Increasing evidence suggests that multipotent stem cells are harbored within a vascular niche inside various organs. Although a precise phenotype of resident vascular stem cells (VSCs) that can function as multipotent stem cells remains unclear, accumulating evidence shows that multipotent VSCs are likely vascular pericytes (PCs) that localize within blood vessels. These PCs are multipotent, possessing the ability to differentiate into various cell types, including vascular lineage cells. In addition, brain PCs are unique: They are derived from neural crest and can differentiate into neural lineage cells. Because PCs in the central nervous system (CNS) can contribute to both neurogenesis and vasculogenesis, they may mediate the reparative process of neurovascular units that are constructed by neural and vascular cells. Here, we describe the activity of PCs when viewed as multipotent VSCs, primarily regarding their neurogenic and vasculogenic potential in the CNS. We also discuss similarities between PCs and other candidates for multipotent VSCs, including perivascular mesenchymal stem cells, neural crest-derived stem cells, adventitial progenitor cells, and adipose-derived stem cells.
Get full access to this article
View all access options for this article.
References
1.
AsaharaT, MuroharaT, SullivanA, SilverM, van der ZeeR, LiT, WitzenbichlerB, SchattemanG and IsnerJM. (1997). Isolation of putative progenitor endothelial cells for angiogenesis. Science, 275:964–967.
BautchVL. (2011). Stem cells and the vasculature. Nat Med, 17:1437–1443.
5.
FerreiraLS, GerechtS, ShiehHF, WatsonN, RupnickMA, DallabridaSM, Vunjak-NovakovicG and LangerR. (2007). Vascular progenitor cells isolated from human embryonic stem cells give rise to endothelial and smooth muscle like cells and form vascular networks in vivo. Circ Res, 101:286–294.
6.
NakagomiT, MolnarZ, Nakano-DoiA, TaguchiA, SainoO, KuboS, ClausenM, YoshikawaH, NakagomiN and MatsuyamaT. (2011). Ischemia-induced neural stem/progenitor cells in the pia mater following cortical infarction. Stem Cells Dev, 20:2037–2051.
7.
NakagomiT, KuboS, Nakano-DoiA, SakumaR, LuS, NaritaA, KawaharaM, TaguchiA and MatsuyamaT. (2015). Brain vascular pericytes following ischemia have multipotential stem cell activity to differntiate into neural and vascular lineage cells. Stem Cells, 33:1962–1974.
8.
GaengelK, GenoveG, ArmulikA and BetsholtzC. (2009). Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol, 29:630–638.
9.
ArmulikA, AbramssonA and BetsholtzC. (2005). Endothelial/pericyte interactions. Circ Res, 97:512–523.
10.
AlltG and LawrensonJG. (2001). Pericytes: cell biology and pathology. Cells Tissues Organs, 169:1–11.
11.
PopescuBO, GherghiceanuM, KostinS, CeafalanL and PopescuLM. (2012). Telocytes in meninges and choroid plexus. Neurosci Lett, 516:265–269.
BirbrairA, ZhangT, WangZM, MessiML, EnikolopovGN, MintzA and DelbonoO. (2012). Skeletal muscle pericyte subtypes differ in their differentiation potential. Stem Cell Res, 10:67–84.
14.
MorikawaS, BalukP, KaidohT, HaskellA, JainRK and McDonaldDM. (2002). Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol, 160:985–1000.
15.
MitchellTS, BradleyJ, RobinsonGS, ShimaDT and NgYS. (2008). RGS5 expression is a quantitative measure of pericyte coverage of blood vessels. Angiogenesis, 11:141–151.
16.
BirbrairA, ZhangT, WangZM, MessiML, OlsonJD, MintzA and DelbonoO. (2014). Type-2 pericytes participate in normal and tumoral angiogenesis. Am J Physiol Cell Physiol, 307:C25–C38.
17.
KarowM, SanchezR, SchichorC, MasserdottiG, OrtegaF, HeinrichC, GasconS, KhanMA, LieDC, et al. (2012). Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells. Cell Stem Cell, 11:471–476.
18.
NakagomiT, MolnarZ, TaguchiA, Nakano-DoiA, LuS, KasaharaY, NakagomiN and MatsuyamaT. (2012). Leptomeningeal-derived doublecortin-expressing cells in poststroke brain. Stem Cells Dev, 21:2350–2354.
