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Chinese Neurosurgical Journal

Open Access

Mesenchymal stem cell-based therapy for ischemic stroke

  • Johnathon D. Anderson1, 11Email author,
  • Missy T. Pham1,
  • Zelenia Contreras1,
  • Madeline Hoon1,
  • Kyle D. Fink1,
  • Henrik J. Johansson2,
  • Julien Rossignol3,
  • Gary L. Dunbar3,
  • Megan Showalter4,
  • Oliver Fiehn4, 5,
  • Charles S. Bramlett1,
  • Renee L. Bardini1,
  • Gerhard Bauer1,
  • Brian Fury1,
  • Kyle J. Hendrix1,
  • Frederic Chedin6,
  • Samir EL-Andaloussi7, 8, 9,
  • Billianna Hwang10,
  • Michael S. Mulligan10,
  • Janne Lehtiö2 and
  • Jan A. Nolta1
Chinese Neurosurgical Journal20162:36

https://doi.org/10.1186/s41016-016-0053-4

Received: 14 July 2016

Accepted: 12 September 2016

Published: 1 November 2016

Abstract

Ischemic stroke represents a major, worldwide health burden with increasing incidence. Patients affected by ischemic strokes currently have few clinically approved treatment options available. Most currently approved treatments for ischemic stroke have narrow therapeutic windows, severely limiting the number of patients able to be treated. Mesenchymal stem cells represent a promising novel treatment for ischemic stroke. Numerous studies have demonstrated that mesenchymal stem cells functionally improve outcomes in rodent models of ischemic stroke. Recent studies have also shown that exosomes secreted by mesenchymal stem cells mediate much of this effect. In the present review, we summarize the current literature on the use of mesenchymal stem cells to treat ischemic stroke. Further studies investigating the mechanisms underlying mesenchymal stem cells tissue healing effects are warranted and would be of benefit to the field.

Keywords

Mesenchymal stem cellsExosomesIschemic stroke

Background

Stroke is the second leading cause of death and its prevalence is increasing [1]. Stroke can be classified into two types, ischemic and hemorrhagic, of which the former comprises up to 80 % of all cases [2]. Ischemic stroke occurs when blood flow decreases in the cerebrum as a result of an obstruction, such as an embolism or thrombus [3]. Currently, the only approved treatment for ischemic stroke is tissue plasminogen activator (tPA) [4]. However, tPA has a narrow therapeutic window of only 4.5 h from the onset of symptom [5]. Consequently, most stroke patients don’t qualify for this treatment and would greatly benefit from the development of novel treatments that have an expanded therapeutic window [5].

Adult stem cell-based therapies, such as mesenchymal stem cells (MSCs) have emerged as a promising approach for the treatment of ischemic stroke [6]. MSCs are good candidates for the treatment of stroke as they are easily obtained and have a strong safety profile [7]. MSCs have demonstrated beneficial effects in improving functional outcome through mechanisms implicated in brain plasticity such as neurogenesis, axonal sprouting, and angiogenesis [6].

In this review, we summarize the current literature on MSCs and their potential use as a therapeutic in cases of ischemic stroke.

Review

Phenotype of MSCs

MSCs are adult multipotent cells which can differentiate into osteo, adipo and chondro lineages [8]. MSCs can be isolated from bone marrow, umbilical cord and adipose tissue [9]. MSCs express the mesenchymal markers CD105, CD90, and CD73 but express few HLA class I and no HLA class II molecules, allowing them to evade allogeneic immune response, making them well suited for allogenic use [10].

MSC mediate tissue healing in damaged organs including ischemic stroke, myocardial infarction and liver injury [11]. MSC activate endogenous cellular repair programs by releasing various secretory proteins such as fibroblast growth factor, epidermal growth factor, insulin-like growth factor and monocyte chemoattractant protein-1 [12]. MSCs have also been shown to induce angiogenesis and vascular remodeling via factors such as vascular endothelial growth factor, angiopoietins and hepatocyte growth factor [13]. Additionally, MSCs secrete IL-10, IL-6 and nitric oxide which induce a localized anti-inflammatory state, thereby facilitating the healing of damaged tissue [14].

Several studies demonstrate that small cellularly secreted vesicles called exosomes mediate much of MSCs’ tissue healing capabilities [1528]. MSC derived exosomes are internalized by target cells and transfer proteins, RNA, lipids and metabolites [29]. Our recent study determined that ex-vivo expanded MSCs substantially increase their secretion of exosomes upon exposure to in vivo-like conditions and that these exosomes contain a diverse profile of prosurvival and angiogenic proteins [30].

