• Users Online: 880
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

   Table of Contents      
Year : 2018  |  Volume : 4  |  Issue : 3  |  Page : 118-123

White-matter repair: Interaction between oligodendrocytes and the neurovascular unit

Department of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA

Date of Submission24-Jul-2018
Date of Acceptance10-Sep-2018
Date of Web Publication09-Oct-2018

Correspondence Address:
Dr. Ken Arai
Department of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bc.bc_15_18

Rights and Permissions

There are currently no adequate treatments for white-matter injury, which often follows central nervous system maladies and their accompanying neurodegenerative processes. Indeed, the white matter is compromised by the deterioration of the blood–brain barrier and the demyelination of neuronal axons. Key repairs to the white matter are mediated by oligodendrocyte lineage cells after damaging events. Oligodendrocytes are supported by other cells in the neurovascular unit and these cells collaborate in processes such as angiogenesis, neurogenesis, and oligodendrogenesis. Understanding the various interactions between these cells and oligodendrocytes will be imperative for developing reparative therapies for impaired white matter. This minireview will discuss how oligodendrocytes and oligodendrocyte lineage cells mend damage to the white matter and restore brain function ensuing neural injury.

Keywords: Myelination, neurovascular unit, oligodendrocyte, oligodendrocyte precursor cell, white-matter repair

How to cite this article:
Hamanaka G, Ohtomo R, Takase H, Lok J, Arai K. White-matter repair: Interaction between oligodendrocytes and the neurovascular unit. Brain Circ 2018;4:118-23

How to cite this URL:
Hamanaka G, Ohtomo R, Takase H, Lok J, Arai K. White-matter repair: Interaction between oligodendrocytes and the neurovascular unit. Brain Circ [serial online] 2018 [cited 2022 Oct 2];4:118-23. Available from: http://www.braincirculation.org/text.asp?2018/4/3/118/242904

  Introduction Top

To better comprehend stroke pathology, the notion of the neurovascular unit (NVU) was created which encompasses how various cell types communicate to mediate regular brain processes.[1],[2] The idea of the NVU has been connected to central nervous system (CNS) diseases and the corresponding injury and recovery phases, and how glial cells play a role in neurodegeneration, advancing the initial concept of the NVU as the interplay between gray matter neurons in stroke's acute stage.

With their ability to generate myelin sheaths composed of hydrophobic membranes, oligodendrocytes in the white matter facilitate the saltatory conduction that propagates nerve signals and is necessary for neuronal communication. The initial construction of the nervous system and healing white matter postinjury especially require proper oligodendrocyte myelination. Oligodendrocytes and their lineage cells are implicated in ameliorating white-matter damage, though the precise mechanisms are uncertain. Here, we discuss how oligodendrocytes function in neurogenesis, angiogenesis, and oligodendrogenesis, and interact with other NVU-associated cells.

  Neurons and Oligodendrocytes Top

By devastating cortical neurons and stymieing action potential conduction in the axons of connecting neurons, CNS injuries including trauma, neurodegenerative diseases, and stroke may impair neural networks. Inhibiting signal transduction can exacerbate axon damage by increasing white-matter levels of calcium ions and neurotransmitters, which demyelinates the surrounding neurons, kills oligodendrocytes, and incapacitates axons.[3],[4] Oligodendrocytes are centralized near neuronal axons to support them through various means such as by supplying glucose, as evidenced by electromyography (EMG) studies involving the corpus callosum, which may implicate the oligodendrocytes' ability to preserve neurons during ischemic stroke and other situations with minimal glucose.[5] Neurons can also aid oligodendrocytes such as by secreting growth factors such as neuregulin, which mitigates injury-induced damage to the CNS[6],[7] and boosts oligodendrocyte myelin production,[8] and releasing neurotransmitters that enable oligodendrocyte lineage cells to proliferate, migrate, and differentiate.[9],[10],[11],[12],[13] Subjecting mice to ischemic stress reduces oligodendrocytes and myelin, demonstrating that neural injuries interfere with the mutual benefits between neurons and oligodendrocytes.[14] Additional interactions between the two cell types during disease states are further implicated, as damage to the white matter is abated by preemptively adding a GluN2C/D-negative allosteric modulator incorporating N-methyl-D-aspartate (NMDA) glutamate receptors.

Damage to neuronal axons and myelin sheaths triggers the proliferation, migration, and differentiation of oligodendrocyte precursor cells (OPCs), which repair injuries to myelinated axons with the cooperation of other cells. Endogenous myelin-associated inhibitors (MAIs), which originate from myelin and are overexpressed by oligodendrocyte lineage cells and astroglial cells during CNS damage, include chondroitin sulfate proteoglycans, oligodendrocyte myelin glycoprotein, Nogo-A, and myelin-associated glycolin, and counter the regrowth of axons critical to the post white-matter injury restoration of myelinated axons, neural plasticity, and neuronal function.[15],[16] By binding to MAI receptor complexes on neuronal axons and activating inhibitory signaling avenues including the Rho/Rho-associated coiled-coil containing protein kinase (Rho/ROCK) pathway, MAIs preclude axons from expanding. Through alternate downstream pathways, the neuronal receptor paired Ig-like receptor B, which has common ligands with Nogo-66 receptor-1 (NgR1), can prevent the lengthening of axons.[17],[18],[19] Axonal growth is also blocked by a combination of the Rho/ROCK pathway and interactions between the sphingosine-1-phosphate receptor 2 in neurons and a specific Nogo-A region.[20] By helping NgR1 mature and utilizing the Rho/ROCK pathway, the nociception receptor ORL1 also hampers axon extension.[21] Delivering NgR1 decoys systemically in older mice improves motor function and white-matter restoration after stroke and increases the quantity of mature OPCs, illustrating that impeding MAI-related downstream signaling avenues can ameliorate white-matter damage.[22] Healing white-matter injury via increasing oligodendrocytes and restoring neuronal axons will conceivably benefit from regulating MAI-related signaling, given the involvement of MAIs in promoting CNS stability.

