Skip to main content
Top
Published in: EJNMMI Research 1/2018

Open Access 01-12-2018 | Original research

[18F]DPA-714 PET imaging shows immunomodulatory effect of intravenous administration of bone marrow stromal cells after transient focal ischemia

Authors: Chengbo Tan, Songji Zhao, Kei Higashikawa, Zifeng Wang, Masahito Kawabori, Takeo Abumiya, Naoki Nakayama, Ken Kazumata, Naoyuki Ukon, Hironobu Yasui, Nagara Tamaki, Yuji Kuge, Hideo Shichinohe, Kiyohiro Houkin

Published in: EJNMMI Research | Issue 1/2018

Login to get access

Abstract

Background

The potential application of bone marrow stromal cell (BMSC) therapy in stroke has been anticipated due to its immunomodulatory effects. Recently, positron emission tomography (PET) with [18F]DPA-714, a translocator protein (TSPO) ligand, has become available for use as a neural inflammatory indicator. We aimed to evaluate the effects of BMSC administration after transient middle cerebral artery occlusion (MCAO) using [18F]DPA-714 PET.
The BMSCs or vehicle were administered intravenously to rat MCAO models at 3 h after the insult. Neurological deficits, body weight, infarct volume, and histology were analyzed. [18F]DPA-714 PET was performed 3 and 10 days after MCAO.

Results

Rats had severe neurological deficits and body weight loss after MCAO. Cell administration ameliorated these effects as well as the infarct volume. Although weight loss occurred in the spleen and thymus, cell administration suppressed it. In both vehicle and BMSC groups, [18F]DPA-714 PET showed a high standardized uptake value (SUV) around the ischemic area 3 days after MCAO. Although SUV was increased further 10 days after MCAO in both groups, the increase was inhibited in the BMSC group, significantly. Histological analysis showed that an inflammatory reaction occurred in the lymphoid organs and brain after MCAO, which was suppressed in the BMSC group.