Studies have demonstrated that MSCs are immunomodulatory and are capable of reducing pathogenic inflammation [31]. MSCs can exert profound immunosuppression both in vitro and in vivo by inhibiting the proliferation of T-cells, natural killer cells, and dendritic cells [32]. MSC have also been reported to induce proliferation of immune suppressive Treg cells, at least in part by inducing the differentiation of monocytes towards resident M2 macrophages [33].

MSCs in the treatment of ischemic stroke

Ischemic stroke is a major cause of death and disability in the aged population [34]. During cerebral infarction, transplanted MSCs migrate to areas of damage and mediate tissue healing [35]. MSCs induce angiogenesis, neurogenesis and neurite outgrowth in the surrounding endogenous tissue through the secretion of neuroprotective factors [6, 24, 36]. MSC have generally been injected intracranially or intravascularly [6]. Some evidence suggests that intravascular MSC administration after stroke may be a viable alternative to intracranial transplantation, but more work in this area is needed before definitive statements can be made [37]. However, intravascular delivery may be better for larger lesions as it could lead to a wider distribution of transplanted cells around lesions than intracranial delivery, but also potentially dilutes out the therapeutic effect across a larger volume.

Numerous studies have reported favorable outcomes in immune-competent ischemic stroke rodent models upon treatment with MSCs (Table 1) [3857]. Many, but not all, of these studies reported MSCs reduced infarct size and induced functional recovery as reported by lessening of motor deficits or special learning as measured by the radial maze test [3857]. Many of these studies report a lowering of deficits as assessed by the composite modified neurological severity score (mNSS), while others demonstrated reduced inflammation and apoptosis, as well as increased neurite outgrowth and plasticity [3857]. Interestingly, recent studies have also determined that exosomes secreted by MSCs are capable of inducing functional recovery in models of ischemic stroke [24, 41, 47, 55, 58].
Table 1

Studies demonstrating the efficacy of MSC-based therapies for the treatment of ischemic stroke in rodent models

Author

Type of Cells

Stroke model

Delivery

Effect

Histology

Outcomes

Brenneman, M

BM-MSC (Rat)

CCAO/MCAO

24 h

Y

TCC, TUNEL, DAPI, Fluorescein

Decreased infarct

Chen J

BM-MSC (Rat)

MCAO

24 h

Y

H&E, Y chr, TUNEL

Increased rotarod, adhesive

Chen, JR

BM-MSCs (Rat)

MCAO

Immediate

Y

Nissel, GFAP, GalC, MAP2, Tuj1, BrdU

Decreased infarct

Doeppner TR

BM MSC & Exosomes (Human)

MCAO

Days 1,3,5

Y

cresyl violet, Neun, BrdU

Increase rotarod, tightrope

Goldmacher, GV

BM-MSCs (rat)

MCAO

Immediate

Y

TTC, HNA, GFAP, CD11

Decreased nMSS

Fernandez, M

Adipose-MSC (Human, Rat)

Permanent MCAO

30 mins

Y

H&E, TUNEL, GFAP. VEGF, SYP, DAPI

Decreased cell death

Honma, T

MCS-Telomerase (Human)

MCAO

12 h

Y

H&E, TTC. Beta-gal, NeuN, GFAP

Decreased infarct, inflammation

Koh, SH

UC-MSC (Human)

MCAO

2 weeks

Y

Neun, SNE, GFAP, nestin

Decreased nMSS

Li Y

BM-MSC (Human)

MCAO

1 day

Y

H&E, NeuN, MAP-2, GFAP, vWF, TUNEL

Decreased mNSS

Lim, JY

UC-MSC (Human)

MCAO

72 h

Y

TTC, NeuN, GFAP, DAPI, TUNEL

Decreased infarct

Liu, N

BM-MSC-SVV (Rat)

MCAO

26 h

Y

TCC, NeuN, GFP

Decreased infarct

Nomura, T

BM-MSC-BDNF (Human)

MCAO

6 h

Y

TCC, Beta-gal, NeuN, GFAP

Decreased infarct

Quittet MS

BM-MSC-PAM-VEGF (Rat)

MCAO

24 h

N

BrdU, NeuN, GFAP, CASP2, DCX, Ki67

No Difference

Wei, L

BM-MSC (Rat)

MCAO

24 h

Y

BrdU, NeuN, MAP2, GFAP, Tuj1, lba-1

Increased rotarod

Yamauchi T

BM-MSC (Human)

Permanent MCAO

7 days

Y

Tuj-1, NeuN, GFAP

Increased rotarod, radial maze

Yang C

BM-MSC-HIF1a (Rat)

MCAO

6 h

Y

TTC, CD105

Decreased infarct, nMSS

Toyoshima, A

BM-MSC (Rat)