Neuronal activity-induced neural plasticity demonstrates the interplay between neurons and oligodendrocytes necessary to mend white-matter damage. Investigations incorporating human magnetic resonance imaging (MRI) have mainly observed this plasticity thus far, initially only exploring gray matter until advances in MRI technology featuring structural MRI analysis and increased spatiotemporal resolution enabled effective evaluation of white-matter plasticity in relation to CNS activity. Rearrangement of neural networks to link different areas of the CNS pertinent to various tasks is possible based on functional MRIs demonstrating a connection between organizing fiber tracts and practicing a musical instrument.[23] Indeed, EMG and MRI data convey that even brief stimuli can cause alterations in white-matter structures.[24] Thus, white-matter plasticity can potentially be attributed to modifying present myelin or the adaptability of recently synthesized myelin, and neuronal stimuli can augment this plasticity and organize neural connections.[25] In fact, learning motor-based tasks requires the generation of new oligodendrocytes in white matter, as revealed by animal studies utilizing MRI and histological analyses.[26],[27] Activating S1 pyramidal neurons in the corpus callosum of mice increases axon myelination and OPC count, signifying that myelination following neuronal stimulation is a specific event in which the activation of both white-matter axons and gray-matter neurons contributes to plasticity and myelin formation in neural cells in white matter.[28] Repairing white-matter injury will necessitate a precise understanding of this relationship between myelin and neurons.

  The Cerebrovascular System and Oligodendrocytes Top

The blood–brain barrier (BBB) mediates the transfer of molecules between the cerebrospinal fluid, blood, and the brain, comprises several NVU components, and is part of the cerebral vascular system, which regulates homeostasis of the CNS in addition to blood circulation. Neurodegenerative diseases compromise tight junctions and consequently, deteriorate the BBB,[29],[30],[31],[32] so comprehending how this affects the cerebral vascular system and its related processes will be imperative.

With the localization of oligodendrocytes around cerebral endothelial cells, it is conceivable that oligodendrocyte lineage cells also monitor the BBB and endothelial cell processes, in addition to pericytes and astrocytes.[33],[34],[35],[36] BBB impairment appears to follow diminished communication between endothelial cells and oligodendrocytes, as exhibited in mice with either oligodendrocytes hyperactivated by HRas or oligodendrocytes lacking neurofibromatosis type 1.[37] OPCs produce transforming growth factor-β1, which utilizes the MEK/ERK pathway and increases tight junction proteins, thus bolstering the BBB.[36] Angiogenesis also implicates the roles of OPCs, as the formation of blood vessels during early development requires endothelial cell–OPC communication, and OPCs under low oxygen conditions produce Wnt7a and Wnt7b which facilitate endothelial cell proliferation in vitro and angiogenesis in vivo.[38] Nogo signaling pathways in the brains of postnatal mice, in which blood vessels are still developing, exhibit how oligodendrocytes can also inhibit angiogenesis through negative regulation.[39],[40] Blood vessels increase when Nogo-A is reduced via gene knockout, inhibition by an antibody, or knockdown induced by a virus. Moreover, adding the antibody to Nogo-A nullifies Nogo-A-mediated obstruction of brain microvascular endothelial cell migration. Matrix metalloproteinase-9 (MMP-9) released by oligodendrocytes following damage to white matter alter vascular structures, indicating that these oligodendrocyte-induced effects on angiogenesis may also apply to injured white matter.[35] In contrast, conditions of inflammation and oxidative stress trigger OPCs to produce exceedingly large quantities of MMP-9, disrupting the BBB.[41] For white-matter restoration, it will be important to elucidate which specific pathways and mediators control which OPC effects on the cerebrovascular system.

