Title: Early Tissue Distribution of Bone Marrow Mononuclear Cells After Intra-Arterial Delivery in a Patient With Chronic Stroke
Abstract: HomeCirculationVol. 120, No. 6Early Tissue Distribution of Bone Marrow Mononuclear Cells After Intra-Arterial Delivery in a Patient With Chronic Stroke Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUBEarly Tissue Distribution of Bone Marrow Mononuclear Cells After Intra-Arterial Delivery in a Patient With Chronic Stroke Lea Mirian Barbosa da Fonseca, Valeria Battistella, Gabriel Rodriguez de Freitas, Bianca Gutfilen, Regina Coeli dos Santos Goldenberg, Angelo Maiolino, Eduardo Wajnberg, Paulo Henrique Rosado de Castro, Rosalia Mendez-Otero and Charles Andre Lea Mirian Barbosa da FonsecaLea Mirian Barbosa da Fonseca From Hospital Universitário Clementino Fraga Filho (L.M.B.d.F., V.B., G.R.d.F., B.G., A.M., E.W., P.H.R.d.C., C.A.) and Instituto de Biofísica Carlos Chagas Filho (R.C.d.S.G., R.M.-O.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. , Valeria BattistellaValeria Battistella From Hospital Universitário Clementino Fraga Filho (L.M.B.d.F., V.B., G.R.d.F., B.G., A.M., E.W., P.H.R.d.C., C.A.) and Instituto de Biofísica Carlos Chagas Filho (R.C.d.S.G., R.M.-O.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. , Gabriel Rodriguez de FreitasGabriel Rodriguez de Freitas From Hospital Universitário Clementino Fraga Filho (L.M.B.d.F., V.B., G.R.d.F., B.G., A.M., E.W., P.H.R.d.C., C.A.) and Instituto de Biofísica Carlos Chagas Filho (R.C.d.S.G., R.M.-O.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. , Bianca GutfilenBianca Gutfilen From Hospital Universitário Clementino Fraga Filho (L.M.B.d.F., V.B., G.R.d.F., B.G., A.M., E.W., P.H.R.d.C., C.A.) and Instituto de Biofísica Carlos Chagas Filho (R.C.d.S.G., R.M.-O.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. , Regina Coeli dos Santos GoldenbergRegina Coeli dos Santos Goldenberg From Hospital Universitário Clementino Fraga Filho (L.M.B.d.F., V.B., G.R.d.F., B.G., A.M., E.W., P.H.R.d.C., C.A.) and Instituto de Biofísica Carlos Chagas Filho (R.C.d.S.G., R.M.-O.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. , Angelo MaiolinoAngelo Maiolino From Hospital Universitário Clementino Fraga Filho (L.M.B.d.F., V.B., G.R.d.F., B.G., A.M., E.W., P.H.R.d.C., C.A.) and Instituto de Biofísica Carlos Chagas Filho (R.C.d.S.G., R.M.-O.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. , Eduardo WajnbergEduardo Wajnberg From Hospital Universitário Clementino Fraga Filho (L.M.B.d.F., V.B., G.R.d.F., B.G., A.M., E.W., P.H.R.d.C., C.A.) and Instituto de Biofísica Carlos Chagas Filho (R.C.d.S.G., R.M.-O.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. , Paulo Henrique Rosado de CastroPaulo Henrique Rosado de Castro From Hospital Universitário Clementino Fraga Filho (L.M.B.d.F., V.B., G.R.d.F., B.G., A.M., E.W., P.H.R.d.C., C.A.) and Instituto de Biofísica Carlos Chagas Filho (R.C.d.S.G., R.M.-O.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. , Rosalia Mendez-OteroRosalia Mendez-Otero From Hospital Universitário Clementino Fraga Filho (L.M.B.d.F., V.B., G.R.d.F., B.G., A.M., E.W., P.H.R.d.C., C.A.) and Instituto de Biofísica Carlos Chagas Filho (R.C.d.S.G., R.M.-O.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. and Charles AndreCharles Andre From Hospital Universitário Clementino Fraga Filho (L.M.B.d.F., V.B., G.R.d.F., B.G., A.M., E.W., P.H.R.d.C., C.A.) and Instituto de Biofísica Carlos Chagas Filho (R.C.d.S.G., R.M.-O.), Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. Originally published11 Aug 2009https://doi.org/10.1161/CIRCULATIONAHA.109.863084Circulation. 