10.
go back to reference Pittenger MF, Mackay AM, Beck SC et al (1999) Multilineage potential of adult human mesenchymal stem cells. Sci 284:143–147CrossRef Pittenger MF, Mackay AM, Beck SC et al (1999) Multilineage potential of adult human mesenchymal stem cells. Sci 284:143–147CrossRef
11.
go back to reference Venkataramana NK, Kumar SK, Balaraju S et al (2010) Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease. Transl Res 155:62–70CrossRefPubMed Venkataramana NK, Kumar SK, Balaraju S et al (2010) Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease. Transl Res 155:62–70CrossRefPubMed
12.
go back to reference Danielyan L, Schafer R, von Ameln-Mayerhofer A et al (2011) Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. Rejuvenation Res 14:3–16CrossRefPubMed Danielyan L, Schafer R, von Ameln-Mayerhofer A et al (2011) Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease. Rejuvenation Res 14:3–16CrossRefPubMed
13.
go back to reference Xiong N, Zhang Z, Huang J et al (2011) VEGF-expressing human umbilical cord mesenchymal stem cells, an improved therapy strategy for Parkinson’s disease. Gene Ther 18:394–402CrossRefPubMed Xiong N, Zhang Z, Huang J et al (2011) VEGF-expressing human umbilical cord mesenchymal stem cells, an improved therapy strategy for Parkinson’s disease. Gene Ther 18:394–402CrossRefPubMed
14.
go back to reference Scherfler C, Donnemiller E, Schocke M et al (2002) Evaluation of striatal dopamine transporter function in rats by in vivo beta-[123I]CIT pinhole SPECT. Neuroimage 17:128–141CrossRefPubMed Scherfler C, Donnemiller E, Schocke M et al (2002) Evaluation of striatal dopamine transporter function in rats by in vivo beta-[123I]CIT pinhole SPECT. Neuroimage 17:128–141CrossRefPubMed
15.
go back to reference Booij J, Speelman JD, Horstink MW, Wolters EC (2001) The clinical benefit of imaging striatal dopamine transporters with [123I]FP-CIT SPET in differentiating patients with presynaptic parkinsonism from those with other forms of parkinsonism. Eur J Nucl Med 28:266–272CrossRefPubMed Booij J, Speelman JD, Horstink MW, Wolters EC (2001) The clinical benefit of imaging striatal dopamine transporters with [123I]FP-CIT SPET in differentiating patients with presynaptic parkinsonism from those with other forms of parkinsonism. Eur J Nucl Med 28:266–272CrossRefPubMed
16.
go back to reference Winogrodzka A, Bergmans P, Booij J, van Royen EA, Janssen AG, Wolters EC (2001) [123I]FP-CIT SPECT is a useful method to monitor the rate of dopaminergic degeneration in early-stage Parkinson’s disease. J Neural Transm 108:1011–1019CrossRefPubMed Winogrodzka A, Bergmans P, Booij J, van Royen EA, Janssen AG, Wolters EC (2001) [123I]FP-CIT SPECT is a useful method to monitor the rate of dopaminergic degeneration in early-stage Parkinson’s disease. J Neural Transm 108:1011–1019CrossRefPubMed
17.
go back to reference Nakano Y, Hirko AC, Smith AD et al (2004) Presynaptic dopaminergic properties of differentiated mouse embryonic stem cells. Neurochem Int 45:1067–1073CrossRefPubMed Nakano Y, Hirko AC, Smith AD et al (2004) Presynaptic dopaminergic properties of differentiated mouse embryonic stem cells. Neurochem Int 45:1067–1073CrossRefPubMed
18.
go back to reference Kyono K, Takashima T, Katayama Y et al (2011) Use of [18F]FDOPA-PET for in vivo evaluation of dopaminergic dysfunction in unilaterally 6-OHDA-lesioned rats. EJNMMI Res 1:25CrossRefPubMedCentralPubMed Kyono K, Takashima T, Katayama Y et al (2011) Use of [18F]FDOPA-PET for in vivo evaluation of dopaminergic dysfunction in unilaterally 6-OHDA-lesioned rats. EJNMMI Res 1:25CrossRefPubMedCentralPubMed
19.
