Brain-peripheral cell crosstalk in white matter damage and repair.

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Biochim Biophys Acta. Author manuscript; available in PMC 2017 May 01. Published in final edited form as: Biochim Biophys Acta. 2016 May ; 1862(5): 901–908. doi:10.1016/j.bbadis.2015.08.006.

Brain-Peripheral Cell Crosstalk in White Matter Damage and Repair Kazuhide Hayakawa and Eng H. Lo Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA

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Abstract

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White matter damage is an important part of cerebrovascular disease and may be a significant contributing factor in vascular mechanisms of cognitive dysfunction and dementia. It is well accepted that white matter homeostasis involves multifactorial interactions between all cells in the axon-glia-vascular unit. But more recently, it has been proposed that beyond cell-cell signaling within the brain per se, dynamic crosstalk between brain and systemic responses such as circulating immune cells and stem/progenitor cells may also be important. In this review, we explore the hypothesis that peripheral cells contribute to damage and repair after white matter damage. Depending on timing, phenotype and context, monocyte/macrophage can possess both detrimental and beneficial effects on oligodendrogenesis and white matter remodeling. Endothelial progenitor cells (EPCs) can be activated after CNS injury and the response may also influence white matter repair process. These emerging findings support the hypothesis that peripheralderived cells can be both detrimental or beneficial in white matter pathology in cerebrovascular disease.

1. Introduction

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The pathophysiology of cerebrovascular disease is highly complex. Both acute as well as chronic responses after injury involve multifactorial interactions between all cells in the neurovascular unit, comprising neuronal, glial, and vascular compartments [1]. For the most part, the concept of the neurovascular unit is used to guide investigation in gray matter. However, cell-cell interactions are likely to be important in white matter as well. White matter is vulnerable to ischemic and oxidative stress and white matter damage is a clinically important part of cerebrovascular disease [2]. Perturbations in cell-cell signaling within white matter are now thought to play a significant role in vascular underpinnings of cognitive dysfunction and dementia. Therefore, rigorously investigating white matter

Corresponding author: Kazuhide Hayakawa, Neuroprotection Research Laboratory, MGH East 149-2401, Charlestown, MA 02129, USA. Tel: 617.724.4043. FAX: 617.726.7830. [email protected]. Or Eng H. Lo, Neuroprotection Research Laboratory, MGH East 149-2401, Charlestown, MA 02129, USA. Tel: 617.724.4043. FAX: 617.726.7830. [email protected] Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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mechanisms may be essential for finding ways to protect and recover the neurological function after cerebrovascular disease. The main components of white matter comprise the neuronal axon, oligodendrocytes (and associated myelin) and their precursors, astrocyte, microglia and endothelium. As in the neurovascular unit in gray matter, astrocytes and cerebral endothelial cells work together to maintain blood-brain barrier function in white matter [3]. Brain endothelium may interact with oligodendrocyte precursor cells (OPC) to promote migration [4, 5], and oligodendrocytes produce MMP-9 which may promote vascular remodeling [6] after white matter injury. This fundamental idea of the cell-cell trophic coupling is now well accepted in white matter.

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More recently, it has been proposed that beyond cell-cell signaling within the brain per se, dynamic crosstalk between brain and systemic responses such as circulating blood cells may also be important [7, 8]. After CNS injury or disease, peripherally circulating immune cells can across the disrupted BBB and influence neurovascular dysfunction and neuroinflammation [9]. Depending on context and timing, the systemic and local immune responses and inflammation have crucial roles in brain remodeling and functional recovery as well [10–12]. Particularly in CNS demyelinating disease, immune cell recruitment plays a significant role in both demyelination and remyelination process by breaking down myelin, cleaning myelin debris and dead cells [13]. Circulating progenitors/stem cells also influence white matter recovery after injury [14, 15]. In this review, we will focus on key findings that highlight the interactions between peripheral cells and brain which may influence both damage and repair in white matter during cerebrovascular disease.