While oligodendrocytes can regulate components of the cerebrovascular system such as the BBB, the cerebrovascular system can also control aspects of oligodendrocytes, as brain-derived neurotrophic factor (BDNF) and fibroblast growth factor (FGF) manufactured by cerebral endothelial cells enable OPCs to survive and increase in number.[42] OPCs migrate without proliferating when in the presence of vascular endothelial growth factor A (VEGF-A).[43] Moreover, endothelial cell-derived extracellular vesicles are speculated to carry FGF, BDNF, and VEGF-A to OPCs.[44] Additionally, endothelial cells modulate the centralization of oligodendrocyte lineage cells via stromal cell-derived factor 1 (SDF-1) stimulation of the Wnt-chemokine receptor 4.[45] Endothelial progenitor cells (EPCs) modified with the SDF-1 gene enhance remyelination and proliferation of OPCs,[46] in addition to elevating the amount of blood vessels.[47] Secretomes from EPCs may also treat white-matter afflictions, helping OPCs mature and enabling both endothelial cells and OPCs to proliferate in in vivo and in vitro settings.[48]

As mediators of the BBB, cerebral blood flow, and other aspects of the cerebrovascular system, the mural cells known as pericytes are found within the basal membrane of blood vessel endothelial cells and promote functional white-matter tissue.[49] The localization of OPCs and pericytes in the cerebral white matter's peri-vascular area and close proximity to each other indicate that they likely swap soluble factors to communicate,[50] but the exact process in which they interact is undetermined. Moreover, pericytes release growth factors such as BMP4 and TGFβ-1 which regenerate oligodendrocytes[51] and help OPCs migrate during the initial formation of the cerebral cortex,[52] respectively. OPC maturation to oligodendrocytes is also facilitated by pericyte-induced growth factors, whose generation is mediated by protein A-kinase anchor protein.[53] Following injury to white matter, interplay in the peri-vascular region between pericytes, oligodendrocyte lineage cells, and other NVU-related cells leads to the creation of new blood vessels and oligodendrocytes, which implies that future therapies for treating white-matter damage should bolster the beneficial interactions between these cells.

  Glial Cells and Oligodendrocytes Top

Glial cell types include oligodendrocyte lineage cells, microglia, and astrocytes, and the latter two promote the proliferation and differentiation of OPCs via noncell autonomous means, aside from regulating other brain processes.

Given their close distance to oligodendrocytes, astrocytes can attach to these cells via gap junctions and utilize Cx43 hemichannels to transfer small molecules such as ATP.[9],[54],[55],[56] In an ischemic environment, glutamate transporters in astrocytes expel glutamate, which prevents OPCs from differentiating[57] by activating oligodendrocyte lineage cells' NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors.[58],[59],[60] Furthermore, OPC differentiation can be facilitated by precluding the release of glutamate by blocking the Cx43 hemichannel.[61] Cx43 may be key to ameliorating white-matter damage, as its modulation may enable the remyelination of damaged axons and the generation of new oligodendrocytes. Aside from detrimental factors, astrocytes also release beneficial growth factors after nervous tissue damage that promote regenerative processes. For instance, the quantity of oligodendrocytes in white-matter increase upon astrocyte secretion of BDNF in a cerebral hypoperfusion mouse model.[33] Additionally, astrocytes derived from induced pluripotent stem cells assist with OPC maturation and secrete tropic factors that boost oligodendrogenesis.[62]

During diseased states, such as those featuring reduced oligodendrocytes and myelination, microglia may modulate oligodendrocytes and promote remyelination by eliminating apoptotic cells and defective myelin. Microglial cells then convert to the M2-anti-inflammatory state (M2) from their M1-pro-inflammatory state (M1), during the remyelination process.[63] This M2 microglia phenotype augments the differentiation of oligodendrocytes in both in vivo and in vitro situations[63] and shifting between the two phenotypes may increase oligodendrocytes poststroke. OPC proliferation and mature oligodendrocyte count rises upon administration of the peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, in stroke-afflicted mice.[64] Rosiglitazone increases M2 microglia and decreases M1 microglia, which enables OPCs to differentiate.[64] Following demyelination in axons, activated microglial cells can localize at the demyelinated region and utilize neural stem and progenitor cells to produce additional OPCs from the corpus callosum's subventricular zone.[65] Of note, OPC generation is diminished when microglial activation is hindered and OPCs are killed when M1 microglia utilize TLR4 signaling pathways.[66] Thus, healing white-matter injury and initiating remyelination may benefit from employing the conversion between microglial phenotypes.

  Conclusion Top

The white matter is characterized by myelin sheaths, a critical component produced by oligodendrocytes that facilitate the efficient transmission of electrical signals and enable communication between gray-matter neurons throughout various areas. Oligodendrocyte quantities rely on OPCs, which possess the ability to divide and generate more oligodendrocytes, unlike mature oligodendrocytes. However, cells of the oligodendrocyte lineage rely on other cells in the NVU, which assist in regenerating oligodendrocytes following damage to white matter and perform other tasks to help oligodendrocytes. In turn, oligodendrocytes aid other NVU cells in preserving healthy white matter. Angiogenesis and neurogenesis may also be useful for treating white-matter injury, given that oligodendrogenesis may not be sufficient to fully repair damage. Further knowledge regarding cooperative events between various cells during angiogenesis, oligodendrogenesis, and neurogenesis will be critical for developing reparative white-matter therapies. Moreover, as stem cell transplants induce endogenous brain repair via various regenerative pathways,[67] they may complement other methods for white-matter recovery. While oligodendrocytes protect white matter in collaboration with other NVU cells, their exact roles and the mechanisms underlying oligodendrogenesis post white-matter injury are still uncertain, and can be explored in future investigations.

Financial support and sponsorship

National Institutes of Health.

Conflicts of interest

There are no conflicts of interest.