go back to reference Mahmood A, Lu D, Chopp M (2004) Intravenous administration of marrow stromal cells (MSCs) increases the expression of growth factors in rat brain after traumatic brain injury. J Neurotrauma 21:33–39CrossRefPubMed Mahmood A, Lu D, Chopp M (2004) Intravenous administration of marrow stromal cells (MSCs) increases the expression of growth factors in rat brain after traumatic brain injury. J Neurotrauma 21:33–39CrossRefPubMed
20.
go back to reference Gutierrez-Fernandez M, Rodriguez-Frutos B, Ramos-Cejudo J et al (2013) Effects of intravenous administration of allogenic bone marrow- and adipose tissue-derived mesenchymal stem cells on functional recovery and brain repair markers in experimental ischemic stroke. Stem Cell Res Ther 4:11CrossRefPubMedCentralPubMed Gutierrez-Fernandez M, Rodriguez-Frutos B, Ramos-Cejudo J et al (2013) Effects of intravenous administration of allogenic bone marrow- and adipose tissue-derived mesenchymal stem cells on functional recovery and brain repair markers in experimental ischemic stroke. Stem Cell Res Ther 4:11CrossRefPubMedCentralPubMed
21.
go back to reference Casteels C, Vermaelen P, Nuyts J et al (2006) Construction and evaluation of multitracer small-animal PET probabilistic atlases for voxel-based functional mapping of the rat brain. J Nucl Med 47:1858–1866PubMed Casteels C, Vermaelen P, Nuyts J et al (2006) Construction and evaluation of multitracer small-animal PET probabilistic atlases for voxel-based functional mapping of the rat brain. J Nucl Med 47:1858–1866PubMed
22.
go back to reference Nie B, Chen K, Zhao S et al (2013) A rat brain MRI template with digital stereotaxic atlas of fine anatomical delineations in paxinos space and its automated application in voxel-wise analysis. Hum Brain Mapp 34:1306–1318CrossRefPubMedCentralPubMed Nie B, Chen K, Zhao S et al (2013) A rat brain MRI template with digital stereotaxic atlas of fine anatomical delineations in paxinos space and its automated application in voxel-wise analysis. Hum Brain Mapp 34:1306–1318CrossRefPubMedCentralPubMed
23.
go back to reference Dabbeni-Sala F, Di Santo S, Franceschini D, Skaper SD, Giusti P (2001) Melatonin protects against 6-OHDA-induced neurotoxicity in rats: a role for mitochondrial complex I activity. FASEB J 15:164–170CrossRefPubMed Dabbeni-Sala F, Di Santo S, Franceschini D, Skaper SD, Giusti P (2001) Melatonin protects against 6-OHDA-induced neurotoxicity in rats: a role for mitochondrial complex I activity. FASEB J 15:164–170CrossRefPubMed
24.
go back to reference Nagatsu T, Levitt M, Udenfriend S (1964) Tyrosine hydroxylase. The initial step in norepinephrine biosynthesis. J Biol Chem 239:2910–2917PubMed Nagatsu T, Levitt M, Udenfriend S (1964) Tyrosine hydroxylase. The initial step in norepinephrine biosynthesis. J Biol Chem 239:2910–2917PubMed
25.
go back to reference Alvarez-Fischer D, Blessmann G, Trosowski C et al (2007) Quantitative [(123)I]FP-CIT pinhole SPECT imaging predicts striatal dopamine levels, but not number of nigral neurons in different mouse models of Parkinson’s disease. Neuroimage 38:5–12CrossRefPubMed Alvarez-Fischer D, Blessmann G, Trosowski C et al (2007) Quantitative [(123)I]FP-CIT pinhole SPECT imaging predicts striatal dopamine levels, but not number of nigral neurons in different mouse models of Parkinson’s disease. Neuroimage 38:5–12CrossRefPubMed
26.
27.
