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Immunomodulation by Stem Cells and Hematopoietic Growth Factors for Neurorestoration

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6 Copyright © 2012 The Korean Society of Vascular Neurology

Introduction

Immune responses in injured brain are complex, but should not be ignored when it comes to repair strategies involving cel- lular transplants or pharmacologic treatments. The immune re- sponses are regulated depending on several factors.1 For exam- ple, in response to a transplant, lymphocytes are activated, pro- liferate, and then enter the blood circulation. The brain endo- thelium can express a number of these homing signals, under the control of transcription factors that respond to inflamma- tory stimulus. Pro-inflammatory cytokines such as tumor ne- crosis factor-α (TNF-α), interleukin-1 (IL-1), and nitric oxide in- duce expression of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 which are crucial for the en- try of cells to the central nervous system.2 Notably, inflamma- tory cytokines such as IL-1β, IL-6 and TNF-α can be produced by microglia and astrocytes, and can consort to increase blood- brain barrier (BBB) permeability.3 Physiological and pathologi- cal changes in the activity of glial cell populations can also we- aken BBB integrity.3 After transplants in brain, the rejection pro-

cess has both a cellular and humoral component.4,5 The key cellular mediators of graft rejection being the T lymphocytes (CD4+ and CD8+) and microglial cells.6 However, certain types of stem cells, especially mesenchymal stem cells (MSCs) and neural stem cells (NSCs) or neural precursor cells (NPCs) might also have immunomodatory effects in the injured brain. Thus, the immune response to grafted tissue is complex, but is de- pendent on a number of variables, which include the phyloge- netic relationship of donor tissue to host and its composition and mode of implantation.1

Stem Cell Transplantation

The immunology of grafted stem cells has not been exten- sively studied in depth.7 When grafting tissue of different im- munological disparity, there is local cytokine production that may affect the stability of stem cells.8 It is predicted that rejec- tion will occur with many different types of stem cells, espe- cially embryonic stem cells and non-NSCs.1 However, recent evidence shows that transplantation of NSCs or NPCs might

REVIEW ARTICLE

Vascular Neurology 2012;4:6-9 ISSN 2092-6855

Immunomodulation by Stem Cells and Hematopoietic Growth Factors for Neurorestoration

Ji-Hye Yu,1,2,3 Sung-Rae Cho1,2,3

1Department & Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea

2Clinical Research Center, Yonsei University Health System, Seoul, Korea

3Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, Korea

Received October 10, 2012 Revised October 23, 2012 Accepted October 28, 2012 Correspondence Sung-Rae Cho, MD, PhD Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea Tel +82-2-2228-3715 Fax +82-2-363-2795 E-mail srcho918@yuhs.ac

The immune response to grafted tissue is complex, but is dependent on a number of variables, which include the phylogenetic relationship of donor tissue to host and its composition and mode of implantation. After transplants in brain, the rejection process has both a cellular and humoral component. However, certain types of stem cells, especially mesenchymal stem cells and neural stem cells or neural precursor cells might also have immunomodatory effects in the injured brain.

They can release soluble molecules such as cytokines and chemokines and express immune-rele- vant receptors such as chemokine receptors and cell adhesion molecules, which are able to pro- foundly change inflammatory environments. Granulocyte-colony stimulating factor (G-CSF) has immunomodulatory effects. In vivo administration of G-CSF in both animal models and humans has concordantly shown immunomodulatory effects such as suppressing the production of pro- inflammatory cytokines in peripheral blood mononuclear cells, inducing tolerant dendritic cells, and enhancing interleukin-4 but reducing interferon and production in lymphocytes. Erythropoi- etin (EPO) has emerged as an exciting potential strategy for immune system modulation. Both EPO-receptor structure and its presence on leukocytes indicated that beyond erythropoietic func- tion, suggesting that EPO might possess some immunomodulatory properties.

Vascular Neurology 2012;4:6-9 Key Wordsaa Immunomodulation, Mesenchymal stem cell, Neural stem cell, Neural precursor cell,

Erythropoietin, Granulocyte-colony stimulating factor.

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JH Yu, et al.