  References Top

del Zoppo GJ, Mabuchi T. Cerebral microvessel responses to focal ischemia. J Cereb Blood Flow Metab 2003;23:879-94.  Back to cited text no. 1
Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 2003;4:399-415.  Back to cited text no. 2
Itoh K, Maki T, Lok J, Arai K. Mechanisms of cell-cell interaction in oligodendrogenesis and remyelination after stroke. Brain Res 2015;1623:135-49.  Back to cited text no. 3
Rosenzweig S, Carmichael ST. The axon-glia unit in white matter stroke: Mechanisms of damage and recovery. Brain Res 2015;1623:123-34.  Back to cited text no. 4
Meyer N, Richter N, Fan Z, Siemonsmeier G, Pivneva T, Jordan P, et al. Oligodendrocytes in the mouse corpus callosum maintain axonal function by delivery of glucose. Cell Rep 2018;22:2383-94.  Back to cited text no. 5
Dammann O, Bueter W, Leviton A, Gressens P, Dammann CE. Neuregulin-1: A potential endogenous protector in perinatal brain white matter damage. Neonatology 2008;93:182-7.  Back to cited text no. 6
Li Y, Xu Z, Ford GD, Croslan DR, Cairobe T, Li Z, et al. Neuroprotection by neuregulin-1 in a rat model of permanent focal cerebral ischemia. Brain Res 2007;1184:277-83.  Back to cited text no. 7
Lundgaard I, Luzhynskaya A, Stockley JH, Wang Z, Evans KA, Swire M, et al. Neuregulin and BDNF induce a switch to NMDA receptor-dependent myelination by oligodendrocytes. PLoS Biol 2013;11:e1001743.  Back to cited text no. 8
Butt AM, Fern RF, Matute C. Neurotransmitter signaling in white matter. Glia 2014;62:1762-79.  Back to cited text no. 9
De Angelis F, Bernardo A, Magnaghi V, Minghetti L, Tata AM. Muscarinic receptor subtypes as potential targets to modulate oligodendrocyte progenitor survival, proliferation, and differentiation. Dev Neurobiol 2012;72:713-28.  Back to cited text no. 10
Gudz TI, Komuro H, Macklin WB. Glutamate stimulates oligodendrocyte progenitor migration mediated via an alphav integrin/myelin proteolipid protein complex. J Neurosci 2006;26:2458-66.  Back to cited text no. 11
Wake H, Lee PR, Fields RD. Control of local protein synthesis and initial events in myelination by action potentials. Science 2011;333:1647-51.  Back to cited text no. 12
Zonouzi M, Renzi M, Farrant M, Cull-Candy SG. Bidirectional plasticity of calcium-permeable AMPA receptors in oligodendrocyte lineage cells. Nat Neurosci 2011;14:1430-8.  Back to cited text no. 13
Doyle S, Hansen DB, Vella J, Bond P, Harper G, Zammit C, et al. Vesicular glutamate release from central axons contributes to myelin damage. Nat Commun 2018;9:1032.  Back to cited text no. 14
Krumbholz M, Theil D, Derfuss T, Rosenwald A, Schrader F, Monoranu CM, et al. BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma. J Exp Med 2005;201:195-200.  Back to cited text no. 15
Kurihara Y, Saito Y, Takei K. Blockade of chondroitin sulfate proteoglycans-induced axonal growth inhibition by LOTUS. Neuroscience 2017;356:265-74.  Back to cited text no. 16
Atwal JK, Pinkston-Gosse J, Syken J, Stawicki S, Wu Y, Shatz C, et al. PirB is a functional receptor for myelin inhibitors of axonal regeneration. Science 2008;322:967-70.  Back to cited text no. 17
Bi YY, Quan Y. PirB inhibits axonal outgrowth via the PI3K/Akt/mTOR signaling pathway. Mol Med Rep 2018;17:1093-8.  Back to cited text no. 18
Filbin MT. PirB, a second receptor for the myelin inhibitors of axonal regeneration nogo66, MAG, and OMgp: Implications for regeneration in vivo. Neuron 2008;60:740-2.  Back to cited text no. 19
Kempf A, Tews B, Arzt ME, Weinmann O, Obermair FJ, Pernet V, et al. The sphingolipid receptor S1PR2 is a receptor for nogo-a repressing synaptic plasticity. PLoS Biol 2014;12:e1001763.  Back to cited text no. 20
Sekine Y, Siegel CS, Sekine-Konno T, Cafferty WB, Strittmatter SM. The nociceptin receptor inhibits axonal regeneration and recovery from spinal cord injury. Sci Signal 2018;11. pii: eaao4180.  Back to cited text no. 21
Sozmen EG, Rosenzweig S, Llorente IL, DiTullio DJ, Machnicki M, Vinters HV, et al. Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice. Proc Natl Acad Sci U S A 2016;113:E8453-62.  Back to cited text no. 22
Bengtsson SL, Nagy Z, Skare S, Forsman L, Forssberg H, Ullén F, et al. Extensive piano practicing has regionally specific effects on white matter development. Nat Neurosci 2005;8:1148-50.  Back to cited text no. 23
Taubert M, Draganski B, Anwander A, Müller K, Horstmann A, Villringer A, et al. Dynamic properties of human brain structure: Learning-related changes in cortical areas and associated fiber connections. J Neurosci 2010;30:11670-7.  Back to cited text no. 24