MCAO

24 h

Y

DAPI, Q-Tracker, TCC

Decreased infarct, nMSS

Xin. H

BM-MSC (Rat)

MCAO

24 h

Y

BDA-DAB, NF-200, SYP

Decreased adhesive, foot-fault

Xin. H

BM-MSC (Mouse)

MCAO

24 h

Y

Nissl, Luxol, SYP, Apo-TAG

Increased neurites, plasticity

Lowrance, SA

BM-MSC (Rat)

MCAO

7 days

Y

Hoescht, GFAP

Decreased SORT

MSCs, their mechanism of action and safety profile

While not fully understood, postulated mechanisms of actions proposed to account for therapeutic effects of MSCs include cell replacement, growth factor secretion, and biobridge formation [59]. Stroke therapeutics have been categorized as ‘neuroprotective’ for the acute phase or ‘neuroregenerative’ for the subacute and chronic stages of stroke [59]. The acute treatment in stroke is relegated to tPA and other drugs that are designed to maintain structure and functionality of the blood vessels. The subacute (several hours to a few days) and chronic (several days, to weeks, months, and even years) phases are the targeted window for MSC transplant therapy. For the subacute phase, MSC transplantation has been shown to abrogate the early secondary cell death responses associated with stroke, such as dampening the oxidative stress, inflammation, mitochondrial impairment, and apoptosis [60]. On the other hand, MSC treatment in the chronic phase has been demonstrated to trigger brain remodeling via angiogenesis, vasculogenesis, neurogenesis, and synaptogenesis [61]. The minimally invasive intravenous or intra-arterial delivery of stem cells has been the preferred choice for the subacute phase due to an already injured brain produced by the primary ischemic insult, combined with chemoattractants that can guide migration of MSCs from the periphery to the brain. The direct intracerebral implantation of stem cells to the peri-infarct region is utilized for the chronic phase with the stroke brain more tolerant of an invasive treatment procedure, but also because of tapered levels of chemoattractants [62]. Direct transplantation was initially examined in chronic stroke patients using neural progenitor cells (NT2N) [63] and in recent years using Notch-induced bone marrow cells (SB-623) [64], with subsequent clinical trials employing intravenous and intra-arterial administration of MSCs in subacute stroke patients [65, 66].

Cell therapy for stroke has tested several types of transplantable cells in the laboratory, with a few reaching clinical trials, such as fetal cells, NT2N cells, CTX0E3, embryonic stem cells, neural stem/progenitor cells, umbilical cord blood, amnion, adipose, and induced pluripotent stem cells [6772]. Compared to these other stem cells, MSCs have established a solid safety profile in other disease indications, providing the basis for on-going clinical trials to explore MSCs and their cell subpopulations [73, 74]. As noted above, MSCs have been transplanted intracerebrally and peripherally [73, 7578], with encouraging pilot studies reporting safety, but efficacy remains to be fully assessed [74].

Translational challenges of MSC therapy for stroke

Recent clinical trials on transplantation of MSCs have shown their safety in stroke [75, 7981]. In addition to the small number of patients enrolled in these clinical trials, the translation of laboratory protocols for clinical transplant regimens has been marred with major discrepancies including the lack of well-defined release criteria of the donor cells, varying timing, cell dose and route of transplant intervention, altogether deviating from the established preclinical readouts. In particular, many of the clinical trials were not performed along the guidelines of Stem cell Therapeutics as an Emerging Paradigm for Stroke or STEPS lab-to-clinic translational guidelines [82]. The recommended translational research approach is to use at least two models of stroke using small animals (rodents). Any unanswered issues related to safety and efficacy, as well as insights into mechanisms of action, need to be pursued using a large animal model (non-human primates). A rigorous preclinical testing, as recommended by the STEPS guidelines will increase the likelihood of success of future clinical trials of MSC transplant therapy for stroke.

Conclusions

Although numerous studies have demonstrated that MSCs facilitate tissue healing and functional recovery in rodent models of ischemic stroke, several outstanding issues in the field warrant further investigation. The underlying mechanisms by which MSCs respond to their environmental niche upon injection healing is poorly understood [83]. MSCs generally have a relatively short half-life which limits their ability to heal damaged tissue [84]. A major goal for the field should be to develop strategies augment the half-life of MSCs upon injection into affected tissue [10]. Hypoxic preconditioning has garnered some beneficial effects in this regard, but more investigation is needed [8].