19.
GerhardtH and BetsholtzC. (2003). Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res, 314:15–23.
20.
LindahlP, HellstromM, KalenM and BetsholtzC. (1998). Endothelial-perivascular cell signaling in vascular development: lessons from knockout mice. Curr Opin Lipidol, 9:407–411.
21.
HellstromM, KalenM, LindahlP, AbramssonA and BetsholtzC. (1999). Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development, 126:3047–3055.
22.
HallCN, ReynellC, GessleinB, HamiltonNB, MishraA, SutherlandBA, O'FarrellFM, BuchanAM, LauritzenM and AttwellD. (2014). Capillary pericytes regulate cerebral blood flow in health and disease. Nature, 508:55–60.
23.
ArmulikA, GenoveG, MaeM, NisanciogluMH, WallgardE, NiaudetC, HeL, NorlinJ, LindblomP, et al. (2010). Pericytes regulate the blood-brain barrier. Nature, 468:557–561.
24.
WinklerEA, BellRD and ZlokovicBV. (2011). Central nervous system pericytes in health and disease. Nat Neurosci, 14:1398–1405.
25.
BellRD, WinklerEA, SagareAP, SinghI, LaRueB, DeaneR and ZlokovicBV. (2010). Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron, 68:409–427.
26.
BanerjeeS and BhatMA. (2007). Neuron-glial interactions in blood-brain barrier formation. Annu Rev Neurosci, 30:235–258.
27.
Farrington-RockC, CroftsNJ, DohertyMJ, AshtonBA, Griffin-JonesC and CanfieldAE. (2004). Chondrogenic and adipogenic potential of microvascular pericytes. Circulation, 110:2226–2232.
28.
DohertyMJ, AshtonBA, WalshS, BeresfordJN, GrantME and CanfieldAE. (1998). Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res, 13:828–838.
29.
DarA, DomevH, Ben-YosefO, TzukermanM, Zeevi-LevinN, NovakA, GermanguzI, AmitM and Itskovitz-EldorJ. (2012). Multipotent vasculogenic pericytes from human pluripotent stem cells promote recovery of murine ischemic limb. Circulation, 125:87–99.
30.
BirbrairA, ZhangT, WangZM, MessiML, MintzA and DelbonoO. (2014). Pericytes: multitasking cells in the regeneration of injured, diseased, and aged skeletal muscle. Front Aging Neurosci, 6:245
31.
TiggesU, Welser-AlvesJV, BoroujerdiA and MilnerR. (2012). A novel and simple method for culturing pericytes from mouse brain. Microvasc Res, 84:74–80.
32.
LendahlU, ZimmermanLB and McKayRD. (1990). CNS stem cells express a new class of intermediate filament protein. Cell, 60:585–595.
33.
MokryJ, CizkovaD, FilipS, EhrmannJ, OsterreicherJ, KolarZ and EnglishD. (2004). Nestin expression by newly formed human blood vessels. Stem Cells Dev, 13:658–664.
34.
SuzukiS, NamikiJ, ShibataS, MastuzakiY and OkanoH. (2010). The neural stem/progenitor cell marker nestin is expressed in proliferative endothelial cells, but not in mature vasculature. J Histochem Cytochem, 58:721–730.
35.
MignoneJL, KukekovV, ChiangAS, SteindlerD and EnikolopovG. (2004). Neural stem and progenitor cells in nestin-GFP transgenic mice. J Comp Neurol, 469:311–324.
36.
BifariF, DecimoI, ChiamuleraC, BersanE, MalpeliG, JohanssonJ, LisiV, BonettiB, FumagalliG, PizzoloG and KramperaM. (2009). Novel stem/progenitor cells with neuronal differentiation potential reside in the leptomeningeal niche. J Cell Mol Med, 13:3195–3208.
37.
Dore-DuffyP, OwenC, BalabanovR, MurphyS, BeaumontT and RafolsJA. (2000). Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc Res, 60:55–69.
38.
TsangWP, ShuY, KwokPL, ZhangF, LeeKK, TangMK, LiG, ChanKM, ChanWY and WanC. (2013). CD146+ human umbilical cord perivascular cells maintain stemness under hypoxia and as a cell source for skeletal regeneration. PLoS One, 8:e76153
39.