7 be therapeutically efficacious through a bystander immuno-

modulation mechanism alternative to cell replacement.9 They can release soluble molecules such as cytokines and chemo- kines and express immune-relevant receptors such as chemo- kine receptors and cell adhesion molecules, which are able to profoundly change inflammatory environments.9-11 On the oth- er hand, transplanted NPCs might induce apoptosis of inflam- matory T lymphocytes by upregulating membrane expression of certain death receptor ligands such as Fas ligand, TNF-related apoptosis-inducing ligand (TRAIL) and Apo3 ligand, as has re- cently been shown in vitro and in mice with experimental auto- immune encephalomyelitis.12 This NPC-mediated mechanism is triggered by pro-inflammatory cytokines such as IFNγ, IL- 1β and TNFα, but not anti-inflammatory cytokines such as IL- 4, IL-5 and IL-13. Transplanted NPCs can specifically down- regulate effector functions of inflammatory T cells and macro- phages in the target tissue.9 In animal models of stroke, NSCs decreased infiltration of mononuclear cells at lesion borders of ischemic areas in the brain.13,14 MSCs are particularly attractive for clinical therapy not only due to their ability to differentiate into various cell types, but also for their immunosuppressive properties.15 Recent reports that most of the genes down-regu- lated by MSCs were involved in inflammatory and immune re- sponses.16 So a major effect of human MSCs was to modulate inflammatory and immune reactions to the ischemic environ- ment. The effects of MSCs mediated through microglia and/or macrophages are consistent with indications that both microg- lia and macrophages can be alternatively activated to play con- trasting roles in response to injury.16 While MSCs transplanted into rodents protected against neuronal injury and reduced the neuronal death after permanent or transient focal ischemia,17-21 the MSCs produce anti-immune or immune-suppressive re- sponses consistent with numerous reports that the cells have similar effects in culture, in animal disease models, and in pa- tients with graft-versus-host disease.22,23

Hematopoietic Growth Factor Treatment

Granulocyte-colony stimulating factor (G-CSF) has immu- nomodulatory effects.24 When exogenously administered to human patients or animals, G-CSF has been shown to have a role in maintaining local immune homeostasis in tissues. G-CSF also acts on neutrophils to enhance their maturation process, survival, and effector function such as phagocytosis, bacterici- dal activity, antibody-dependent cellular toxicity, and cytokine production.25 In addition to its immunostimulatory effects on neutrophils, G-CSF has direct and indirect immunomodulatory effects on other immune cells. In vivo administration of G-CSF in both animal models and humans has concordantly shown immunomodulatory effects such as suppressing the produc- tion of pro-inflammatory cytokines in peripheral blood mono-

nuclear cells, inducing tolerant dendritic cells (DCs), and en- hancing IL-4 but reducing interferon and production in lym- phocytes.26 In vitro, G-CSF inhibits TLR-induced inflammatory cytokine production such as TNFα, IL-12, and IL-8 in mono- cytes/macrophages27-29 and neutrophils.30 Injection of G-CSF into human patients and volunteers leads to the mobilization of type 2 DCs that induce IL-4 and IL-10 expression from T cells, probably through increased serum IL-10 in G-CSF-injected individuals.31,32 As with the well-studied anti-inflammatory cy- tokine IL-10, one key component of G-CSF signaling is STAT3.

The activation of STAT3 in macrophages is important for the down-regulation of LPS-induced TNFα by G-CSF.33 STAT3 activated by G-CSF blocks LPS- or E.coli-induced cJun N-ter- minal kinase activation, which is involved in the suppression of TNFα production in macrophages.29

Erythropoietin (EPO) has emerged as an exciting potential strategy for immune system modulation.34 EPO limits leuko- cyte inflammation,35 prevents transplant cell loss, fosters angio- genesis,36 blocks the progression of ulcers in scleroderma,37 and educes renal inflammation during injury.38 It is also effective against experimental models of arthritis,39 limits immune me- diated fibrosis,40 protects against pancreatic inflammation,41 and may be effective against cell injury during demyelinating dis- ease.42 At the cellular level, EPO is protective against TNFα- induced apoptosis,43 blocks IL-6 and CXCR4 cytokine gene ex- pression,44 controls pro-inflammatory mediators,45 governs mi- croglial activation and proliferation,46 and prevents the disposal of functional cells targeted by phosphatidylserine exposure.47 Re- ceptor for erythropoietin (EPO-R) has been found in other tis- sues and cells apart from erythroid cells, including neurons, en- dothelial cells, some solid tumor cells and various types of renal cells, but also polymorphonuclear leukocytes.48 Both EPO-R structure and its presence on leukocytes indicated that beyond erythropoietic function, suggesting that EPO might possess some immunomodulatory properties.49

Conclusion

The evidence reviewed in this article challenges the view that transplantation of NSCs or NPCs might be therapeutically effi- cacious through the immunomodulation mechanism alterna- tive to cell replacement and the effects of MSCs on microglia and/or macrophages are consistent with indications that mi- croglia and/or macrophages can be alternatively activated to play contrasting roles in response to injury. G-CSF and EPO have been shown to have a role in maintaining local immune ho- meostasis in tissues, and they have emerged as an exciting po- tential strategy for immune system modulation.

Acknowledgments

This study was supported by grants from National Research Foundation (NRF-2010-0020408; 2010-0024334) funded by the Ministry of Science and Technology, Republic of Korea.

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Immunomodulation by Stem Cells and Growth Factors

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