The molecular mechanisms underlying MSCs therapeutic effects are also poorly understood at present. More detailed mechanistic studies of MSCs’ therapeutics effects are warranted and sorely needed. These endeavors would be greatly rewarding in a field where more and more labs are attempting to genetically engineer MSCs with enhanced therapeutic profiles [9]. In addition, MSC secreted exosomes is a field that merits continued exploration, as the discovery of these vesicles has given us the profound insight that the sheer variety of communication signals MSC use to mediate tissue is likely orders of magnitudes higher than previously expected. Indeed, the field has only recently begun to investigate the protein, RNA, lipid and metabolite cargo exosomes transport from MSCs to neighboring cells.

Abbreviations

mNSS: 

Modified neurological severity score

MSCs: 

Mesenchymal stem cells

tPA: 

Tissue plasminogen activator

Declarations

Acknowledgement

The authors acknowledge the funding sources NIH Transformative R01GM099688, NSF GRFP 2011116000, NIH T32-GM008799, NSF GROW 201111600, NIH T32-HL086350, NIH U2DK097154.

Funding

The authors are supported by NIH Transformative R01GM099688, NSF GRFP 2011116000, NIH T32-GM008799, NSF GROW 201111600, NIH T32-HL086350, NIH U2DK097154.

Availability of data and materials

This paper is a review article. Referred literature in this paper has been listed in the references part. The datasets supporting the conclusions of this article are available online by searching the PubMed. Some original points in this article come from the laboratory and clinical practice in our research centers and the authors’ experiences.

Authors’ contributions

JDA: Conception and design, collection and/or assembly of data and interpretation, manuscript writing, final approval of manuscript; HJJ: Collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; CSG: manuscript writing, final approval of manuscript; MV Collection and/or assembly of data; MTP: Collection and/or assembly of data, final approval of manuscript; CSB: Collection and/or assembly of data, final approval of manuscript; MSM: Collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; RLB: Collection and/or assembly of data, data analysis and interpretation, final approval of manuscript; GB: Conception and design, manuscript writing, final approval of manuscript; KDF: Manuscript writing, final approval of manuscript; BF: Conception and design, manuscript writing, final approval of manuscript; FC: Conception and design, manuscript writing, final approval of manuscript; SEA: Conception and design, manuscript writing, final approval of manuscript JL: Financial support, manuscript writing, final approval of manuscript; JAN: Financial support, manuscript writing, final approval of manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

All authors approved the publication of this manuscript.

Ethics approval and consent to participate

Not applicable.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Internal Medicine, Stem Cell Program, University of California Davis
(2)
Department of Oncology-Pathology, Karolinska Institutet, Cancer Proteomics
(3)
College of Medicine, Central Michigan University
(4)
West Coast Metabolomics Center, University of California
(5)
Biochemistry Department, Faculty of Science, King Abdulaziz University
(6)
Department of Molecular and Cellular Biology, University of California Davis
(7)
Department of Laboratory Medicine, Karolinska Institutet
(8)
Department of Physiology, Anatomy and Genetics, University of Oxford
(9)
Department of Surgery, University of Washington
(10)
Department of Surgery, Center for Lung Biology, University of Washington
(11)
Institute for Regenerative Cures, University of California Davis Medical Center