ChenCW, OkadaM, ProtoJD, GaoX, SekiyaN, BeckmanSA, CorselliM, CrisanM, SaparovA, et al. (2013). Human pericytes for ischemic heart repair. Stem Cells, 31:305–316.
40.
NakagomiT, Nakano-DoiA and MatsuyamaT. (2015). Leptomeninges: a novel stem cell niche harboring ischemia-induced neural progenitors. Histol Histopathol, 30:391–399.
41.
NakagomiN, NakagomiT, KuboS, Nakano-DoiA, SainoO, TakataM, YoshikawaH, SternDM, MatsuyamaT and TaguchiA. (2009). Endothelial cells support survival, proliferation, and neuronal differentiation of transplanted adult ischemia-induced neural stem/progenitor cells after cerebral infarction. Stem Cells, 27:2185–2195.
42.
Nakano-DoiA, NakagomiT, FujikawaM, NakagomiN, KuboS, LuS, YoshikawaH, SomaT, TaguchiA and MatsuyamaT. (2010). Bone marrow mononuclear cells promote proliferation of endogenous neural stem cells through vascular niches after cerebral infarction. Stem Cells, 28:1292–1302.
43.
VodyanikMA, YuJ, ZhangX, TianS, StewartR, ThomsonJA and SlukvinII. (2010). A mesoderm-derived precursor for mesenchymal stem and endothelial cells. Cell Stem Cell, 7:718–729.
44.
TropelP, NoelD, PlatetN, LegrandP, BenabidAL and BergerF. (2004). Isolation and characterisation of mesenchymal stem cells from adult mouse bone marrow. Exp Cell Res, 295:395–406.
45.
PaulG, OzenI, ChristophersenNS, ReinbotheT, BengzonJ, VisseE, JanssonK, DannaeusK, Henriques-OliveiraC, et al. (2012). The adult human brain harbors multipotent perivascular mesenchymal stem cells. PLoS One, 7:e35577
46.
CrisanM, YapS, CasteillaL, ChenCW, CorselliM, ParkTS, AndrioloG, SunB, ZhengB, et al. (2008). A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell, 3:301–313.
47.
BouacidaA, RossetP, TrichetV, GuillotonF, EspagnolleN, CordonierT, HeymannD, LayrolleP, SensebeL and DeschaseauxF. (2012). Pericyte-like progenitors show high immaturity and engraftment potential as compared with mesenchymal stem cells. PLoS One, 7:e48648
48.
OzenI, BoixJ and PaulG. (2012). Perivascular mesenchymal stem cells in the adult human brain: a future target for neuroregeneration?. Clin Transl Med, 1:30.
49.
KurodaY, WakaoS, KitadaM, MurakamiT, NojimaM and DezawaM. (2013). Isolation, culture and evaluation of multilineage-differentiating stress-enduring (Muse) cells. Nat Protoc, 8:1391–1415.
50.
KurodaY, KitadaM, WakaoS, NishikawaK, TanimuraY, MakinoshimaH, GodaM, AkashiH, InutsukaA, et al. (2010). Unique multipotent cells in adult human mesenchymal cell populations. Proc Natl Acad Sci U S A, 107:8639–8643.
51.
LuqueA, SlevinM, TuruMM, Juan-BabotO, BadimonL and KrupinskiJ. (2009). CD105 positive neovessels are prevalent in early stage carotid lesions, and correlate with the grade in more advanced carotid and coronary plaques. J Angiogenes Res, 1:6
52.
CovasDT, PanepucciRA, FontesAM, SilvaWAJr., OrellanaMD, FreitasMC, NederL, SantosAR, PeresLC, JamurMC and ZagoMA. (2008). Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional properties and gene-expression profile with CD146+ perivascular cells and fibroblasts. Exp Hematol, 36:642–654.
53.
EspagnolleN, GuillotonF, DeschaseauxF, GadelorgeM, SensebeL and BourinP. (2014). CD146 expression on mesenchymal stem cells is associated with their vascular smooth muscle commitment. J Cell Mol Med, 18:104–114.
54.
CaplanAI. (2008). All MSCs are pericytes?. Cell Stem Cell, 3:229–230.
55.
FengJ, MantessoA, De BariC, NishiyamaA and SharpePT. (2011). Dual origin of mesenchymal stem cells contributing to organ growth and repair. Proc Natl Acad Sci U S A, 108:6503–6508.