Conclusions

The present results suggest that BMSC therapy could be effective in ischemic stroke due to modulation of systemic inflammatory responses. The [18F]DPA-714 PET/CT system can accurately demonstrate brain inflammation and evaluate the BMSC therapeutic effect in an imaging context. It has great potential for clinical application.
Literature
2.
go back to reference Acosta SA, Tajiri N, Hoover J, Kaneko Y, Borlongan CV. Intravenous bone marrow stem cell grafts preferentially migrate to spleen and abrogate chronic inflammation in stroke. Stroke. 2015;46(9):2616–27.CrossRefPubMedPubMedCentral Acosta SA, Tajiri N, Hoover J, Kaneko Y, Borlongan CV. Intravenous bone marrow stem cell grafts preferentially migrate to spleen and abrogate chronic inflammation in stroke. Stroke. 2015;46(9):2616–27.CrossRefPubMedPubMedCentral
4.
go back to reference McColl BW, Allan SM, Rothwell NJ. Systemic infection, inflammation and acute ischemic stroke. Neuroscience. 2009;158(3):1049–61.CrossRefPubMed McColl BW, Allan SM, Rothwell NJ. Systemic infection, inflammation and acute ischemic stroke. Neuroscience. 2009;158(3):1049–61.CrossRefPubMed
5.
go back to reference Elkind MS, Cheng J, Rundek T, Boden-Albala B, Sacco RL. Leukocyte count predicts outcome after ischemic stroke: the Northern Manhattan Stroke Study. J Stroke Cerebrovasc Dis. 2004;13(5):220–7.CrossRefPubMed Elkind MS, Cheng J, Rundek T, Boden-Albala B, Sacco RL. Leukocyte count predicts outcome after ischemic stroke: the Northern Manhattan Stroke Study. J Stroke Cerebrovasc Dis. 2004;13(5):220–7.CrossRefPubMed
6.
go back to reference Savitz SI, Chopp M, Deans R, Carmichael ST, Phinney D, Wechsler L. Stem cell therapy as an emerging paradigm for stroke (STEPS) II. Stroke. 2011;42(3):825–9.CrossRefPubMed Savitz SI, Chopp M, Deans R, Carmichael ST, Phinney D, Wechsler L. Stem cell therapy as an emerging paradigm for stroke (STEPS) II. Stroke. 2011;42(3):825–9.CrossRefPubMed
7.
go back to reference Azizi SA, Stokes D, Augelli BJ, DiGirolamo C, Prockop DJ. Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats--similarities to astrocyte grafts. Proc Natl Acad Sci U S A. 1998;95(7):3908–13.CrossRefPubMedPubMedCentral Azizi SA, Stokes D, Augelli BJ, DiGirolamo C, Prockop DJ. Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats--similarities to astrocyte grafts. Proc Natl Acad Sci U S A. 1998;95(7):3908–13.CrossRefPubMedPubMedCentral
8.
go back to reference Chopp M, Li Y. Treatment of neural injury with marrow stromal cells. Lancet Neurol. 2002;1(2):92–100.CrossRefPubMed Chopp M, Li Y. Treatment of neural injury with marrow stromal cells. Lancet Neurol. 2002;1(2):92–100.CrossRefPubMed
9.
go back to reference Tan C, Shichinohe H, Wang Z, Hamauchi S, Abumiya T, Nakayama N, et al. Feasibility and Efficiency of Human Bone Marrow Stromal Cell Culture with Allogeneic Platelet Lysate-Supplementation for Cell Therapy against Stroke. Stem Cells Int. 2016;2016:6104780.PubMedPubMedCentral Tan C, Shichinohe H, Wang Z, Hamauchi S, Abumiya T, Nakayama N, et al. Feasibility and Efficiency of Human Bone Marrow Stromal Cell Culture with Allogeneic Platelet Lysate-Supplementation for Cell Therapy against Stroke. Stem Cells Int. 2016;2016:6104780.PubMedPubMedCentral
10.
go back to reference Teng X, Chen L, Chen W, Yang J, Yang Z, Shen Z. Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell Physiol Biochem. 2015;37(6):2415–24.CrossRefPubMed Teng X, Chen L, Chen W, Yang J, Yang Z, Shen Z. Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell Physiol Biochem. 2015;37(6):2415–24.CrossRefPubMed
11.
go back to reference Yoshimatsu G, Sakata N, Tsuchiya H, Minowa T, Takemura T, Morita H, et al. The co-transplantation of bone marrow derived mesenchymal stem cells reduced inflammation in intramuscular islet transplantation. PLoS One. 2015;10(2):e0117561.CrossRefPubMedPubMedCentral Yoshimatsu G, Sakata N, Tsuchiya H, Minowa T, Takemura T, Morita H, et al. The co-transplantation of bone marrow derived mesenchymal stem cells reduced inflammation in intramuscular islet transplantation. PLoS One. 2015;10(2):e0117561.CrossRefPubMedPubMedCentral
12.