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2. Upregulation of peripheral cell "attractants" in damaged brain Data from both experimental models and clinical studies suggest that brain cells produce cytokines, chemokines and adherent factors during the inflammatory process after CNS injury or disease. Chemokines are small, inducible, secreted, proinflammatory cytokines that act primarily as chemoattractants and activators of granulocytes, macrophages, and other inflammatory cells. Adherent factors produced by damaged endothelium regulate the attachment, rolling and migration of circulating blood cells (Figure 1). Here we introduce key mechanisms that underlie peripheral cell infiltration into the damaged brain via "attractants" after CNS injury. 2-1. CCL2 and the receptor CCR2

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Chemokines play a major role in selectively recruiting monocytes, neutrophils, and lymphocytes. Accumulating evidence suggest that CNS injury triggers immune responses leading to inflammatory cell activation and infiltration into cerebral parenchyma. Upregulation of a variety of chemokines can be detected and studies confirmed involvement of chemokine CCL2 (monocyte chemotactic protein-1: MCP-1) and its receptor CCR2 in white matter injury caused by stroke, multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) [16] and cognitive decline during early stages of Alzheimer's disease [17].

Biochim Biophys Acta. Author manuscript; available in PMC 2017 May 01.

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CCL2 (MCP-1) is a member of the C-C chemokine family, and a potent chemotactic factor for monocytes. MCP-1 is believed to be identical to JE, a gene whose expression is induced in mouse fibroblasts by platelet-derived growth factor [18]. However, the human homolog that has been best characterized as CCL2 was first purified from human cell lines on the basis of its monocyte chemoattractant properties. CCL2 is produced by many cell types, including endothelial cell, fibroblasts, epithelial cell, smooth muscle cell, mesangial cell, astrocyte, monocyte, microglia and oligodendrocyte [18] and regulates the migration and infiltration of monocytes, memory T lymphocytes, and natural killer (NK) cells. CCL2 binds to its receptor CCR2 to produce the effects, and, unlike CCL2, CCR2 expression is relatively restricted to certain types of cells. There are two alternatively spliced forms of CCR2 which are CCR2A and CCR2B [19]. CCR2A is the major isoform expressed by mononuclear cells and vascular smooth muscle cells [20], whereas monocytes and activated NK cells express predominantly the CCR2B isoform. It has been reported that CCR2 has bidirectional roles and induces both proinflammatory and anti-inflammatory signals. The proinflammatory role of CCR2 is dependent on APCs and T cells, whereas the anti-inflammatory role of CCR2 is dependent on CCR2 expression in regulatory T cells. These results suggest that CCL2/CCR2 signaling is important to modulate inflammatory response mediated by circulating blood immune cells after CNS injury. 2-2. High-mobility group box 1 (HMGB1)

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The biological processes that become triggered after cerebral ischemia are complex. Energy deprivation and excitotoxicity are the main causes of the initial tissue damage. In respond to initial injury, damage-associated molecular patterns (DAMPs) may be released into the extracellular micro-environment that amplify secondary processes of blood-brain barrier disruption, and post-ischemic inflammation [9]. HMGB1, a highly conserved non-histone nuclear DNA-binding protein, is widely expressed in most eukaryotic cells including neural cells in several animal species including humans [21]. HMGB1 can be passively released from damaged cells or actively secreted from stimulated cells including neurons, reactive astrocytes, endothelial cells, and activated microglia in the brain. Release of HMGB1 is observed after traumatic brain injury, white matter injury and ischemic stroke. In rodent middle cerebral artery occlusion models, levels of HMGB1 in the ischemic core are immediately decreased, and in turn, serum HMGB1 is rapidly increased [22, 23]. In clinical stroke patients, HMGB1 is upregulated in serum of up to day 7 after stroke onset [24]. HMGB1 is also increased in cerebrospinal fluid of subarachnoid hemorrhage patients on day 3, 7, and 14 after onset [24]. In addition, plasma HMGB1 in patients is acutely elevated 30 minutes after severe trauma in comparison to healthy subjects [25]. These findings suggest that HMGB1 is highly relevant to human CNS diseases.