56.
CorselliM, ChenCW, CrisanM, LazzariL and PeaultB. (2010). Perivascular ancestors of adult multipotent stem cells. Arterioscler Thromb Vasc Biol, 30:1104–1109.
57.
EtcheversHC, VincentC, Le DouarinNM and CoulyGF. (2001). The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development, 128:1059–1068.
58.
KornJ, ChristB and KurzH. (2002). Neuroectodermal origin of brain pericytes and vascular smooth muscle cells. J Comp Neurol, 442:78–88.
59.
TengL and LaboskyPA. (2006). Neural crest stem cells. Adv Exp Med Biol, 589:206–212.
60.
NagoshiN, ShibataS, NakamuraM, MatsuzakiY, ToyamaY and OkanoH. (2009). Neural crest-derived stem cells display a wide variety of characteristics. J Cell Biochem, 107:1046–1052.
61.
NagoshiN, ShibataS, KubotaY, NakamuraM, NagaiY, SatohE, MorikawaS, OkadaY, MabuchiY, et al. (2008). Ontogeny and multipotency of neural crest-derived stem cells in mouse bone marrow, dorsal root ganglia, and whisker pad. Cell Stem Cell, 2:392–403.
62.
KubotaY, TakuboK, HirashimaM, NagoshiN, KishiK, OkunoY, Nakamura-IshizuA, SanoK, MurakamiM, et al. (2011). Isolation and function of mouse tissue resident vascular precursors marked by myelin protein zero. J Exp Med, 208:949–960.
63.
CalloniGW, Le DouarinNM and DupinE. (2009). High frequency of cephalic neural crest cells shows coexistence of neurogenic, melanogenic, and osteogenic differentiation capacities. Proc Natl Acad Sci U S A, 106:8947–8952.
64.
CalloniGW, Glavieux-PardanaudC, Le DouarinNM and DupinE. (2007). Sonic Hedgehog promotes the development of multipotent neural crest progenitors endowed with both mesenchymal and neural potentials. Proc Natl Acad Sci U S A, 104:19879–19884.
65.
Wislet-GendebienS, LaudetE, NeirinckxV, AlixP, LeprinceP, GlejzerA, PouletC, HennuyB, SommerL, ShakhovaO and RogisterB. (2012). Mesenchymal stem cells and neural crest stem cells from adult bone marrow: characterization of their surprising similarities and differences. Cell Mol Life Sci, 69:2593–2608.
66.
IsernJ, Garcia-GarciaA, MartinAM, ArranzL, Martin-PerezD, TorrojaC, Sanchez-CaboF and Mendez-FerrerS. (2014). The neural crest is a source of mesenchymal stem cells with specialized hematopoietic stem cell niche function. Elife, 3:e03696
67.
LouissaintAJr., RaoS, LeventhalC and GoldmanSA. (2002). Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron, 34:945–960.
68.
CimadamoreF, FishwickK, GiustoE, GnedevaK, CattarossiG, MillerA, PluchinoS, BrillLM, Bronner-FraserM and TerskikhAV. (2011). Human ESC-derived neural crest model reveals a key role for SOX2 in sensory neurogenesis. Cell Stem Cell, 8:538–551.
69.
RingKL, TongLM, BalestraME, JavierR, Andrews-ZwillingY, LiG, WalkerD, ZhangWR, KreitzerAC and HuangY. (2012). Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell, 11:100–109.
70.
GiorgettiA, MarchettoMC, LiM, YuD, FazzinaR, MuY, AdamoA, ParamonovI, CardosoJC, et al. (2012). Cord blood-derived neuronal cells by ectopic expression of Sox2 and c-Myc. Proc Natl Acad Sci U S A, 109:12556–12561.
71.
TakemotoT, UchikawaM, YoshidaM, BellDM, Lovell-BadgeR, PapaioannouVE and KondohH. (2011). Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells. Nature, 470:394–398.
72.
LuoJ, QiaoF and YinX. (2011). Hypoxia induces FGF2 production by vascular endothelial cells and alters MMP9 and TIMP1 expression in extravillous trophoblasts and their invasiveness in a cocultured model. J Reprod Dev, 57:84–91.
73.
