Skip to main content

Advertisement

Log in

Intra-Arterial Transplantation of Low-Dose Stem Cells Provides Functional Recovery Without Adverse Effects After Stroke

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

A Correction to this article was published on 30 January 2020

This article has been updated

Abstract

Cell transplantation therapy for cerebral infarction has emerged as a promising treatment to reduce brain damage and enhance functional recovery. We previously reported that intra-arterial delivery of bone marrow mesenchymal stem cells (MSCs) enables superselective cell administration to the infarct area and results in significant functional recovery after ischemic stroke in a rat model. However, to reduce the risk of embolism caused by the transplanted cells, an optimal cell number should be determined. At 24 h after middle cerebral artery occlusion and reperfusion, we administered human MSCs (low dose: 1 × 104 cells; high dose: 1 × 106 cells) and then assessed functional recovery, inflammatory responses, cell distribution, and mortality. Rats treated with high- or low-dose MSCs showed behavioral recovery. At day 8 post-stroke, microglial activation was suppressed significantly, and interleukin (IL)-1β and IL-12p70 were reduced in both groups. Although high-dose MSCs were more widely distributed in the cortex and striatum of rats, the degree of intravascular cell aggregation and mortality was significantly higher in the high-dose group. In conclusion, selective intra-arterial transplantation of low-dose MSCs has anti-inflammatory effects and reduces the adverse effects of embolic complication, resulting in sufficient functional recovery of the affected brain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Change history

  • 30 January 2020

    The original version of this article unfortunately contained an error in affiliation of Yuhtaka Fukuda.

References

  • Abe K, Yamashita T, Takizawa S, Kuroda S, Kinouchi H, Kawahara N (2012) Stem cell therapy for cerebral ischemia: from basic science to clinical applications. J Cereb Blood Flow Metab 32:1317–1331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Amar AP, Zlokovic BV, Apuzzo MLJ (2003) Endovascular restorative neurosurgery: a novel concept for molecular and cellular therapy of the nervous system. Neurosurgery 52:402–413

    Article  PubMed  Google Scholar 

  • Andres RH, Choi R, Pendharkar AV, Gaeta X, Wang N, Nathan JK, Chua JY, Lee SW, Palmer TD, Steinberg GK, Guzman R (2011a) The CCR2/CCL2 interaction mediates the transendothelial recruitment of intravascularly delivered neural stem cells to the ischemic brain. Stroke 42:2923–2931

    Article  PubMed  PubMed Central  Google Scholar 

  • Andres RH, Horie N, Slikker W, Keren-Gill H, Zhan K, Sun G, Manley NC, Pereira MP, Sheikh LA, McMillan EL, Schaar BT, Svendsen CN, Bliss TM, Steinberg GK (2011b) Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain. Brain 134:1777–1789

    Article  PubMed  PubMed Central  Google Scholar 

  • Bliss T, Guzman R, Daadi M, Steinberg GK (2007) Cell transplantation therapy for stroke. Stroke 38:817–826

    Article  PubMed  Google Scholar 

  • Boutin H, LeFeuvre RA, Horai R, Asano M, Iwakura Y, Rothwell NJ (2001) Role of IL-1alpha and IL-1beta in ischemic brain damage. J Neurosci 21:5528–5534

    CAS  PubMed  Google Scholar 

  • Byun JS, Kwak BK, Kim JK, Jung J, Ha BC, Park S (2013) Engraftment of human mesenchymal stem cells in a rat photothrombotic cerebral infarction model: comparison of intra-arterial and intravenous infusion using MRI and histological analysis. J Korean Neurosurg Soc 54:467–476

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, Chopp M (2001) Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32:1005–1011

    Article  CAS  PubMed  Google Scholar 

  • Chua JY, Pendharkar AV, Wang N, Choi R, Andres RH, Gaeta X, Zhang J, Moseley ME, Guzman R (2011) Intra-arterial injection of neural stem cells using a microneedle technique does not cause microembolic strokes. J Cereb Blood Flow Metab 31:1263–1271