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Extracellular HMGB1 can bind to its receptors and activate downstream pathway which leads to upregulation of cytokines and other pro-inflammatory molecules. Extracellular HMGB1 can act both as a chemoattractant for leukocytes and as a proinflammatory mediator to induce both recruited leukocytes through upregulation of TNFα, IL-1β, ICAM-1, VCAM-1, E-selectin and iNOS in different cell types [26]. HMGB1 may signal via its putative receptors such as receptor for advanced glycation end products (RAGE), tolllike receptor-2 (TLR2) and TLR4. RAGE expression usually is low under normal condition


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but enhanced expression of RAGE was observed in diabetic vasculature and other inflammatory diseases [27]. TLR2 and TLR4 have been shown to play a critical role in infectious diseases [28]. Higher constitutive expression levels of TLR4 have been found in brain regions that lack a tight BBB, such as the circumventricular organs and choroid plexus [29, 30]. Activation of HMGB1 receptors leads to activation of NF-κB and MAP kinase [31]. Blockade of either RAGE or TLR4 results in reduction of cytokine and nitric oxide production and decrease of inflammation [22, 28, 32], suggesting that HMGB1 potently contributes to induction of inflammation.

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Under some pathological conditions have also shown beneficial effect of HMGB1 in terms of its ability to recruit stem cells and promote their proliferation [33]. HMGB1 was found to enable endothelial progenitor cells to home to ischemic muscle in animal models of hind limb ischemia, transient focal cerebral ischemia and white matter injury induced by lysophosphatidylcholine (LPC) [34–36]. More recently, it was reported that endogenous HMGB1 was crucial for endothelial progenitor cells (EPCs) homing after ischemic insult [34, 35], suggesting that HMGB1 may have beneficial effects on tissue regeneration and remodeling via the recruitment of stem and progenitor cells [37]. 2-3. Adherent factors (selectins, cell adhesion molecules (CAMs), and integrins)


Inflammatory mechanisms involving leukocyte-brain endothelium adhesion after CNS injury or disease have been well studied. Three overall classes of adhesion molecules have been identified, comprising selectins, cell adhesion molecules (CAMs), and integrins. Selectins regulate the rolling of leukocytes, and both CAMs and integrins regulate firm adhesion and transmigration into the CNS. Among selectins, E-selectin is rapidly upregulated in endothelium stimulated by cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and attract neutrophils and monocytes [38]. P-selectin expresses in endothelium and is upregulated by thrombin and histamine [39]. L-selectin expresses in all leukocytes and is able to bind E-selectin and P-selectin. Selectin blockade may be a therapeutic strategy to prevent the progression of inflammation after CNS injury. For example, treatment with blocking antibody prepared against common P- and E- selectin epitopes reduces polymorphonuclear leukocyte (PMN) infiltration into ischemic cortex, reduced infarct volumes, improved neurological score, and improved ability to self-care in non-human primate after stroke [40]. Inhibition of E-selectin robustly attenuates histological white matter damage in concert with improvement of behavioral and memory deficits in vascular cognitive impairment model [41]. However, acute inhibition of P-selectin using monoclonal antibody resulted in decreased survival of treated animals after global ischemia [42]. And L-selectin inhibition did not show beneficial protective effect against experimental stroke in rabbit [43]. Taken together, these findings suggest that selectin mechanisms are complex and a nuanced approach maybe needed for therapeutic gain. CAMs, known as members of the immunoglobulin superfamily, include Intracellular adhesion molecule-1 (ICAM-1), Intracellular adhesion molecule-2 (ICAM-2), Vascular cell adhesion molecule-1(VCAM-1), Platelet-endothelial cell adhesion molecule-1 (PECAM-1) and Mucosal vascular addressin cell adhesion molecule 1 (MADCAM-1).


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CAMs express in brain endothelial cell and cause a stronger adherence of leukocytes to the brain endothelium than the selectins. ICAM-2 and PECAM-1 are continuously present on the cell membranes of endothelial cells and are not increased by cytokine stimulation [38]. ICAM-1 and VCAM-1 expressions are increased by cytokines such as TNF-α and IL-1β and lead to firm attachment of leukocytes and extravasation into brain parenchyma [44]. Recent study demonstrates that ICAM-1 and VCAM-1 are involved in the endothelial dysfunction and the subsequent white matter lesions after chronic cerebral hypoperfusion in rats. Treatment with anti-oxidant property clearly reduces both ICAM-1 and VCAM-1 along with reducing immunological infiltration and white matter lesion formation [45]. In addition to endothelial expression, VCAM-1 is also expressed by macrophage/microglia in MS lesions. VCAM-1 positive macrophage/microglia may be associated with oligodendrocyte loss, suggesting the possibility that the interaction is detrimental to oligodendrocyte survival [46].