References

  1. Thrift AG, Cadilhac DA, Thayabaranathan T, et al. Global stroke statistics. Int J Stroke. 2014;9:6–18.View ArticlePubMedGoogle Scholar
  2. Silver B, Lu M, Morris DC, et al. Blood pressure declines and less favorable outcomes in the NINDS tPA stroke study. J Neurol Sci. 2008;271:61–7.View ArticlePubMedPubMed CentralGoogle Scholar
  3. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016;133:e38–e360.View ArticlePubMedGoogle Scholar
  4. Sugg RM, Pary JK, Uchino K, et al. Argatroban tPA stroke study: study design and results in the first treated cohort. Arch Neurol. 2006;63:1057–62.View ArticlePubMedGoogle Scholar
  5. Keldahl ML, Eskandari MK. Timing of carotid surgery after acute stroke. Expert Rev Cardiovasc Ther. 2010;8:1399–403.View ArticlePubMedGoogle Scholar
  6. Vu Q, Xie K, Eckert M, et al. Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke. Neurology. 2014;82:1277–86.View ArticlePubMedPubMed CentralGoogle Scholar
  7. Chamorro A, Meisel A, Planas AM, et al. The immunology of acute stroke. Nat Rev Neurol. 2012;8:401–10.View ArticlePubMedGoogle Scholar
  8. Rosova I, Dao M, Capoccia B, et al. Hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells. Stem Cells. 2008;26:2173–82.View ArticlePubMedPubMed CentralGoogle Scholar
  9. Fierro FA, Kalomoiris S, Sondergaard CS, et al. Effects on proliferation and differentiation of multipotent bone marrow stromal cells engineered to express growth factors for combined cell and gene therapy. Stem Cells. 2011;29:1727–37.View ArticlePubMedPubMed CentralGoogle Scholar
  10. Meyerrose T, Olson S, Pontow S, et al. Mesenchymal stem cells for the sustained in vivo delivery of bioactive factors. Adv Drug Deliv Rev. 2010;62:1167–74.View ArticlePubMedGoogle Scholar
  11. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8:726–36.View ArticlePubMedGoogle Scholar
  12. Bronckaers A, Hilkens P, Martens W, et al. Mesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis. Pharmacol Ther. 2014;143:181–96.View ArticlePubMedGoogle Scholar
  13. Kwon HM, Hur SM, Park KY, et al. Multiple paracrine factors secreted by mesenchymal stem cells contribute to angiogenesis. Vascul Pharmacol. 2014;63:19–28.View ArticlePubMedGoogle Scholar
  14. Hu J, Zhang L, Wang N, et al. Mesenchymal stem cells attenuate ischemic acute kidney injury by inducing regulatory T cells through splenocyte interactions. Kidney Int. 2013;84:521–31.View ArticlePubMedPubMed CentralGoogle Scholar
  15. Zhang Y, Chopp M, Meng Y, et al. Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury. J Neurosurg. 2015;122:856–67.View ArticlePubMedPubMed CentralGoogle Scholar
  16. Chen TS, Arslan F, Yin Y, et al. Enabling a robust scalable manufacturing process for therapeutic exosomes through oncogenic immortalization of human ESC-derived MSCs. J Transl Med. 2011;9:47.View ArticlePubMedPubMed CentralGoogle Scholar
  17. Li T, Yan Y, Wang B, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev. 2013;22:845–54.View ArticlePubMedGoogle Scholar
  18. Tadokoro H, Umezu T, Ohyashiki K, et al. Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells. J Biol Chem. 2013;288:34343–51.View ArticlePubMedPubMed CentralGoogle Scholar
  19. Katsuda T, Tsuchiya R, Kosaka N, et al. Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Sci Rep. 2013;3:1197.View ArticlePubMedPubMed CentralGoogle Scholar
  20. Shabbir A, Cox A, Rodriguez-Menocal L, et al. Mesenchymal Stem Cell Exosomes Induce Proliferation and Migration of Normal and Chronic Wound Fibroblasts, and Enhance Angiogenesis In Vitro. Stem Cells Dev. 2015;24:1635–47.View ArticlePubMedPubMed CentralGoogle Scholar
  21. Arslan F, Lai RC, Smeets MB, et al. Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res. 2013;10:301–12.View ArticlePubMedGoogle Scholar
  22. Zhang B, Yin Y, Lai RC, et al. Mesenchymal stem cells secrete immunologically active exosomes. Stem Cells Dev. 2014;23:1233–44.View ArticlePubMedGoogle Scholar
  23. Kordelas L, Rebmann V, Ludwig AK, et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014;28:970–3.PubMedGoogle Scholar
  24. Xin H, Li Y, Cui Y, et al. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab. 2013;33:1711–5.View ArticlePubMedPubMed CentralGoogle Scholar
  25. Tomasoni S, Longaretti L, Rota C, et al. Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells Dev. 2013;22:772–80.View ArticlePubMedGoogle Scholar