    Article  PubMed  Google Scholar 

  • Eckert MA, Vu Q, Xie K, Yu J, Liao W, Cramer SC, Zhao W (2013) Evidence for high translational potential of mesenchymal stromal cell therapy to improve recovery from ischemic stroke. J Cereb Blood Flow Metab 33:1322–1334

    Article  PubMed  PubMed Central  Google Scholar 

  • Encarnacion A, Horie N, Keren-Gill H, Bliss TM, Steinberg GK, Shamloo M (2011) Long-term behavioral assessment of function in an experimental model for ischemic stroke. J Neurosci Methods 196:247–257

    Article  PubMed  PubMed Central  Google Scholar 

  • Gutierrez-Fernandez M, Rodriguez-Frutos B, Alvarez-Grech J, Vallejo-Cremades MT, Exposito-Alcaide M, Merino J, Roda JM, Diez-Tejedor E (2011) Functional recovery after hematic administration of allogenic mesenchymal stem cells in acute ischemic stroke in rats. Neuroscience 175:394–405

    Article  CAS  PubMed  Google Scholar 

  • Guzman R, Choi R, Gera A, De Los Angeles A, Andres RH, Steinberg GK (2008a) Intravascular cell replacement therapy for stroke. Neurosurg Focus 24:E15

    Article  PubMed  Google Scholar 

  • Guzman R, De Los Angeles A, Cheshier S, Choi R, Hoang S, Liauw J, Schaar B, Steinberg G (2008b) Intracarotid injection of fluorescence activated cell-sorted CD49d-positive neural stem cells improves targeted cell delivery and behavior after stroke in a mouse stroke model. Stroke 39:1300–1306

    Article  PubMed  Google Scholar 

  • Horie N, Maag AL, Hamilton SA, Shichinohe H, Bliss TM, Steinberg GK (2008) Mouse model of focal cerebral ischemia using endothelin-1. J Neurosci Methods 173:286–290

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Horie N, Pereira MP, Niizuma K, Sun G, Keren-Gill H, Encarnacion A, Shamloo M, Hamilton SA, Jiang K, Huhn S, Palmer TD, Bliss TM, Steinberg GK (2011) Transplanted stem cell-secreted vascular endothelial growth factor effects poststroke recovery, inflammation, and vascular repair. Stem Cells 29:274–285

    Article  CAS  PubMed  Google Scholar 

  • Ishizaka S, Horie N, Satoh K, Fukuda Y, Nishida N, Nagata I (2013) Intra-arterial cell transplantation provides timing-dependent cell distribution and functional recovery after stroke. Stroke 44:720–726

    Article  PubMed  Google Scholar 

  • Janowski M, Lyczek A, Engels C, Xu J, Lukomska B, Bulte JW, Walczak P (2013) Cell size and velocity of injection are major determinants of the safety of intracarotid stem cell transplantation. J Cereb Blood Flow Metab 33:921–927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamiya N, Ueda M, Igarashi H, Nishiyama Y, Suda S, Inaba T, Katayama Y (2008) Intra-arterial transplantation of bone marrow mononuclear cells immediately after reperfusion decreases brain injury after focal ischemia in rats. Life Sci 83:433–437

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Chen J, Wang L, Lu M, Chopp M (2001) Treatment of stroke in rat with intracarotid administration of marrow stromal cells. Neurology 56:1666–1672

    Article  CAS  PubMed  Google Scholar 

  • Lindvall O, Kokaia Z (2011) Stem cell research in stroke: how far from the clinic? Stroke 42:2369–2375

    Article  PubMed  Google Scholar 

  • Liu H, Honmou O, Harada K, Nakamura K, Houkin K, Hamada H, Kocsis JD (2006) Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia. Brain 129:2734–2745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGuckin CP, Jurga M, Miller AM, Sarnowska A, Wiedner M, Boyle NT, Lynch MA, Jablonska A, Drela K, Lukomska B, Domanska-Janik K, Kenner L, Moriggl R, Degoul O, Perruisseau-Carrier C, Forraz N (2013) Ischemic brain injury: a consortium analysis of key factors involved in mesenchymal stem cell-mediated inflammatory reduction. Arch Biochem Biophys 534:88–97