KubotaY, HirashimaM, KishiK, StewartCL and SudaT. (2008). Leukemia inhibitory factor regulates microvessel density by modulating oxygen-dependent VEGF expression in mice. J Clin Invest, 118:2393–2403.
TiggesU, HyerEG, ScharfJ and StallcupWB. (2008). FGF2-dependent neovascularization of subcutaneous Matrigel plugs is initiated by bone marrow-derived pericytes and macrophages. Development, 135:523–532.
76.
BirnbaumT, HildebrandtJ, NueblingG, SostakP and StraubeA. (2011). Glioblastoma-dependent differentiation and angiogenic potential of human mesenchymal stem cells in vitro. J Neurooncol, 105:57–65.
CrisanM, ChenCW, CorselliM, AndrioloG, LazzariL and PeaultB. (2009). Perivascular multipotent progenitor cells in human organs. Ann N Y Acad Sci, 1176:118–123.
79.
PaciniS and PetriniI. (2014). Are MSCs angiogenic cells? new insights on human nestin-positive bone marrow-derived multipotent cells. Front Cell Dev Biol, 2:20.
SlukvinII and VodyanikM. (2011). Endothelial origin of mesenchymal stem cells. Cell Cycle, 10:1370–1373.
82.
WangCH, HsiehIC, ChenSJ, WangJS, CherngWJ, ChenCC, LamIJ and LinSJ. (2012). VE-Cadherin(low)alpha-smooth muscle actin+ component of vascular progenitor cells correlates with the coronary artery Gensini score. Circ J, 76:477–484.
83.
PassmanJN, DongXR, WuSP, MaguireCT, HoganKA, BautchVL and MajeskyMW. (2008). A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1+ smooth muscle progenitor cells. Proc Natl Acad Sci U S A, 105:9349–9354.
84.
CampagnoloP, CesselliD, Al Haj ZenA, BeltramiAP, KrankelN, KatareR, AngeliniG, EmanueliC and MadedduP. (2010). Human adult vena saphena contains perivascular progenitor cells endowed with clonogenic and proangiogenic potential. Circulation, 121:1735–1745.
85.
HuY, ZhangZ, TorsneyE, AfzalAR, DavisonF, MetzlerB and XuQ. (2004). Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J Clin Invest, 113:1258–1265.
86.
KleinD, MeissnerN, KleffV, JastrowH, YamaguchiM, ErgunS and JendrossekV. (2014). Nestin(+) tissue-resident multipotent stem cells contribute to tumor progression by differentiating into pericytes and smooth muscle cells resulting in blood vessel remodeling. Front Oncol, 4:169
87.
KleinD, WeisshardtP, KleffV, JastrowH, JakobHG and ErgunS. (2011). Vascular wall-resident CD44+ multipotent stem cells give rise to pericytes and smooth muscle cells and contribute to new vessel maturation. PLoS One, 6:e20540
88.
YamashimaT, TonchevAB, VachkovIH, PopivanovaBK, SekiT, SawamotoK and OkanoH. (2004). Vascular adventitia generates neuronal progenitors in the monkey hippocampus after ischemia. Hippocampus, 14:861–875.
89.
KleinD, BenchellalM, KleffV, JakobHG and ErgunS. (2013). Hox genes are involved in vascular wall-resident multipotent stem cell differentiation into smooth muscle cells. Sci Rep, 3:2178
90.
SpaethEL, LabaffAM, TooleBP, KloppA, AndreeffM and MariniFC. (2014). Mesenchymal CD44 expression contributes to the acquisition of an activated fibroblast phenotype via TWIST activation in the tumor microenvironment. Cancer Res, 73:5347–5359.
91.
TraktuevDO, Merfeld-ClaussS, LiJ, KoloninM, ArapW, PasqualiniR, JohnstoneBH and MarchKL. (2008). A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circ Res, 102:77–85.
92.
AmosPJ, ShangH, BaileyAM, TaylorA, KatzAJ and PeirceSM. (2008). IFATS collection: the role of human adipose-derived stromal cells in inflammatory microvascular remodeling and evidence of a perivascular phenotype. Stem Cells, 26:2682–2690.
93.
ChungMT, ZimmermannAS, PaikKJ, MorrisonSD, HyunJS, LoDD, McArdleA, MontoroDT, WalmsleyGG, et al. (2013). Isolation of human adipose-derived stromal cells using laser-assisted liposuction and their therapeutic potential in regenerative medicine. Stem Cells Transl Med, 2:808–817.