After rolling of the leukocyte on the endothelial surface has arrested its flow, leukocyte integrins are activated by chemokines, chemoattractants, and cytokines. Integrins are transmembrane cell surface proteins. The CD18 or β2 integrins are restricted to leukocytes and bind to their counterreceptors of the immunoglobulin gene superfamily. They share a common β chain and 3 distinct α chains (CD11a, CD11b, or CD11c). Their surface expression is increased by agonists such as TNF-α and after adhesion to E-selectin. Leukocyte integrins are involved in the firm adherence of the leukocyte through binding to the endothelial Ig gene superfamily molecules. Leukocytes and monocytes also express the integrin α4β1 (very late antigen-4 [VLA-4], CD49d), which binds to VCAM-1 and to ligands from the subendothelial matrix. In animal study, blockade of integrins αL, αM, or α4 diminish the severity of experimental autoimmune encephalomyelitis [47, 48]. In a Phase II trial of patients with acute exacerbations of MS, α4 blockade, natalizumab, showed shortterm efficacy in relapsing-remitting MS [49]. Additionally, the humanized anti-β2 mAb, rovelizumab was shown to be safe, but demonstrated no clinical benefit for the recovery of neurological functioning [50]. Taken together, adhesion molecules may play a critical role in CNS diseases including white matter pathophysiology and targeting these molecules may provide therapeutic opportunity to lead to favorable outcome, although further investigation is warranted to optimize targeting and efficacy. 2-4. Stromal Derived Factor-1 (SDF-1)

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Chemokines, small pro-inflammatory chemoattractant cytokines, are major regulators of cell trafficking, cell survival and growth. Chemokines usually bind to multiple receptors, and the same receptor may bind to more than one chemokine. Interestingly, the α-chemokine stromal-derived factor (SDF)-1 has CXCR4 and CXCR7 as its receptors. SDF-1 is well known as a bone marrow stromal cell-derived chemoattractant and upregulated in the ischemic penumbra to regulate bone marrow cell homing [51]. More recently, it has been shown that SDF-1 signaling may also play a uniquely important biological role in myelin homeostasis in white matter. Oligodendrocyte precursor cells (OPCs) are essential for the assembly of myelin in the central nervous system via its migration, proliferation and differentiation into mature oligodendrocyte. Interestingly, OPCs express CXCR4 and SDF-1


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stimulation leads to intracellular Ca elevation along with promoting migration and differentiation [52]. In a mouse demyelination model induced by the copper chelator cuprizone, blockade of CXCR4 in OPCs results in decreased OPC differentiation and failure to remyelinate in the injured corpus callosum [53]. In addition to CXCR4 signaling pathway, CXCR7 may also have a role in OPC maturation and remyelination in the demyelinated adult CNS [54]. These findings suggest that SDF-1 signaling may be critical for remyelination and white matter repair through promoting OPC recruitment and differentiation.

3. Bidirectional crosstalk between peripheral cells and white matter

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Systemic immune responses may influence injury and recovery after both ischemia and hemorrhage [7, 8]. Changes in gene expression patterns in circulating blood cells may mirror stroke etiology [55, 56]. It is now well recognized that the peripheral and the nervous system are engaged in bi-directional crosstalk (Figure 2). In this section, we survey some basic principles that may underlie bi-directional crosstalk between the peripheral cell and damaged white matter. 3-1. Lymphocyte/leukocyte accumulation in damaged white matter

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Lymphocytes are key responders in white matter injury. Their actions are immune-cell specific and driven by a dynamic environment where early endothelium injury, axonal degeneration, and demyelination. In 1979, L-selectin was verified as a key adherent factor for interaction between lymphocytes and white matter regions of the CNS [57]. Other reports demonstrate that transgenic mice with a T cell receptor specific for myelin basic protein (MBP) exhibit rapid onset of paralysis and demyelination after immunization with an MBP peptide. When L-selectin is deficient, the mice fail to develop myelin damage along with no significant clinical outcome in experimental allergic encephalomyelitis [58]. However, whether L-selectin engagement of a myelin ligand is involved in this pathogenic process remains to be fully determined.