28.
go back to reference McLarty K, Reilly RM (2007) Molecular imaging as a tool for personalized and targeted anticancer therapy. Clin Pharmacol Ther 81:420–424CrossRefPubMed McLarty K, Reilly RM (2007) Molecular imaging as a tool for personalized and targeted anticancer therapy. Clin Pharmacol Ther 81:420–424CrossRefPubMed
29.
go back to reference Nurmi E, Ruottinen HM, Bergman J et al (2001) Rate of progression in Parkinson’s disease: a 6-[18F]fluoro-L-dopa PET study. Mov Disord 16:608–615CrossRefPubMed Nurmi E, Ruottinen HM, Bergman J et al (2001) Rate of progression in Parkinson’s disease: a 6-[18F]fluoro-L-dopa PET study. Mov Disord 16:608–615CrossRefPubMed
30.
go back to reference Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand Suppl 367:69–93CrossRefPubMed Ungerstedt U (1971) Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system. Acta Physiol Scand Suppl 367:69–93CrossRefPubMed
31.
go back to reference Kawasaki H, Mizuseki K, Nishikawa S et al (2000) Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron 28:31–40CrossRefPubMed Kawasaki H, Mizuseki K, Nishikawa S et al (2000) Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron 28:31–40CrossRefPubMed
32.
go back to reference Brederlau A, Correia AS, Anisimov SV et al (2006) Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson’s disease: effect of in vitro differentiation on graft survival and teratoma formation. Stem Cells 24:1433–1440CrossRefPubMed Brederlau A, Correia AS, Anisimov SV et al (2006) Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson’s disease: effect of in vitro differentiation on graft survival and teratoma formation. Stem Cells 24:1433–1440CrossRefPubMed
33.
go back to reference Kim JH, Auerbach JM, Rodriguez-Gomez JA et al (2002) Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nat 418:50–56CrossRef Kim JH, Auerbach JM, Rodriguez-Gomez JA et al (2002) Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nat 418:50–56CrossRef
34.
go back to reference Li Y, Chen J, Wang L, Zhang L, Lu M, Chopp M (2001) Intracerebral transplantation of bone marrow stromal cells in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Neurosci Lett 316:67–70CrossRefPubMed Li Y, Chen J, Wang L, Zhang L, Lu M, Chopp M (2001) Intracerebral transplantation of bone marrow stromal cells in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Neurosci Lett 316:67–70CrossRefPubMed
35.
go back to reference Hellmann MA, Panet H, Barhum Y, Melamed E, Offen D (2006) Increased survival and migration of engrafted mesenchymal bone marrow stem cells in 6-hydroxydopamine-lesioned rodents. Neurosci Lett 395:124–128CrossRefPubMed Hellmann MA, Panet H, Barhum Y, Melamed E, Offen D (2006) Increased survival and migration of engrafted mesenchymal bone marrow stem cells in 6-hydroxydopamine-lesioned rodents. Neurosci Lett 395:124–128CrossRefPubMed
36.
go back to reference Park HJ, Lee PH, Bang OY, Lee G, Ahn YH (2008) Mesenchymal stem cells therapy exerts neuroprotection in a progressive animal model of Parkinson’s disease. J Neurochem 107:141–151CrossRefPubMed Park HJ, Lee PH, Bang OY, Lee G, Ahn YH (2008) Mesenchymal stem cells therapy exerts neuroprotection in a progressive animal model of Parkinson’s disease. J Neurochem 107:141–151CrossRefPubMed
37.
go back to reference Fu YS, Cheng YC, Lin MY et al (2006) Conversion of human umbilical cord mesenchymal stem cells in Wharton’s jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism. Stem Cells 24:115–124CrossRefPubMed Fu YS, Cheng YC, Lin MY et al (2006) Conversion of human umbilical cord mesenchymal stem cells in Wharton’s jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism. Stem Cells 24:115–124CrossRefPubMed
38.