Zatorre RJ, Fields RD, Johansen-Berg H. Plasticity in gray and white: Neuroimaging changes in brain structure during learning. Nat Neurosci 2012;15:528-36.  Back to cited text no. 25
McKenzie IA, Ohayon D, Li H, de Faria JP, Emery B, Tohyama K, et al. Motor skill learning requires active central myelination. Science 2014;346:318-22.  Back to cited text no. 26
Sampaio-Baptista C, Khrapitchev AA, Foxley S, Schlagheck T, Scholz J, Jbabdi S, et al. Motor skill learning induces changes in white matter microstructure and myelination. J Neurosci 2013;33:19499-503.  Back to cited text no. 27
Mitew S, Gobius I, Fenlon LR, McDougall SJ, Hawkes D, Xing YL, et al. Pharmacogenetic stimulation of neuronal activity increases myelination in an axon-specific manner. Nat Commun 2018;9:306.  Back to cited text no. 28
Bowman GL, Kaye JA, Moore M, Waichunas D, Carlson NE, Quinn JF, et al. Blood-brain barrier impairment in Alzheimer disease: Stability and functional significance. Neurology 2007;68:1809-14.  Back to cited text no. 29
Mizee MR, Nijland PG, van der Pol SM, Drexhage JA, van Het Hof B, Mebius R, et al. Astrocyte-derived retinoic acid: A novel regulator of blood-brain barrier function in multiple sclerosis. Acta Neuropathol 2014;128:691-703.  Back to cited text no. 30
Rosenberg GA. Extracellular matrix inflammation in vascular cognitive impairment and dementia. Clin Sci (Lond) 2017;131:425-37.  Back to cited text no. 31
Zhang CE, Wong SM, van de Haar HJ, Staals J, Jansen JF, Jeukens CR, et al. Blood-brain barrier leakage is more widespread in patients with cerebral small vessel disease. Neurology 2017;88:426-32.  Back to cited text no. 32
Miyamoto N, Maki T, Shindo A, Liang AC, Maeda M, Egawa N, et al. Astrocytes promote oligodendrogenesis after white matter damage via brain-derived neurotrophic factor. J Neurosci 2015;35:14002-8.  Back to cited text no. 33
Miyamoto N, Pham LD, Seo JH, Kim KW, Lo EH, Arai K, et al. Crosstalk between cerebral endothelium and oligodendrocyte. Cell Mol Life Sci 2014;71:1055-66.  Back to cited text no. 34
Pham LD, Hayakawa K, Seo JH, Nguyen MN, Som AT, Lee BJ, et al. Crosstalk between oligodendrocytes and cerebral endothelium contributes to vascular remodeling after white matter injury. Glia 2012;60:875-81.  Back to cited text no. 35
Seo JH, Maki T, Maeda M, Miyamoto N, Liang AC, Hayakawa K, et al. Oligodendrocyte precursor cells support blood-brain barrier integrity via TGF-β signaling. PLoS One 2014;9:e103174.  Back to cited text no. 36
Mayes DA, Rizvi TA, Titus-Mitchell H, Oberst R, Ciraolo GM, Vorhees CV, et al. Nf1 loss and ras hyperactivation in oligodendrocytes induce NOS-driven defects in myelin and vasculature. Cell Rep 2013;4:1197-212.  Back to cited text no. 37
Yuen TJ, Silbereis JC, Griveau A, Chang SM, Daneman R, Fancy SP, et al. Oligodendrocyte-encoded HIF function couples postnatal myelination and white matter angiogenesis. Cell 2014;158:383-96.  Back to cited text no. 38
Wälchli T, Pernet V, Weinmann O, Shiu JY, Guzik-Kornacka A, Decrey G, et al. Nogo-A is a negative regulator of CNS angiogenesis. Proc Natl Acad Sci U S A 2013;110:E1943-52.  Back to cited text no. 39
Wälchli T, Ulmann-Schuler A, Hintermüller C, Meyer E, Stampanoni M, Carmeliet P, et al. Nogo-A regulates vascular network architecture in the postnatal brain. J Cereb Blood Flow Metab 2017;37:614-31.  Back to cited text no. 40
Seo JH, Miyamoto N, Hayakawa K, Pham LD, Maki T, Ayata C, et al. Oligodendrocyte precursors induce early blood-brain barrier opening after white matter injury. J Clin Invest 2013;123:782-6.  Back to cited text no. 41
Arai K, Lo EH. An oligovascular niche: Cerebral endothelial cells promote the survival and proliferation of oligodendrocyte precursor cells. J Neurosci 2009;29:4351-5.  Back to cited text no. 42
Hayakawa K, Seo JH, Pham LD, Miyamoto N, Som AT, Guo S, et al. Cerebral endothelial derived vascular endothelial growth factor promotes the migration but not the proliferation of oligodendrocyte precursor cells in vitro. Neurosci Lett 2012;513:42-6.  Back to cited text no. 43
Kurachi M, Mikuni M, Ishizaki Y. Extracellular vesicles from vascular endothelial cells promote survival, proliferation and motility of oligodendrocyte precursor cells. PLoS One 2016;11:e0159158.  Back to cited text no. 44
Tsai HH, Niu J, Munji R, Davalos D, Chang J, Zhang H, et al. Oligodendrocyte precursors migrate along vasculature in the developing nervous system. Science 2016;351:379-84.  Back to cited text no. 45