go back to reference Liao W, Zhong J, Yu J, Xie J, Liu Y, Du L, et al. Therapeutic benefit of human umbilical cord derived mesenchymal stromal cells in intracerebral hemorrhage rat: implications of anti-inflammation and angiogenesis. Cell Physiol Biochem. 2009;24(3–4):307–16.CrossRefPubMed Liao W, Zhong J, Yu J, Xie J, Liu Y, Du L, et al. Therapeutic benefit of human umbilical cord derived mesenchymal stromal cells in intracerebral hemorrhage rat: implications of anti-inflammation and angiogenesis. Cell Physiol Biochem. 2009;24(3–4):307–16.CrossRefPubMed
13.
go back to reference Huang P, Gebhart N, Richelson E, Brott TG, Meschia JF, Zubair AC. Mechanism of mesenchymal stem cell-induced neuron recovery and anti-inflammation. Cytotherapy. 2014;16(10):1336–44.CrossRefPubMed Huang P, Gebhart N, Richelson E, Brott TG, Meschia JF, Zubair AC. Mechanism of mesenchymal stem cell-induced neuron recovery and anti-inflammation. Cytotherapy. 2014;16(10):1336–44.CrossRefPubMed
15.
go back to reference Martin A, Boisgard R, Kassiou M, Dolle F, Tavitian B. Reduced PBR/TSPO expression after minocycline treatment in a rat model of focal cerebral ischemia: a PET study using [(18)F]DPA-714. Mol Imaging Biol. 2011;13(1):10–5.CrossRefPubMed Martin A, Boisgard R, Kassiou M, Dolle F, Tavitian B. Reduced PBR/TSPO expression after minocycline treatment in a rat model of focal cerebral ischemia: a PET study using [(18)F]DPA-714. Mol Imaging Biol. 2011;13(1):10–5.CrossRefPubMed
16.
go back to reference Qi X, Xu J, Wang F, Xiao J. Translocator protein (18 kDa): a promising therapeutic target and diagnostic tool for cardiovascular diseases. Oxidative Med Cell Longev. 2012;2012:162934.CrossRef Qi X, Xu J, Wang F, Xiao J. Translocator protein (18 kDa): a promising therapeutic target and diagnostic tool for cardiovascular diseases. Oxidative Med Cell Longev. 2012;2012:162934.CrossRef
18.
go back to reference Ribeiro MJ, Vercouillie J, Debiais S, Cottier JP, Bonnaud I, Camus V, et al. Could (18) F-DPA-714 PET imaging be interesting to use in the early post-stroke period? EJNMMI Res. 2014;4:28.CrossRefPubMedPubMedCentral Ribeiro MJ, Vercouillie J, Debiais S, Cottier JP, Bonnaud I, Camus V, et al. Could (18) F-DPA-714 PET imaging be interesting to use in the early post-stroke period? EJNMMI Res. 2014;4:28.CrossRefPubMedPubMedCentral
19.
go back to reference Tan C, Shichinohe H, Abumiya T, Nakayama N, Kazumata K, Hokari M, et al. Short-, middle- and long-term safety of superparamagnetic iron oxide-labeled allogeneic bone marrow stromal cell transplantation in rat model of lacunar infarction. Neuropathology. 2015;35(3):197–208.CrossRefPubMed Tan C, Shichinohe H, Abumiya T, Nakayama N, Kazumata K, Hokari M, et al. Short-, middle- and long-term safety of superparamagnetic iron oxide-labeled allogeneic bone marrow stromal cell transplantation in rat model of lacunar infarction. Neuropathology. 2015;35(3):197–208.CrossRefPubMed
20.
go back to reference Kurisu K, Abumiya T, Ito M, Gekka M, Osanai T, Shichinohe H, et al. Transarterial regional hypothermia provides robust neuroprotection in a rat model of permanent middle cerebral artery occlusion with transient collateral hypoperfusion. Brain Res. 2016;1651:95–103.CrossRefPubMed Kurisu K, Abumiya T, Ito M, Gekka M, Osanai T, Shichinohe H, et al. Transarterial regional hypothermia provides robust neuroprotection in a rat model of permanent middle cerebral artery occlusion with transient collateral hypoperfusion. Brain Res. 2016;1651:95–103.CrossRefPubMed
21.
go back to reference Kurisu K, Abumiya T, Nakamura H, Shimbo D, Shichinohe H, Nakayama N, et al. Transarterial regional brain hypothermia inhibits acute aquaporin-4 surge and sequential microvascular events in ischemia/reperfusion injury. Neurosurgery. 2016;79(1):125–34.CrossRefPubMed Kurisu K, Abumiya T, Nakamura H, Shimbo D, Shichinohe H, Nakayama N, et al. Transarterial regional brain hypothermia inhibits acute aquaporin-4 surge and sequential microvascular events in ischemia/reperfusion injury. Neurosurgery. 2016;79(1):125–34.CrossRefPubMed
22.
go back to reference Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, et al. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke. 2001;32(4):1005–11.CrossRefPubMed Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, et al. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke. 2001;32(4):1005–11.CrossRefPubMed
23.
go back to reference Yasuda H, Shichinohe H, Kuroda S, Ishikawa T, Iwasaki Y. Neuroprotective effect of a heat shock protein inducer, geranylgeranylacetone in permanent focal cerebral ischemia. Brain Res. 2005;1032(1–2):176–82.CrossRefPubMed Yasuda H, Shichinohe H, Kuroda S, Ishikawa T, Iwasaki Y. Neuroprotective effect of a heat shock protein inducer, geranylgeranylacetone in permanent focal cerebral ischemia. Brain Res. 2005;1032(1–2):176–82.CrossRefPubMed