  26. Lin SS, Zhu B, Guo ZK, et al. Bone marrow mesenchymal stem cell-derived microvesicles protect rat pheochromocytoma PC12 cells from glutamate-induced injury via a PI3K/Akt dependent pathway. Neurochem Res. 2014;39:922–31.View ArticlePubMedGoogle Scholar
  27. Bruno S, Grange C, Deregibus MC, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009;20:1053–67.View ArticlePubMedPubMed CentralGoogle Scholar
  28. Zhang HC, Liu XB, Huang S, et al. Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo. Stem Cells Dev. 2012;21:3289–97.View ArticlePubMedPubMed CentralGoogle Scholar
  29. Marcus ME, Leonard JN. FedExosomes: Engineering Therapeutic Biological Nanoparticles that Truly Deliver. Pharmaceuticals (Basel). 2013;6:659–80.View ArticleGoogle Scholar
  30. Anderson JD, Johansson HJ, Graham CS, et al. Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via NFkB Signaling. Stem Cells.Google Scholar
  31. Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol. 2012;12:383–96.View ArticlePubMedGoogle Scholar
  32. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32:252–60.View ArticlePubMedPubMed CentralGoogle Scholar
  33. Cho DI, Kim MR, Jeong HY, et al. Mesenchymal stem cells reciprocally regulate the M1/M2 balance in mouse bone marrow-derived macrophages. Exp Mol Med. 2014;46, e70.View ArticlePubMedPubMed CentralGoogle Scholar
  34. Koton S, Schneider AL, Rosamond WD, et al. Stroke incidence and mortality trends in US communities, 1987 to 2011. JAMA. 2014;312:259–68.View ArticlePubMedGoogle Scholar
  35. Lee SH, Jin KS, Bang OY, et al. Differential Migration of Mesenchymal Stem Cells to Ischemic Regions after Middle Cerebral Artery Occlusion in Rats. PLoS One. 2015;10, e0134920.View ArticlePubMedPubMed CentralGoogle Scholar
  36. Dulamea AO. The potential use of mesenchymal stem cells in stroke therapy--From bench to bedside. J Neurol Sci. 2015;352:1–11.View ArticlePubMedGoogle Scholar
  37. Rowart P, Erpicum P, Detry O, et al. Mesenchymal Stromal Cell Therapy in Ischemia/Reperfusion Injury. J Immunol Res. 2015;2015:602597.View ArticlePubMedPubMed CentralGoogle Scholar
  38. Brenneman M, Sharma S, Harting M, et al. Autologous bone marrow mononuclear cells enhance recovery after acute ischemic stroke in young and middle-aged rats. J Cereb Blood Flow Metab. 2010;30:140–9.View ArticlePubMedGoogle Scholar
  39. Chen J, Li Y, Katakowski M, et al. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res. 2003;73:778–86.View ArticlePubMedGoogle Scholar
  40. Chen JR, Cheng GY, Sheu CC, et al. Transplanted bone marrow stromal cells migrate, differentiate and improve motor function in rats with experimentally induced cerebral stroke. J Anat. 2008;213:249–58.View ArticlePubMedPubMed CentralGoogle Scholar
  41. Doeppner TR, Herz J, Gorgens A, et al. Extracellular Vesicles Improve Post-Stroke Neuroregeneration and Prevent Postischemic Immunosuppression. Stem Cells Transl Med. 2015;4:1131–43.View ArticlePubMedPubMed CentralGoogle Scholar
  42. Goldmacher GV, Nasser R, Lee DY, et al. Tracking transplanted bone marrow stem cells and their effects in the rat MCAO stroke model. PLoS One. 2013;8, e60049.View ArticlePubMedPubMed CentralGoogle Scholar
  43. Gutierrez-Fernandez M, Rodriguez-Frutos B, Ramos-Cejudo J, et al. Comparison between xenogeneic and allogeneic adipose mesenchymal stem cells in the treatment of acute cerebral infarct: proof of concept in rats. J Transl Med. 2015;13:46.View ArticlePubMedPubMed CentralGoogle Scholar
  44. Honma T, Honmou O, Iihoshi S, et al. Intravenous infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Exp Neurol. 2006;199:56–66.View ArticlePubMedGoogle Scholar
  45. Koh SH, Kim KS, Choi MR, et al. Implantation of human umbilical cord-derived mesenchymal stem cells as a neuroprotective therapy for ischemic stroke in rats. Brain Res. 2008;1229:233–48.View ArticlePubMedGoogle Scholar
  46. Li Y, Chen J, Chen XG, et al. Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology. 2002;59:514–23.View ArticlePubMedGoogle Scholar
  47. Lim JY, Jeong CH, Jun JA, et al. Therapeutic effects of human umbilical cord blood-derived mesenchymal stem cells after intrathecal administration by lumbar puncture in a rat model of cerebral ischemia. Stem Cell Res Ther. 2011;2:38.View ArticlePubMedPubMed CentralGoogle Scholar