Yuan F, Chang S, Luo L, Li Y, Wang L, Song Y, et al. Cxcl12 gene engineered endothelial progenitor cells further improve the functions of oligodendrocyte precursor cells. Exp Cell Res 2018;367:222-31.  Back to cited text no. 46
Li Y, Chang S, Li W, Tang G, Ma Y, Liu Y, et al. Cxcl12-engineered endothelial progenitor cells enhance neurogenesis and angiogenesis after ischemic brain injury in mice. Stem Cell Res Ther 2018;9:139.  Back to cited text no. 47
Maki T, Morancho A, Martinez-San Segundo P, Hayakawa K, Takase H, Liang AC, et al. Endothelial progenitor cell secretome and oligovascular repair in a mouse model of prolonged cerebral hypoperfusion. Stroke 2018;49:1003-10.  Back to cited text no. 48
Montagne A, Nikolakopoulou AM, Zhao Z, Sagare AP, Si G, Lazic D, et al. Pericyte degeneration causes white matter dysfunction in the mouse central nervous system. Nat Med 2018;24:326-37.  Back to cited text no. 49
Maki T, Maeda M, Uemura M, Lo EK, Terasaki Y, Liang AC, et al. Potential interactions between pericytes and oligodendrocyte precursor cells in perivascular regions of cerebral white matter. Neurosci Lett 2015;597:164-9.  Back to cited text no. 50
Uemura MT, Ihara M, Maki T, Nakagomi T, Kaji S, Uemura K, et al. Pericyte-derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion. Brain Pathol 2018;28:521-35.  Back to cited text no. 51
Choe Y, Huynh T, Pleasure SJ. Migration of oligodendrocyte progenitor cells is controlled by transforming growth factor β family proteins during corticogenesis. J Neurosci 2014;34:14973-83.  Back to cited text no. 52
Maki T, Choi YK, Miyamoto N, Shindo A, Liang AC, Ahn BJ, et al. A-kinase anchor protein 12 is required for oligodendrocyte differentiation in adult white matter. Stem Cells 2018;36:751-60.  Back to cited text no. 53
Li X, Zhao H, Tan X, Kostrzewa RM, Du G, Chen Y, et al. Inhibition of connexin43 improves functional recovery after ischemic brain injury in neonatal rats. Glia 2015;63:1553-67.  Back to cited text no. 54
Rouach N, Avignone E, Même W, Koulakoff A, Venance L, Blomstrand F, et al. Gap junctions and connexin expression in the normal and pathological central nervous system. Biol Cell 2002;94:457-75.  Back to cited text no. 55
Schulz R, Görge PM, Görbe A, Ferdinandy P, Lampe PD, Leybaert L, et al. Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection. Pharmacol Ther 2015;153:90-106.  Back to cited text no. 56
Niu J, Li T, Yi C, Huang N, Koulakoff A, Weng C, et al. Connexin-based channels contribute to metabolic pathways in the oligodendroglial lineage. J Cell Sci 2016;129:1902-14.  Back to cited text no. 57
Baltan S, Besancon EF, Mbow B, Ye Z, Hamner MA, Ransom BR, et al. White matter vulnerability to ischemic injury increases with age because of enhanced excitotoxicity. J Neurosci 2008;28:1479-89.  Back to cited text no. 58
Micu I, Jiang Q, Coderre E, Ridsdale A, Zhang L, Woulfe J, et al. NMDA receptors mediate calcium accumulation in myelin during chemical ischaemia. Nature 2006;439:988-92.  Back to cited text no. 59
Tekkök SB, Ye Z, Ransom BR. Excitotoxic mechanisms of ischemic injury in myelinated white matter. J Cereb Blood Flow Metab 2007;27:1540-52.  Back to cited text no. 60
Wang Q, Wang Z, Tian Y, Zhang H, Fang Y, Yu Z, et al. Inhibition of astrocyte connexin 43 channels facilitates the differentiation of oligodendrocyte precursor cells under hypoxic conditions in vitro. J Mol Neurosci 2018;64:591-600.  Back to cited text no. 61
Jiang P, Chen C, Liu XB, Pleasure DE, Liu Y, Deng W, et al. Human iPSC-derived immature astroglia promote oligodendrogenesis by increasing TIMP-1 secretion. Cell Rep 2016;15:1303-15.  Back to cited text no. 62
Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, et al. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 2013;16:1211-8.  Back to cited text no. 63
Han L, Cai W, Mao L, Liu J, Li P, Leak RK, et al. Rosiglitazone promotes white matter integrity and long-term functional recovery after focal cerebral ischemia. Stroke 2015;46:2628-36.  Back to cited text no. 64
Naruse M, Shibasaki K, Shimauchi-Ohtaki H, Ishizaki Y. Microglial activation induces generation of oligodendrocyte progenitor cells from the subventricular zone after focal demyelination in the corpus callosum. Dev Neurosci 2018;40:54-63.  Back to cited text no. 65
Li Y, Zhang R, Hou X, Zhang Y, Ding F, Li F, et al. Microglia activation triggers oligodendrocyte precursor cells apoptosis via HSP60. Mol Med Rep 2017;16:603-8.  Back to cited text no. 66
Napoli E, Lippert T, Borlongan CV. Stem cell therapy: Repurposing cell-based regenerative medicine beyond cell replacement. Adv Exp Med Biol 2018;1079:87-91.  Back to cited text no. 67