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As another interaction between leukocytes/lymphocytes and the damaged white matter, CD162 (P-selectin glycoprotein ligand-1; PSGL-1) and the receptor CD162R may be the therapeutic target. CD162 is expressed by most peripheral cells such as T cells, monocytes, granulocytes, and some B cells and CD162R is expressed by oligodendrocyte precursor cells [59]. CD162R acts as a trafficking and homing for leukocytes as it promotes cell tethering and rolling on endothelium at inflammation sites. Indeed, in a human MS study, it has shown that CD162 up-regulation enhanced migration of immune cells expressing alternative integrins other than CD49d (VLA-4) to subsequently adhere firmly to the endothelium and the blockade of CD162 completely abrogated subsequent firm adhesion [60]. Of great interest in here is whether CD162 on lymphocytes/leukocytes are attracted by CD162R expressing OPCs during the white matter inflammation/repair. 3-2. Bidirectional interaction between macrophages and oligodendrocytes One of major findings in neuroscience in the past decade is that adult mammalian brain can be surprisingly plastic after stroke and brain injury [1]. In the context of functional recovery,


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white matter connectivity may be especially crucial, and many cells and processes contribute to endogenous mechanisms that promote axonal recovery [61]. But white matter recovery is often incomplete because repair processes are also impaired by the development of inhibitory responses in glial cells. Current knowledge is mostly focused on the potential role of inhibitory matrix substrates such as chondroitin sulfate proteoglycans and NOGO [62, 63]. Beyond axonal growth and reconnections, remyelination should also be an essential component of white matter recovery. Myelin sheaths are generated by oligodendrocyte precursor cells (OPCs) that are capable of migrating into demyelinated areas to promote remyelination [64, 65]. But unlike the developing brain, OPCs are now moving into damaged tissue with a complex inflammatory milieu. How OPCs survive and respond in the inflammatory environment remains to be fully understood.


The concept of macrophage polarization toward different phenotype after CNS injury is increasingly well accepted [66, 67]. In general, macrophage phenotype can be characterized as classically activated pro-inflammatory macrophage (M1) or alternatively activated macrophage (M2). Intracellular signaling for macrophage activation have been extensively investigated. Phosphorylation of STAT1 mediated by interferon-gamma (IFN-γ) and activation of NF-κB induced by LPS/TLRs signaling are well established to polarize macrophages in pro-inflammatory M1 phenotype. In contrast, interleukin-4 (IL-4), IgG, interleukin-10 (IL-10), and M-CSF may promote M2 polarization through activation of STAT6, PI3K pathway, STAT3, and SP1, respectively [66, 67]. M1 macrophages induce secretion of proinflammatory cytokines such as TNF, IL-1β, IL-6, IL-12, or IL-23, and M2 macrophages produce IL-10, TGF-β, and PTX3. Additionally, CREB and C/EBPbeta cascade may contribute to M2 macrophage-specific gene expression [68]. Inflammatory microglia/macrophages promote secondary injury [69], whereas M2-like macrophages may participate to debris clean-up and remodeling [70], and M2-like microglia may promote oligodendrogenesis [71, 72]. Other report demonstrate that LPS did not affect cell survival of oligodendrocyte precursors, but microglial TLR4 activation by LPS caused oligodendrocyte precursor injury in vivo and in vitro [73]. Thus, understanding mechanism how to control the macrophage phenotype is quite important to promote white matter remodeling after CNS injury. 3-3. Glia and vascular/endothelial progenitor crosstalk for white matter repair

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Recently, it has been suggested that the gliovascular coupling may be important in white matter repair. For the most part, the concept of the cell-cell interaction in neuronal, glial, and vascular cells of neurovascular unit is used to guide investigation in gray matter. However, cell-cell trophic interactions are likely to be important in white matter as well. For example, brain endothelium-derived VEGF promotes OPC migration through focal adhesion kinase and reactive oxygen species-dependent mechanisms [4, 5]. After white matter injury, oligodendrocytes produced MMP-9 which may promote vascular remodeling [6], suggesting that crosstalk between oligodendroglia and vascular may play an important role in supporting white matter homeostasis.. Endothelial progenitor cells (EPC) are immature endothelial cells circulating in peripheral blood and are under maturation process to become endothelial cells [74]. EPCs are highly