  48. Liu N, Zhang Y, Fan L, et al. Effects of transplantation with bone marrow-derived mesenchymal stem cells modified by Survivin on experimental stroke in rats. J Transl Med. 2011;9:105.View ArticlePubMedPubMed CentralGoogle Scholar
  49. Nomura T, Honmou O, Harada K, et al. I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Neuroscience. 2005;136:161–9.View ArticlePubMedPubMed CentralGoogle Scholar
  50. Quittet MS, Touzani O, Sindji L, et al. Effects of mesenchymal stem cell therapy, in association with pharmacologically active microcarriers releasing VEGF, in an ischaemic stroke model in the rat. Acta Biomater. 2015;15:77–88.View ArticlePubMedGoogle Scholar
  51. Wei L, Fraser JL, Lu ZY, et al. Transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats. Neurobiol Dis. 2012;46:635–45.View ArticlePubMedPubMed CentralGoogle Scholar
  52. Yamauchi T, Kuroda Y, Morita T, et al. Therapeutic effects of human multilineage-differentiating stress enduring (MUSE) cell transplantation into infarct brain of mice. PLoS One. 2015;10, e0116009.View ArticlePubMedPubMed CentralGoogle Scholar
  53. Yang C, Liu H, Liu D. Mutant hypoxia-inducible factor 1alpha modified bone marrow mesenchymal stem cells ameliorate cerebral ischemia. Int J Mol Med. 2014;34:1622–8.PubMedGoogle Scholar
  54. Toyoshima A, Yasuhara T, Kameda M, et al. Intra-Arterial Transplantation of Allogeneic Mesenchymal Stem Cells Mounts Neuroprotective Effects in a Transient Ischemic Stroke Model in Rats: Analyses of Therapeutic Time Window and Its Mechanisms. PLoS One. 2015;10, e0127302.View ArticlePubMedPubMed CentralGoogle Scholar
  55. Xin H, Li Y, Liu Z, et al. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells. 2013;31:2737–46.View ArticlePubMedPubMed CentralGoogle Scholar
  56. Xin H, Li Y, Shen LH, et al. Increasing tPA activity in astrocytes induced by multipotent mesenchymal stromal cells facilitate neurite outgrowth after stroke in the mouse. PLoS One. 2010;5, e9027.View ArticlePubMedPubMed CentralGoogle Scholar
  57. Lowrance SA, Fink KD, Crane A, et al. Bone-marrow-derived mesenchymal stem cells attenuate cognitive deficits in an endothelin-1 rat model of stroke. Restor Neurol Neurosci. 2015;33:579–88.View ArticlePubMedGoogle Scholar
  58. Xin H, Li Y, Chopp M. Exosomes/miRNAs as mediating cell-based therapy of stroke. Front Cell Neurosci. 2014;8:377.View ArticlePubMedPubMed CentralGoogle Scholar
  59. Borlongan CV. Age of PISCES. Lancet. 2016; In press.Google Scholar
  60. Kasahara Y, Yamahara K, Soma T, Stern DM, Nakagomi T, Matsuyama T, Taguchi A. Transplantation of hematopoietic stem cells: intra-arterial versus intravenous administration impacts stroke outcomes in a murine model. Transl Res. 2016. doi: 10.1016/j.trsl.2016.04.003. [Epub ahead of print]
  61. 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. Transplanted stem cell-secreted vascular endothelial growth factor effects poststroke recovery, inflammation, and vascular repair. Stem Cells. 2011;29(2):274–85. doi:10.1002/stem.584. PubMed PMID: 21732485, PubMed Central PMCID: PMC3524414.View ArticlePubMedGoogle Scholar
  62. Reyes S, Tajiri N, Borlongan CV. Developments in intracerebral stem cell grafts. Expert Rev Neurother. 2015;15(4):381–93. doi:10.1586/14737175.2015.1021787. PubMed PMID: 25739415, PubMed Central PMCID: PMC4681443, Epub 2015 Mar 5. Review.View ArticlePubMedPubMed CentralGoogle Scholar
  63. Kondziolka D, Wechsler L, Goldstein S, Meltzer C, Thulborn KR, Gebel J, Jannetta P, DeCesare S, Elder EM, McGrogan M, Reitman MA, Bynum L. Transplantation of cultured human neuronal cells for patients with stroke. Neurology. 2000;55(4):565–9.View ArticlePubMedGoogle Scholar
  64. Steinberg GK, Kondziolka D, Wechsler LR, Lunsford LD, Coburn ML, Billigen JB, Kim AS, Johnson JN, Bates D, King B, Case C, McGrogan M, Yankee EW, Schwartz NE. Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study. Stroke. 2016;47(7):1817–24. doi:10.1161/STROKEAHA.116.012995. Epub 2016 Jun 2.View ArticlePubMedGoogle Scholar
  65. Savitz SI, Misra V, Kasam M, Juneja H, Cox Jr CS, Alderman S, Aisiku I, Kar S, Gee A, Grotta JC. Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Ann Neurol. 2011;70(1):59–69. doi:10.1002/ana.22458.View ArticlePubMedGoogle Scholar