This article has been cited by
1 Spatial transcriptomic analysis reveals inflammatory foci defined by senescent cells in the white matter, hippocampi and cortical grey matter in the aged mouse brain
Tamas Kiss, Ádám Nyúl-Tóth, Jordan DelFavero, Priya Balasubramanian, Stefano Tarantini, Janet Faakye, Rafal Gulej, Chetan Ahire, Anna Ungvari, Andriy Yabluchanskiy, Graham Wiley, Lori Garman, Zoltan Ungvari, Anna Csiszar
GeroScience. 2022;
[Pubmed] | [DOI]
2 Brain bioenergetics in chronic hypertension: Risk factor for acute ischemic stroke
Federica Ferrari, Roberto Federico Villa
Biochemical Pharmacology. 2022; 205: 115260
[Pubmed] | [DOI]
3 Xi-Xian-Tong-Shuan capsule alleviates vascular cognitive impairment in chronic cerebral hypoperfusion rats by promoting white matter repair, reducing neuronal loss, and inhibiting the expression of pro-inflammatory factors
Feng Yan, Yue Tian, Yuyou Huang, Qi Wang, Ping Liu, Ningqun Wang, Fangfang Zhao, Liyuan Zhong, Wuhan Hui, Yumin Luo
Biomedicine & Pharmacotherapy. 2022; 145: 112453
[Pubmed] | [DOI]
4 Effect of retinoic acid on the neurovascular unit: A review
Manuel R. Pouso, Elisa Cairrao
Brain Research Bulletin. 2022;
[Pubmed] | [DOI]
5 Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: crossing or circumventing the blood-brain barrier (BBB) to manage neurological disorders
A.C. Correia, A.R. Monteiro, R. Silva, J.N. Moreira, J.M. Sousa Lobo, A.C. Silva
Advanced Drug Delivery Reviews. 2022; : 114485
[Pubmed] | [DOI]
6 Effects of PAK1/LIMK1/Cofilin-mediated actin homeostasis on axonal injury after experimental intracerebral hemorrhage
Muyun Luo, Zongqi Wang, Jie Wu, Xueshun Xie, Wanchun You, Zhengquan Yu, Haitao Shen, Xiang Li, Haiying Li, Yanfei Liu, Zhong Wang, Gang Chen
Neuroscience. 2022;
[Pubmed] | [DOI]
7 UINMF performs mosaic integration of single-cell multi-omic datasets using nonnegative matrix factorization
April R. Kriebel, Joshua D. Welch
Nature Communications. 2022; 13(1)
[Pubmed] | [DOI]
8 Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state
Semra Smajic, Cesar A. Prada-Medina, Zied Landoulsi, Jenny Ghelfi, Sylvie Delcambre, Carola Dietrich, Javier Jarazo, Jana Henck, Saranya Balachandran, Sinthuja Pachchek, Christopher M. Morris, Paul Antony, Bernd Timmermann, Sascha Sauer, Sandro L. Pereira, Jens C. Schwamborn, Patrick May, Anne Grünewald, Malte Spielmann
Brain. 2022;
[Pubmed] | [DOI]
9 Connexins Signatures of the Neurovascular Unit and Their Physio-Pathological Functions
Nunzio Vicario, Rosalba Parenti
International Journal of Molecular Sciences. 2022; 23(17): 9510
[Pubmed] | [DOI]
10 Structural and Functional Features of Developing Brain Capillaries, and Their Alteration in Schizophrenia
Micaël Carrier,Jérémie Guilbert,Jean-Philippe Lévesque,Marie-Čve Tremblay,Michčle Desjardins
Frontiers in Cellular Neuroscience. 2021; 14
[Pubmed] | [DOI]
11 Nicotinamide Improves Cognitive Function in Mice With Chronic Cerebral Hypoperfusion
Bin Liu,Guifeng Zhao,Ling Jin,Jingping Shi
Frontiers in Neurology. 2021; 12
[Pubmed] | [DOI]
12 Delayed rFGF21 Administration Improves Cerebrovascular Remodeling and White Matter Repair After Focal Stroke in Diabetic Mice
Yinghua Jiang,Jinrui Han,Yadan Li,Yinga Wu,Ning Liu,Samuel X. Shi,Li Lin,Jing Yuan,Shusheng Wang,Ming-Ming Ning,Aaron S. Dumont,Xiaoying Wang
Translational Stroke Research. 2021;
[Pubmed] | [DOI]
13 Oligodendrocyte precursor cell transplantation promotes angiogenesis and remyelination via Wnt/ß-catenin pathway in a mouse model of middle cerebral artery occlusion
Li-Ping Wang, Jiaji Pan, Yongfang Li, Jieli Geng, Chang Liu, Lin-Yuan Zhang, Panting Zhou, Yao-Hui Tang, Yongting Wang, Zhijun Zhang, Guo-Yuan Yang