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migratory and may be attracted to injured or diseased brain areas. Emerging data suggest that circulating endothelial progenitor cells (EPC) may have a critical role in white matter pathology. Indeed, low levels of circulating EPCs are associated with increased risk of agerelated white matter changes in stroke and cognitive impairment [75]. Therefore, dissecting the mechanisms for interactions between white matter and circulating blood cells may lead us novel approaches for treating white matter dysfunction in CNS disorders. In LPC-induced white matter injury model in mice, we found that Flk1 and CD34-double positive EPCs were accumulated in the damaged corpus callosum and HMGB1 produced by reactive astrocytes mediated the EPCs accumulation [36]. FACS analysis confirmed that accumulated EPCs strongly expressed brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF) [36]. In vitro, we confirmed that reactive astrocytes released HMGB1 that upregulated receptor for advanced glycation endproducts (RAGE) on brain endothelial cells, thus augmenting β2-integrin-mediated EPC adhesion and transmigration [76]. These findings may provide the basis for further investigating the crosstalk that exists between central white matter and peripheral responses after stroke, brain injury and neurodegeneration. However, mechanisms how the accumulated EPCs can contribute to white matter remodeling remain to be fully assessed. Do the accumulated EPCs directly contribute to vascular remodeling by differentiating mature endothelial cells? Or, do they modulate the local environment for the remodeling phase via secreting trophic factors? How glia-EPCs signaling regulate white matter remodeling requires further examination.

4. Cell-based therapy Author Manuscript

Systemically implanted stem/progenitor cells can follow the gradients of chemoattractants, including VCAM-1, SDF-1, HMGB1 and other cytokines that aid in the localization to the damaged CNS parenchyma (Figure 3). In this section, we discuss the potential mechanisms of cell-based therapy-induced white matter repair, which includes cell replacement, enhanced trophic/regenerative support from transplanted cells, immunomodulation, and stimulation of endogenous brain repair processes. 4-1. Mesenchymal stem cells (MSC)

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Mesenchymal stem cells (MSCs) are multipotent stromal cells that can differentiate into a variety of cell types such as bone, cartilage, adipocytes, and hematopoietic supporting tissues [77]. MSCs can produce many growth, trophic and immunomodulation factors including epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), SDF-1, CD47 and CD200 [78, 79]. MSC homing has been demonstrated to involve several important cell trafficking-related molecules such as chemokines, adhesion molecules, and matrix metalloproteinases (MMPs). In a rat myocardial infarction model, SDF-1 receptor, CXCR4 was transduced into MSCs to improve their in vivo engraftment and therapeutic efficacy [80]. The adhesion molecule P-selectin and the VCAM-1 (vascular cell adhesion protein 1) - VLA-4 (very late antigen-4) interaction has been shown to be key mediators in MSC rolling and firm adherence to endothelial cells in vitro and in vivo [81]. More recently, Biochim Biophys Acta. Author manuscript; available in PMC 2017 May 01.

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the VCAM-1 antibody coated MSCs showed a higher efficiency of engraftment in a mouse inflammatory bowel disease model [82], suggesting that the MSCs homing properties can be modified to enhance therapeutic effectiveness.

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The multipotent differentiation of MSCs together with the observed reparative effects of infused MSCs may afford promise in the treatment of white matter diseases. MSCs treatment clearly reduces the ischemic damage including corpus callosum [83, 84]. Interestingly, human umbilical cord matrix MSCs may be able to differentiate into oligodendroglial-like lineage cells [85]. MSCs also possess a specific immunological profile which is useful for immune-base therapies. MSCs are able to inhibit lymphocyte proliferation and modulate expression of both CD200 and CD200R on some T-cells [86]. MSCs-derived CD200 suppress TNF-α secretion and inflammatory responses in CD200R positive macrophages [87], suggesting that MSCs may provide therapeutic opportunities for cell replacement, trophic/regenerative support, and immunomodulation in white matter diseases. 4-2. Endothelial progenitor cell (EPC)