go back to reference Khoo ML, Tao H, Meedeniya AC, Mackay-Sim A, Ma DD (2011) Transplantation of neuronal-primed human bone marrow mesenchymal stem cells in hemiparkinsonian rodents. PLoS One 6:e19025CrossRefPubMedCentralPubMed Khoo ML, Tao H, Meedeniya AC, Mackay-Sim A, Ma DD (2011) Transplantation of neuronal-primed human bone marrow mesenchymal stem cells in hemiparkinsonian rodents. PLoS One 6:e19025CrossRefPubMedCentralPubMed
39.
go back to reference Phinney DG, Prockop DJ (2007) Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair–current views. Stem Cells 25:2896–2902CrossRefPubMed Phinney DG, Prockop DJ (2007) Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair–current views. Stem Cells 25:2896–2902CrossRefPubMed
40.
go back to reference Blandini F, Cova L, Armentero MT et al (2010) Transplantation of undifferentiated human mesenchymal stem cells protects against 6-hydroxydopamine neurotoxicity in the rat. Cell Transplant 19:203–217CrossRefPubMed Blandini F, Cova L, Armentero MT et al (2010) Transplantation of undifferentiated human mesenchymal stem cells protects against 6-hydroxydopamine neurotoxicity in the rat. Cell Transplant 19:203–217CrossRefPubMed
41.
go back to reference Aizman I, Tate CC, McGrogan M, Case CC (2009) Extracellular matrix produced by bone marrow stromal cells and by their derivative, SB623 cells, supports neural cell growth. J Neurosci Res 87:3198–3206CrossRefPubMed Aizman I, Tate CC, McGrogan M, Case CC (2009) Extracellular matrix produced by bone marrow stromal cells and by their derivative, SB623 cells, supports neural cell growth. J Neurosci Res 87:3198–3206CrossRefPubMed
42.
go back to reference Kozlowska H, Jablonka J, Janowski M, Jurga M, Kossut M, Domanska-Janik K (2007) Transplantation of a novel human cord blood-derived neural-like stem cell line in a rat model of cortical infarct. Stem Cells Dev 16:481–488CrossRefPubMed Kozlowska H, Jablonka J, Janowski M, Jurga M, Kossut M, Domanska-Janik K (2007) Transplantation of a novel human cord blood-derived neural-like stem cell line in a rat model of cortical infarct. Stem Cells Dev 16:481–488CrossRefPubMed
43.
go back to reference Kraitchman DL, Tatsumi M, Gilson WD et al (2005) Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circ 112:1451–1461CrossRef Kraitchman DL, Tatsumi M, Gilson WD et al (2005) Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circ 112:1451–1461CrossRef
44.
go back to reference Yoon JK, Park BN, Shim WY, Shin JY, Lee G, Ahn YH (2010) In vivo tracking of 111In-labeled bone marrow mesenchymal stem cells in acute brain trauma model. Nucl Med Biol 37:381–388CrossRefPubMed Yoon JK, Park BN, Shim WY, Shin JY, Lee G, Ahn YH (2010) In vivo tracking of 111In-labeled bone marrow mesenchymal stem cells in acute brain trauma model. Nucl Med Biol 37:381–388CrossRefPubMed
45.
go back to reference Gleave JA, Farncombe TH, Saab C, Doering LC (2011) Correlative single photon emission computed tomography imaging of [123I]altropane binding in the rat model of Parkinson’s. Nucl Med Biol 38:741–749CrossRefPubMed Gleave JA, Farncombe TH, Saab C, Doering LC (2011) Correlative single photon emission computed tomography imaging of [123I]altropane binding in the rat model of Parkinson’s. Nucl Med Biol 38:741–749CrossRefPubMed
Metadata
Title
Improved dopamine transporter binding activity after bone marrow mesenchymal stem cell transplantation in a rat model of Parkinson’s disease: small animal positron emission tomography study with F-18 FP-CIT
Authors
Bok-Nam Park
Jang-Hee Kim
Kwanjae Lee
So Hyun Park
Young-Sil An
Publication date
01-05-2015
Publisher
Springer Berlin Heidelberg
Published in
European Radiology / Issue 5/2015
Print ISSN: 0938-7994
Electronic ISSN: 1432-1084
DOI
https://doi.org/10.1007/s00330-014-3549-3

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