Journal of Cerebral Blood Flow & Metabolism. 2021; : 0271678X21
[Pubmed] | [DOI]
14 Cellular, molecular, and therapeutic characterization of pilocarpine-induced temporal lobe epilepsy
Nicholas D. Henkel,Marissa A. Smail,Xiaojun Wu,Heather A. Enright,Nicholas O. Fischer,Hunter M. Eby,Robert E. McCullumsmith,Rammohan Shukla
Scientific Reports. 2021; 11(1)
[Pubmed] | [DOI]
15 White matter integrity of contralesional and transcallosal tracts may predict response to upper limb task-specific training in chronic stroke
Daniela J.S. Mattos,Jerrel Rutlin,Xin Hong,Joshua S. Shimony,Alexandre R. Carter
NeuroImage: Clinical. 2021; : 102710
[Pubmed] | [DOI]
16 Interactions between glial cells and the blood-brain barrier and their role in Alzheimerćs disease
Ming Zhao,Xue-Fan Jiang,Hui-Qin Zhang,Jia-Hui Sun,Hui Pei,Li-Na Ma,Yu Cao,Hao Li
Ageing Research Reviews. 2021; : 101483
[Pubmed] | [DOI]
17 Alzheimer's disease alters oligodendrocytic glycolytic and ketolytic gene expression
Erin R. Saito, Justin B. Miller, Oscar Harari, Carlos Cruchaga, Kathie A. Mihindukulasuriya, John S. K. Kauwe, Benjamin T. Bikman
Alzheimer's & Dementia. 2021; 17(9): 1474
[Pubmed] | [DOI]
18 Ischemic Preconditioning Induces Oligodendrogenesis in Mouse Brain: Effects of Nrf2 Deficiency
Qianqian Li,Jiyu Lou,Tuo Yang,Zhishuo Wei,Senmiao Li,Feng Zhang
Cellular and Molecular Neurobiology. 2021;
[Pubmed] | [DOI]
19 Neurovascular-glymphatic dysfunction and white matter lesions
Behnam Sabayan,Rudi G. J. Westendorp
GeroScience. 2021;
[Pubmed] | [DOI]
20 Sphingosine 1-Phosphate Receptors in Cerebral Ischemia
Bhakta Prasad Gaire,Ji Woong Choi
NeuroMolecular Medicine. 2020;
[Pubmed] | [DOI]
21 Cellular Senescence and Failure of Myelin Repair in Multiple Sclerosis
Paraskevi N. Koutsoudaki,Dimitrios Papadopoulos,Panagiotis-Georgios Passias,Pinelopi Koutsoudaki,Vassilis G. Gorgoulis
Mechanisms of Ageing and Development. 2020; : 111366
[Pubmed] | [DOI]
22 Applying hiPSCs and Biomaterials Towards an Understanding and Treatment of Traumatic Brain Injury
María Lacalle-Aurioles,Camille Cassel de Camps,Cornelia E. Zorca,Lenore K. Beitel,Thomas M. Durcan
Frontiers in Cellular Neuroscience. 2020; 14
[Pubmed] | [DOI]
23 Perivascular Unit: This Must Be the Place. The Anatomical Crossroad Between the Immune, Vascular and Nervous System
Fernanda Troili,Virginia Cipollini,Marco Moci,Emanuele Morena,Miklos Palotai,Virginia Rinaldi,Carmela Romano,Giovanni Ristori,Franco Giubilei,Marco Salvetti,Francesco Orzi,Charles R. G. Guttmann,Michele Cavallari
Frontiers in Neuroanatomy. 2020; 14
[Pubmed] | [DOI]
24 The Evolving Concept of the Blood Brain Barrier (BBB): From a Single Static Barrier to a Heterogeneous and Dynamic Relay Center
Andres Villabona-Rueda,Clara Erice,Carlos A. Pardo,Monique F. Stins
Frontiers in Cellular Neuroscience. 2019; 13
[Pubmed] | [DOI]
25 Brain White Matter: A Substrate for Resilience and a Substance for Subcortical Small Vessel Disease
Farzaneh A. Sorond,Philip B. Gorelick
Brain Sciences. 2019; 9(8): 193
[Pubmed] | [DOI]
26 Stroke in CNS White Matter: Models and Mechanisms 2019
Selva Baltan
Neuroscience Letters. 2019; : 134411
[Pubmed] | [DOI]
27 Emerging links between cerebrovascular and neurodegenerative diseases—a special role for pericytes
Urban Lendahl,Per Nilsson,Christer Betsholtz
EMBO reports. 2019; 20(11)
[Pubmed] | [DOI]


    Similar in PUBMED
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
Neurons and Olig...
The Cerebrovascu...
Glial Cells and ...

 Article Access Statistics
    PDF Downloaded508    
    Comments [Add]    
    Cited by others 27    

Recommend this journal