24.
go back to reference Miyamoto M, Kuroda S, Zhao S, Magota K, Shichinohe H, Houkin K, et al. Bone marrow stromal cell transplantation enhances recovery of local glucose metabolism after cerebral infarction in rats: a serial 18F-FDG PET study. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2013;54(1):145–50.CrossRef Miyamoto M, Kuroda S, Zhao S, Magota K, Shichinohe H, Houkin K, et al. Bone marrow stromal cell transplantation enhances recovery of local glucose metabolism after cerebral infarction in rats: a serial 18F-FDG PET study. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2013;54(1):145–50.CrossRef
25.
go back to reference Magota K, Kubo N, Kuge Y, Nishijima K, Zhao S, Tamaki N. Performance characterization of the Inveon preclinical small-animal PET/SPECT/CT system for multimodality imaging. Eur J Nucl Med Mol Imaging. 2011;38(4):742–52.CrossRefPubMed Magota K, Kubo N, Kuge Y, Nishijima K, Zhao S, Tamaki N. Performance characterization of the Inveon preclinical small-animal PET/SPECT/CT system for multimodality imaging. Eur J Nucl Med Mol Imaging. 2011;38(4):742–52.CrossRefPubMed
26.
go back to reference Offner H, Subramanian S, Parker SM, Wang C, Afentoulis ME, Lewis A, et al. Splenic atrophy in experimental stroke is accompanied by increased regulatory T cells and circulating macrophages. J Immunol. 2006;176(11):6523–31.CrossRefPubMed Offner H, Subramanian S, Parker SM, Wang C, Afentoulis ME, Lewis A, et al. Splenic atrophy in experimental stroke is accompanied by increased regulatory T cells and circulating macrophages. J Immunol. 2006;176(11):6523–31.CrossRefPubMed
27.
go back to reference Martin A, Aguirre J, Sarasa-Renedo A, Tsoukatou D, Garofalakis A, Meyer H, et al. Imaging changes in lymphoid organs in vivo after brain ischemia with three-dimensional fluorescence molecular tomography in transgenic mice expressing green fluorescent protein in T lymphocytes. Mol Imaging. 2008;7(4):157–67.CrossRefPubMed Martin A, Aguirre J, Sarasa-Renedo A, Tsoukatou D, Garofalakis A, Meyer H, et al. Imaging changes in lymphoid organs in vivo after brain ischemia with three-dimensional fluorescence molecular tomography in transgenic mice expressing green fluorescent protein in T lymphocytes. Mol Imaging. 2008;7(4):157–67.CrossRefPubMed
28.
go back to reference Kawabori M, Yenari MA. The role of the microglia in acute CNS injury. Metab Brain Dis. 2015;30(2):381–92.CrossRefPubMed Kawabori M, Yenari MA. The role of the microglia in acute CNS injury. Metab Brain Dis. 2015;30(2):381–92.CrossRefPubMed
31.
go back to reference Ansboro S, Roelofs AJ, De Bari C. Mesenchymal stem cells for the management of rheumatoid arthritis: immune modulation, repair or both? Curr Opin Rheumatol. 2017;29(2):201–7.CrossRefPubMed Ansboro S, Roelofs AJ, De Bari C. Mesenchymal stem cells for the management of rheumatoid arthritis: immune modulation, repair or both? Curr Opin Rheumatol. 2017;29(2):201–7.CrossRefPubMed
32.
go back to reference Uccelli A, de Rosbo NK. The immunomodulatory function of mesenchymal stem cells: mode of action and pathways. Ann N Y Acad Sci. 2015;1351:114–26.CrossRefPubMed Uccelli A, de Rosbo NK. The immunomodulatory function of mesenchymal stem cells: mode of action and pathways. Ann N Y Acad Sci. 2015;1351:114–26.CrossRefPubMed
33.
go back to reference Yang B, Hamilton JA, Valenzuela KS, Bogaerts A, Xi X, Aronowski J, et al. Multipotent adult progenitor cells enhance recovery after stroke by modulating the immune response from the spleen. Stem Cells. 2017;35(5):1290–302.CrossRefPubMed Yang B, Hamilton JA, Valenzuela KS, Bogaerts A, Xi X, Aronowski J, et al. Multipotent adult progenitor cells enhance recovery after stroke by modulating the immune response from the spleen. Stem Cells. 2017;35(5):1290–302.CrossRefPubMed
34.
go back to reference Akiyama K, Chen C, Wang D, Xu X, Qu C, Yamaza T, et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell. 2012;10(5):544–55.CrossRefPubMedPubMedCentral Akiyama K, Chen C, Wang D, Xu X, Qu C, Yamaza T, et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell. 2012;10(5):544–55.CrossRefPubMedPubMedCentral
35.