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EPCs have demonstrated therapeutic potential in a variety of vascular-related diseases [88]. After the infusion of ex vivo expanded human EPC, high numbers of EPCs could be detected in newly formed vessels in mice with ischemic limbs in accompanied with significant increased rates of blood flow recovery and capillary density [89]. In a rat model of myocardial infarction, donated human CD34 positive cells could be detected in newly formed capillaries [90]. HMGB1 may be a crucial factor for EPCs homing [34, 35]. The efficacy of EPCs transplantation is relevant in CNS diseases as well. In rat models of focal cerebral ischemia, administration of CD34 positive EPCs improve functional outcomes [91]. After traumatic brain injury, intravenous infusion of EPCs improved the white matter integrity and decrease capillary breakdown after traumatic brain injury [14]. More recent study demonstrate that EPCs treatment significantly increased the thickness of corpus callosum which may indicate axonal rewiring/reorganization along with enhanced cortical angiogenesis in a mouse model of ischemic stroke [92]. Interestingly, both soluble factors collected from EPCs and EPCs itself increased angiogenesis but only EPCs treatment could increase white matter track thickness, suggesting the requirement of cell-based interaction in addition to the effects of soluble factors in white matter reorganization. 4-3. Neural crest-derived stem cell (NCSC)

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The neural crest is a unique transient embryonic cell population and originate in the ectoderm at the margins of the neural tube and, after a phase of epithelial-mesenchymal transition and extensive migration, settle down in different parts of the body to contribute to the formation of a plethora of different tissues and organs. Recent findings have shown that trunk neural crest may be a source of mesenchymal stem cells and be able to produce mesenchymal derivatives [93]. Additionally, in vitro studies demonstrate the successful induction of mesenchymal lineage cells from neural crest cells [94]. More recently it has been demonstrated that neural crest stem cell progenitors persist in adult in differentiated tissues, the enteric nervous system of the gut, inferior turbinate and the whisker follicles of the facial skin [95, 96]. Adult bone marrow is also known to contain neural crest-derived


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stem cells [97], suggesting that the neural crest is an ideal source for multipotent adult stem cells. The therapeutic safety and efficacy have been reported. Transplanted human neural crest stem cells derived from the inferior turbinate into a perkinsonian rat model robust restoration of rotation behavior in accompanied with significant recovery of dopamine neurons within the substantia nigra [96]. iPSC-derived neural crest stem cells were mixed with hydrogel and transplanted into the injured spinal cord. Interestingly, transplanted cells survived and integrated, and differentiated into neuronal lineage in repaired spinal cord [98]. In addition, skin-derived precursors give rise to both neural and mesodermal cell types, and myelinated glial cells, Schwann cells, which may contribute to white matter repair of the injured or diseased nervous system [99], suggesting that neural crest-derived stem cells may be a novel candidate for cell-based therapy in CNS diseases including white matter injury.

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Although white matter damage is a key component of cerebrovascular disease and cognitive dysfunction, white matter mechanisms are relatively understudied compared to gray matter. The development of therapies for white matter protection is very challenging because beyond oligodendrocytes and their associated axonal compartments, many different cell types and their various inter-cellular signaling loops must be rescued. Furthermore, both beneficial and detrimental cells are recruited from circulating blood, so therapies must be able to regulate this balance of adaptive crosstalk between CNS and systemic mechanisms. Therapeutic strategies utilizing stem cells and their soluble factors can modulate immune cell activity and may provide opportunities to promote beneficial interactions between peripheral and CNS cells. Ultimately, a more nuanced approach may be needed in order to block acute damage induced by immune cells without interfering with beneficial endogenous mechanisms that lead to oligodendrogenesis and remyelination after CNS injury or disease.