    Article  CAS  PubMed  Google Scholar 

  • Messina LM, Podrazik RM, Whitehill TA, Ekhterae D, Brothers TE, Wilson JM, Burkel WE, Stanley JC (1992) Adhesion and incorporation of lacZ-transduced endothelial cells into the intact capillary wall in the rat. Proc Natl Acad Sci USA 89:12018–12022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Misra V, Ritchie MM, Stone LL, Low WC, Janardhan V (2012) Stem cell therapy in ischemic stroke: role of IV and intra-arterial therapy. Neurology 79:S207–S212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitkari B, Nitzsche F, Kerkela E, Kuptsova K, Huttunen J, Nystedt J, Korhonen M, Jolkkonen J (2014) Human bone marrow mesenchymal stem/stromal cells produce efficient localization in the brain and enhanced angiogenesis after intra-arterial delivery in rats with cerebral ischemia, but this is not translated to behavioral recovery. Behav Brain Res 259:50–59

    Article  PubMed  Google Scholar 

  • Murphy TH, Corbett D (2009) Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci 10:861–872

    Article  CAS  PubMed  Google Scholar 

  • Pendharkar AV, Chua JY, Andres RH, Wang N, Gaeta X, Wang H, De A, Choi R, Chen S, Rutt BK, Gambhir SS, Guzman R (2010) Biodistribution of neural stem cells after intravascular therapy for hypoxic-ischemia. Stroke 41:2064–2070

    Article  PubMed  PubMed Central  Google Scholar 

  • Rosado-de-Castro PH, Pimentel-Coelho PM, da Fonseca LM, de Freitas GR, Mendez-Otero R (2013) The rise of cell therapy trials for stroke: review of published and registered studies. Stem Cells Dev 22:2095–2111

    Article  PubMed  PubMed Central  Google Scholar 

  • Rosenblum S, Wang N, Smith TN, Pendharkar AV, Chua JY, Birk H, Guzman R (2012) Timing of intra-arterial neural stem cell transplantation after hypoxia-ischemia influences cell engraftment, survival, and differentiation. Stroke 43:1624–1631

    Article  CAS  PubMed  Google Scholar 

  • Shichita T, Ago T, Kamouchi M, Kitazono T, Yoshimura A, Ooboshi H (2012) Novel therapeutic strategies targeting innate immune responses and early inflammation after stroke. J Neurochem 123(Suppl 2):29–38

    Article  CAS  PubMed  Google Scholar 

  • Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS) (2009) Bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke 40:510–515

  • Walczak P, Zhang J, Gilad AA, Kedziorek DA, Ruiz-Cabello J, Young RG, Pittenger MF, van Zijl PC, Huang J, Bulte JW (2008) Dual-modality monitoring of targeted intraarterial delivery of mesenchymal stem cells after transient ischemia. Stroke 39:1569–1574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang B, Migliati E, Parsha K, Schaar K, Xi X, Aronowski J, Savitz SI (2013) Intra-arterial delivery is not superior to intravenous delivery of autologous bone marrow mononuclear cells in acute ischemic stroke. Stroke 44:3463–3472

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yavagal DR, Lin B, Raval AP, Garza PS, Dong C, Zhao W, Rangel EB, McNiece I, Rundek T, Sacco RL, Perez-Pinzon M, Hare JM (2014) Efficacy and dose-dependent safety of intra-arterial delivery of mesenchymal stem cells in a rodent stroke model. PLoS ONE 9:e93735

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research to Y.F (No. 25462223).

Disclosure

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nobutaka Horie.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fukuda, Y., Horie, N., Satoh, K. et al. Intra-Arterial Transplantation of Low-Dose Stem Cells Provides Functional Recovery Without Adverse Effects After Stroke. Cell Mol Neurobiol 35, 399–406 (2015). https://doi.org/10.1007/s10571-014-0135-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-014-0135-9

Keywords

Navigation