go back to reference Abumaree MH, Al Jumah MA, Kalionis B, Jawdat D, Al Khaldi A, Abomaray FM, et al. Human placental mesenchymal stem cells (pMSCs) play a role as immune suppressive cells by shifting macrophage differentiation from inflammatory M1 to anti-inflammatory M2 macrophages. Stem Cell Rev. 2013;9(5):620–41.CrossRefPubMed Abumaree MH, Al Jumah MA, Kalionis B, Jawdat D, Al Khaldi A, Abomaray FM, et al. Human placental mesenchymal stem cells (pMSCs) play a role as immune suppressive cells by shifting macrophage differentiation from inflammatory M1 to anti-inflammatory M2 macrophages. Stem Cell Rev. 2013;9(5):620–41.CrossRefPubMed
36.
go back to reference Ory D, Planas A, Dresselaers T, Gsell W, Postnov A, Celen S, et al. PET imaging of TSPO in a rat model of local neuroinflammation induced by intracerebral injection of lipopolysaccharide. Nucl Med Biol. 2015;42(10):753–61.CrossRefPubMed Ory D, Planas A, Dresselaers T, Gsell W, Postnov A, Celen S, et al. PET imaging of TSPO in a rat model of local neuroinflammation induced by intracerebral injection of lipopolysaccharide. Nucl Med Biol. 2015;42(10):753–61.CrossRefPubMed
37.
go back to reference Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P, et al. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006;27(8):402–9.CrossRefPubMed Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapere JJ, Lindemann P, et al. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006;27(8):402–9.CrossRefPubMed
38.
go back to reference Casellas P, Galiegue S, Basile AS. Peripheral benzodiazepine receptors and mitochondrial function. Neurochem Int. 2002;40(6):475–86.CrossRefPubMed Casellas P, Galiegue S, Basile AS. Peripheral benzodiazepine receptors and mitochondrial function. Neurochem Int. 2002;40(6):475–86.CrossRefPubMed
39.
go back to reference Vicidomini C, Panico M, Greco A, Gargiulo S, Coda AR, Zannetti A, et al. In vivo imaging and characterization of [(18)F]DPA-714, a potential new TSPO ligand, in mouse brain and peripheral tissues using small-animal PET. Nucl Med Biol. 2015;42(3):309–16.CrossRefPubMed Vicidomini C, Panico M, Greco A, Gargiulo S, Coda AR, Zannetti A, et al. In vivo imaging and characterization of [(18)F]DPA-714, a potential new TSPO ligand, in mouse brain and peripheral tissues using small-animal PET. Nucl Med Biol. 2015;42(3):309–16.CrossRefPubMed
40.
go back to reference Ozaki H, Zoghbi SS, Hong J, Verma A, Pike VW, Innis RB, et al. In vivo binding of protoporphyrin IX to rat translocator protein imaged with positron emission tomography. Synapse. 2010;64(8):649–53.CrossRefPubMedPubMedCentral Ozaki H, Zoghbi SS, Hong J, Verma A, Pike VW, Innis RB, et al. In vivo binding of protoporphyrin IX to rat translocator protein imaged with positron emission tomography. Synapse. 2010;64(8):649–53.CrossRefPubMedPubMedCentral
41.
go back to reference Bernards N, Pottier G, Theze B, Dolle F, Boisgard R. In vivo evaluation of inflammatory bowel disease with the aid of muPET and the translocator protein 18 kDa radioligand [18F]DPA-714. Mol Imaging Biol. 2015;17(1):67–75.CrossRefPubMed Bernards N, Pottier G, Theze B, Dolle F, Boisgard R. In vivo evaluation of inflammatory bowel disease with the aid of muPET and the translocator protein 18 kDa radioligand [18F]DPA-714. Mol Imaging Biol. 2015;17(1):67–75.CrossRefPubMed
42.
go back to reference Saito H, Magota K, Zhao S, Kubo N, Kuge Y, Shichinohe H, et al. 123I-iomazenil single photon emission computed tomography visualizes recovery of neuronal integrity by bone marrow stromal cell therapy in rat infarct brain. Stroke. 2013;44(10):2869–74.CrossRefPubMed Saito H, Magota K, Zhao S, Kubo N, Kuge Y, Shichinohe H, et al. 123I-iomazenil single photon emission computed tomography visualizes recovery of neuronal integrity by bone marrow stromal cell therapy in rat infarct brain. Stroke. 2013;44(10):2869–74.CrossRefPubMed
Metadata
Title
[18F]DPA-714 PET imaging shows immunomodulatory effect of intravenous administration of bone marrow stromal cells after transient focal ischemia
Authors
Chengbo Tan
Songji Zhao
Kei Higashikawa
Zifeng Wang
Masahito Kawabori
Takeo Abumiya
Naoki Nakayama
Ken Kazumata
Naoyuki Ukon
Hironobu Yasui
Nagara Tamaki
Yuji Kuge
Hideo Shichinohe
Kiyohiro Houkin
Publication date
01-12-2018
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2018
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-018-0392-6

Other articles of this Issue 1/2018

EJNMMI Research 1/2018 Go to the issue