References

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98. Saadai P, Wang A, Nout YS, Downing TL, Lofberg K, Beattie MS, Bresnahan JC, Li S, Farmer DL. Human induced pluripotent stem cell-derived neural crest stem cells integrate into the injured spinal cord in the fetal lamb model of myelomeningocele. J Pediatr Surg. 2013; 48:158–163. [PubMed: 23331809] 99. Biernaskie J, Miller FD. White matter repair: skin-derived precursors as a source of myelinating cells. Can J Neurol Sci. 2010; 37(Suppl 2):S34–S41. [PubMed: 21246933]

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Author Manuscript Author Manuscript Figure 1.

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Chemokines (CCL2, HMGB1, and SDF-1 etc) and adherent factors (selectins, CAMs, and integrins) are upregulated in the interface, whereby circulating peripheral cells are able to interact the damaged brain after CNS injury. Brain endothelium-derived adherent factors may also attract bone-marrow stem cells and endothelial progenitor cells (EPCs), suggesting that both pro-inflammatory and brain remodeling signals may simultaneously occur under pathological condition in CNS diseases.

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Author Manuscript Author Manuscript Author Manuscript Figure 2.

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Under pathological condition in white matter injury, peripheral cells including circulating T cells and monocytes may be recruited from the bloodstream. Oligodendrocyte-derived myelin basic protein (MBP) may increase T-cell accumulation through L-selectin. Oligodendrocyte dysfunction/damage and cytokines (TNF-α, GM-CSF) can activate peripheral-derived macrophage to produce pro-inflammatory cytokines and polarize in M1like phenotype. Some environmental factors (IL-4, IL-10, IgG, and M-CSF) may switch the phenotype toward anti-inflammatory phenotype (M2-like polarization). Furthermore, circulating EPCs may also migrate into the damaged brain and may promote OPC recruitment and differentiation into mature oligodendrocyte for remyelination.


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Author Manuscript Author Manuscript Figure 3.

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Strategy of cell–based therapies for CNS diseases including white matter injury. Brain damage induces the multiple cell death in neuron, astrocytes, oligodendrocytes, and endothelial cells in the cortex and subcortical regions. Stem and progenitor cells could be injected systemically for white matter protection/repair and modulation of inflammation. VCAM-1, SDF-1, and HMGB1 provide examples of how molecular regulation of these cell therapies may be critically important for optimizing these approaches for clinical utility.

Author Manuscript Biochim Biophys Acta. Author manuscript; available in PMC 2017 May 01.

White matter consequences of retinal receptor and ganglion cell damage.

White matter damage in dementia. Introduction.

White matter damage and systemic inflammation in obstructive sleep apnea.

White matter hypoperfusion and damage in dementia: post-mortem assessment.

White matter damage is related to ataxia severity in SCA3.

White matter damage in preterm newborns--an epidemiologic perspective.

Components of myelin damage and repair in the progression of white matter pathology after mild traumatic brain injury.

Oxidative Glial Cell Damage Associated with White Matter Lesions in the Aging Human Brain.

Dose-dependent white matter damage after brain radiotherapy.

Impaired cerebrovascular hemodynamics are associated with cerebral white matter damage.

Oligodendrocyte, Astrocyte, and Microglia Crosstalk in Myelin Development, Damage, and Repair.

Corrigendum: Oligodendrocyte, Astrocyte and Microglia Crosstalk in Myelin Development, Damage, and Repair.

Editorial: White blood cells matter in neonatal white-matter injury.

Crosstalk in glomerular injury and repair.

Crosstalk between BRCA-Fanconi anemia and mismatch repair pathways prevents MSH2-dependent aberrant DNA damage responses.

Retinal vessel alterations and cerebral white matter microstructural damage in obese adolescents with metabolic syndrome.

White matter tract damage in the behavioral variant of frontotemporal and corticobasal dementia syndromes.

Expression of ephrinB2 and EphB4 in a neonatal rat model of periventricular white matter damage.

The axon-glia unit in white matter stroke: mechanisms of damage and recovery.

White and gray matter damage in primary progressive MS: The chicken or the egg?

Association between peripheral oxidative stress and white matter damage in acute traumatic brain injury.

White Matter Damage Relates to Oxygen Saturation in Children With Sickle Cell Anemia Without Silent Cerebral Infarcts.

Facial affect recognition linked to damage in specific white matter tracts in traumatic brain injury.

Inhibition of NADPH oxidase activation reduces EAE-induced white matter damage in mice.