  66. Hess DC, Sila CA, Furlan AJ, Wechsler LR, Switzer JA, Mays RW. A double-blind placebo-controlled clinical evaluation of MultiStem for the treatment of ischemic stroke. Int J Stroke. 2014;9(3):381–6. doi:10.1111/ijs.12065. Epub 2013 May 22.View ArticlePubMedGoogle Scholar
  67. Stroemer P, Patel S, Hope A, Oliveira C, Pollock K, Sinden J. The neural stem cell line CTX0E03 promotes behavioral recovery and endogenous neurogenesis after experimental stroke in a dose-dependent fashion. Neurorehabil Neural Repair. 2009;23:895–909.View ArticlePubMedGoogle Scholar
  68. De La Pena I, Sanberg PR, Acosta S, Lin SZ, Borlongan CV. G-CSF as an adjunctive therapy with umbilical cord blood cell transplantation for traumatic brain injury. Cell Transplant. 2015;24:447–57.View ArticleGoogle Scholar
  69. Hara K, Yasuhara T, Maki M, Matsukawa N, Masuda T, Yu SJ, et al. Neural progenitor NT2N cell lines from teratocarcinoma for transplantation therapy in stroke. Prog Neurobiol. 2008;85:318–34.View ArticlePubMedGoogle Scholar
  70. Kaneko Y, Hayashi T, Yu S, Tajiri N, Bae EC, Solomita MA, et al. Human amniotic epithelial cells express melatonin receptor MT1, but not melatonin receptor MT2: a new perspective to neuroprotection. J Pineal Res. 2011;50:272–80.View ArticlePubMedGoogle Scholar
  71. Liu SP, Fu RH, Wu DC, Hsu CY, Chang CH, Lee W, et al. Mouse-induced pluripotent stem cells generated under hypoxic conditions in the absence of viral infection and oncogenic factors and used for ischemic stroke therapy. Stem Cells Dev. 2014;23:421–33.View ArticlePubMedGoogle Scholar
  72. Li Z, McKercher SR, Cui J, Nie Z, Soussou W, Roberts AJ, et al. Myocyte enhancer factor 2C as a neurogenic and antiapoptotic transcription factor in murine embryonic stem cells. J Neurosci. 2008;28:6557–68.View ArticlePubMedPubMed CentralGoogle Scholar
  73. Borlongan CV, Glover LE, Tajiri N, Kaneko Y, Freeman TB. The great migration of bone marrow-derived stem cells toward the ischemic brain: therapeutic implications for stroke and other neurological disorders. Prog Neurobiol. 2011;95:213–28.View ArticlePubMedPubMed CentralGoogle Scholar
  74. Steinberg GK, Kondziolka D, Wechsler LR, Lunsford LD, Coburn ML, Billigen JB, et al. Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study. Stroke. 2016;47:1817–24.View ArticlePubMedGoogle Scholar
  75. Prasad K, Sharma A, Garg A, Mohanty S, Bhatnagar S, Johri S, et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial. Stroke. 2014;45:3618–24.View ArticlePubMedGoogle Scholar
  76. Borlongan CV. Bone marrow stem cell mobilization in stroke: a ‘bonehead’ may be good after all! Leukemia. 2011;25:1674–86.View ArticlePubMedPubMed CentralGoogle Scholar
  77. Borlongan CV, Lind JG, Dillon-Carter O, Yu G, Hadman M, Cheng C, et al. Intracerebral xenografts of mouse bone marrow cells in adult rats facilitate restoration of cerebral blood flow and blood-brain barrier. Brain Res. 2004;1009:26–33.View ArticlePubMedGoogle Scholar
  78. 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;46:2616–27.View ArticlePubMedPubMed CentralGoogle Scholar
  79. Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005;57:874–82.View ArticlePubMedGoogle Scholar
  80. Savitz SI, Misra V, Kasam M, Juneja H, Cox Jr CS, Alderman S, et al. Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Ann Neurol. 2011;70:59–69.View ArticlePubMedGoogle Scholar
  81. Banerjee S, Bentley P, Hamady M, Marley S, Davis J, Shlebak A, et al. Intra-Arterial Immunoselected CD34+ Stem Cells for Acute Ischemic Stroke. Stem Cells Transl Med. 2014;3:1322–30.View ArticlePubMedPubMed CentralGoogle Scholar
  82. Diamandis T, Borlongan CV. One, two, three steps toward cell therapy for stroke. Stroke. 2015;46:588–91.View ArticlePubMedGoogle Scholar
  83. Prockop DJ, Prockop SE, Bertoncello I. Are clinical trials with mesenchymal stem/progenitor cells too far ahead of the science? Lessons from experimental hematology. Stem Cells. 2014;32:3055–61.View ArticlePubMedPubMed CentralGoogle Scholar
  84. Beegle J, Lakatos K, Kalomoiris S, et al. Hypoxic Preconditioning of Mesenchymal Stromal Cells Induces Metabolic Changes, Enhances Survival and Promotes Cell Retention in Vivo. Stem Cells. 2015;14:919-24.Google Scholar

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