2009;120:539–541A 24-year-old man with a cerebral infarct within the left middle cerebral artery (MCA) territory was enrolled in a study to assess the safety of autologous bone marrow mononuclear cell (BMMC) transplantation in patients with ischemic stroke (NCT00473057). His National Institutes of Health Stroke Scale score was 7. Computed tomography (Figure 1A) and technetium-99m ethyl cysteinate dimer (99mTc ECD) single photon emission computed tomography (SPECT) (Figures 1B and 2 and Movie I in the online-only Data Supplement) indicated the location of the infarct. Sixty-seven days after onset of symptoms, the patient underwent BMMC transplantation. Bone marrow blood was aspirated under local anesthesia from both iliac crests and processed to isolate the mononuclear cell fraction. A total of 5×108 BMMCs was suspended into a volume of 10 mL, and 1 mL of the cell suspension was radiolabeled with 99mTc (radioactivity 111 MBq, physical half-life 6 hours), as described previously,1,2 and then added back to the unlabeled cell suspension. After catheter navigation via femoral artery access under local anesthesia and conscious sedation, cells were injected into the M1 portion of the MCA, and the infusion was completed within ≈10 minutes. To monitor the fate of transplanted BMMCs, whole-body and planar scintigraphies were performed at 2, 24, and 48 hours after cell therapy. The patient had no complications during the procedure or follow-up. Download figureDownload PowerPointFigure 1. A, Computed tomography showing ischemic lesion in the left MCA territory. B, Brain perfusion 99mTc ECD SPECT showing left hypoperfusion. C, 99mTc BMMC brain SPECT revealing accumulation of the BMMCs in the left brain hemisphere 2 hours after cell transplantation.Download figureDownload PowerPointFigure 2. Transverse (A), sagittal (B), and coronal (C) images of 99mTc ECD SPECT scintigraphy, demonstrating decreased perfusion in the left MCA territory.Planar and SPECT views revealed uptake and retention of the labeled BMMCs in the territory of the left MCA for up to 48 hours (Figures 1C, 3, and 4 and Movie II in the online-only Data Supplement). The remaining uptake occurred mainly in the liver and spleen (Figure 4). To our knowledge, there has been only 1 report of BMMC homing in cerebral infarction, which indicated the retention of BMMCs 8 hours after intra-arterial injection in 1 patient in the subacute phase, 9 days after stroke.3 We here report for the first time the migration and homing of BMMCs to the brain of a patient in the chronic phase of stroke, >2 months after the onset of symptoms. The mechanisms involved in the possible therapeutic effect of BMMC therapy are still largely unknown, but accumulating evidence from animal studies suggests that these cells may behave as minipumps producing cytokines and/or trophic factors that support cell survival in the penumbra area and stimulate neurogenesis and angiogenesis, increasing brain remodeling and functional regeneration after ischemia.4 In vivo tracking of BMMCs after grafting is of great importance because the retention of transplanted cells at the site of the lesion may be critical for the success of cell therapy.3,4 In animal models, different methods have been used to track the transplanted cells, and it has been suggested that signals that are involved in the transit of inflammatory cells to injured tissue may also direct the transplanted bone marrow–derived cells.4 Our results indicate that labeling BMMCs with 99mTc is feasible and that noninvasive imaging may be used to study the migration and homing of transplanted cells in vivo in the setting of chronic stroke. Download figureDownload PowerPointFigure 3. Transverse (A), sagittal (B), and coronal (C) images of 99mTc BMMC SPECT scintigraphy, demonstrating cell homing in the left MCA territory 2 hours after cell transplantation.Download figureDownload PowerPointFigure 4. Anterior whole-body scans performed 2 (A), 24 (B), and 48 hours (C) after infusion in the territory of the MCA show the distribution of BMMCs labeled with 99mTc. Uptake in the left brain hemisphere is well visualized. The remaining activity was distributed mainly to the liver and spleen.The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/120/7/539/DC1.Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00473057.Sources of FundingThis study was supported by grants from the Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro to Dr Gutfilen (grant 180.011/2005) and to Dr Mendez-Otero (grant 110.391/2007) and a grant from the Ministry of Health and Ministry of Science and Technology of Brazil to Dr Mendez-Otero (grant 552201/2005-7).DisclosuresNone.FootnotesCorrespondence to Lea Mirian Barbosa da Fonseca, MD, PhD, Hospital Universitário Clementino Fraga Filho, Departamento de Radiologia, subsolo, Universidade Federal do Rio de Janeiro, Rua Professor Rodolpho Paulo Rocco 255, Ilha do Fundão, 21949-913, Rio de Janeiro, Brazil. E-mail [email protected]References1 Carvalho AB, Quintanilha LF, Dias JV, Paredes BD, Mannheimer EG, Carvalho FG, Asensi KD, Gutfilen B, Fonseca LM, Resende CM, Rezende GF, Takiya CM, de Carvalho AC, Goldenberg RC. Bone marrow multipotent mesenchymal stromal cells do not reduce fibrosis or improve function in a rat model of severe chronic liver injury. Stem Cells. 2008; 26: 1307–1314.CrossrefMedlineGoogle Scholar2 Quintanilha LF, Mannheimer EG, Carvalho AB, Paredes BD, Dias JV, Almeida AS, Gutfilen B, Barbosa da Fonseca LM, Resende CM, Rezende GF, Campos de Carvalho AC, Goldenberg RC. Bone marrow cell transplant does not prevent or reverse murine liver cirrhosis. Cell Transplant. 2008; 17: 943–953.CrossrefMedlineGoogle Scholar3 Correa PL, Mesquita CT, Felix RM, Azevedo JC, Barbirato GB, Falcão CH, Gonzalez C, Mendonça ML, Manfrim A, de Freitas G, Oliveira CC, Silva D, Avila D, Borojevic R, Alves S, Oliveira AC Jr, Dohmann HF. Assessment of intra-arterial injected autologous bone marrow mononuclear cell distribution by radioactive labeling in acute ischemic stroke. Clin Nucl Med. 2007; 32: 839–841.CrossrefMedlineGoogle Scholar4 Mendez-Otero R, de Freitas GR, André C, de Mendonça ML, Friedrich M, Oliveira-Filho J. Potential roles of bone marrow stem cells in stroke therapy. Regen Med. 2007; 2: 417–423.CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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Battistella V, de Freitas G, da Fonseca L, Mercante D, Gutfilen B, Goldenberg R, Vieira Dias J, Kasai-Brunswick T, Wajnberg E, Rosado-de-Castro P, Alves-Leon S, Mendez-Otero R and Andre C (2011) Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke, Regenerative Medicine, 10.2217/rme.10.97, 6:1, (45-52), Online publication date: 1-Jan-2011. Pimentel-Coelho P and Mendez-Otero R (2010) Cell Therapy for Neonatal Hypoxic–Ischemic Encephalopathy, Stem Cells and Development, 10.1089/scd.2009.0403, 19:3, (299-310), Online publication date: 1-Mar-2010. Barbosa da Fonseca L, Gutfilen B, Rosado de Castro P, Battistella V, Goldenberg R, Kasai-Brunswick T, Chagas C, Wajnberg E, Maiolino A, Salles Xavier S, Andre C, Mendez-Otero R and de Freitas G (2010) Migration and homing of bone-marrow mononuclear cells in chronic ischemic stroke after intra-arterial injection, Experimental Neurology, 10.1016/j.expneurol.2009.10.010, 221:1, (122-128), Online publication date: 1-Jan-2010. August 11, 2009Vol 120, Issue 6 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.109.863084PMID: 19667245 Originally publishedAugust 11, 2009 PDF download Advertisement SubjectsComputerized Tomography (CT)MetabolismNuclear Cardiology and PETTreatment