94.
GimbleJM, KatzAJ and BunnellBA. (2007). Adipose-derived stem cells for regenerative medicine. Circ Res, 100:1249–1260.
95.
NingH, LiuG, LinG, YangR, LueTF and LinCS. (2009). Fibroblast growth factor 2 promotes endothelial differentiation of adipose tissue-derived stem cells. J Sex Med, 6:967–979.
96.
LinG, GarciaM, NingH, BanieL, GuoYL, LueTF and LinCS. (2008). Defining stem and progenitor cells within adipose tissue. Stem Cells Dev, 17:1053–1063.
97.
LinCS, XinZC, DengCH, NingH, LinG and LueTF. (2010). Defining adipose tissue-derived stem cells in tissue and in culture. Histol Histopathol, 25:807–815.
98.
ZaminyA, Ragerdi KashaniI, BarbarestaniM, HedayatpourA, MahmoudiR and Farzaneh NejadA. (2008). Osteogenic differentiation of rat mesenchymal stem cells from adipose tissue in comparison with bone marrow mesenchymal stem cells: melatonin as a differentiation factor. Iran Biomed J, 12:133–141.
99.
GuastiL, VagaskaB, BulstrodeNW, SeifalianAM and FerrettiP. (2014). Chondrogenic differentiation of adipose tissue-derived stem cells within nanocaged POSS-PCU scaffolds: a new tool for nanomedicine. Nanomedicine, 10:279–289.
100.
NaderiN, WildeC, HaqueT, FrancisW, SeifalianAM, ThorntonCA, XiaZ and WhitakerIS. (2014). Adipogenic differentiation of adipose-derived stem cells in 3-dimensional spheroid cultures (microtissue): implications for the reconstructive surgeon. J Plast Reconstr Aesthet Surg, 67:1726–1734.
101.
ZhangHT, LiuZL, YaoXQ, YangZJ and XuRX. (2012). Neural differentiation ability of mesenchymal stromal cells from bone marrow and adipose tissue: a comparative study. Cytotherapy, 14:1203–1214.
102.
IlzeckaJ. (1996). The structure and function of blood-brain barrier in ischaemic brain stroke process. Ann Univ Mariae Curie Sklodowska Med, 51:123–127.
103.
IiM, NishimuraH, SekiguchiH, KameiN, YokoyamaA, HoriiM and AsaharaT. (2009). Concurrent vasculogenesis and neurogenesis from adult neural stem cells. Circ Res, 105:860–868.
104.
OishiK and Ito-DufrosY. (2006). Angiogenic potential of CD44+ CD90+ multipotent CNS stem cells in vitro. Biochem Biophys Res Commun, 349:1065–1072.
105.
WurmserAE, NakashimaK, SummersRG, ToniN, D'AmourKA, LieDC and GageFH. (2004). Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature, 430:350–356.
106.
ScullyS, FrancesconeR, FaibishM, BentleyB, TaylorSL, OhD, SchapiroR, MoralL, YanW and ShaoR. (2012). Transdifferentiation of glioblastoma stem-like cells into mural cells drives vasculogenic mimicry in glioblastomas. J Neurosci, 32:12950–12960.
107.
Ricci-VitianiL, PalliniR, BiffoniM, TodaroM, InverniciG, CenciT, MairaG, ParatiEA, StassiG, LaroccaLM and De MariaR. (2010). Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature, 468:824–828.
ClarkeLE, YoungKM, HamiltonNB, LiH, RichardsonWD and AttwellD. (2012). Properties and fate of oligodendrocyte progenitor cells in the corpus callosum, motor cortex, and piriform cortex of the mouse. J Neurosci, 32:8173–8185.
110.
GalvaoRP, KasinaA, McNeillRS, HarbinJE, ForemanO, VerhaakRG, NishiyamaA, MillerCR and ZongH. (2014). Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process. Proc Natl Acad Sci U S A, 111:E4214–E4223.
111.
GoritzC, DiasDO, TomilinN, BarbacidM, ShupliakovO and FrisenJ. (2011). A pericyte origin of spinal cord scar tissue. Science, 333:238–242.
112.
OzenI, DeierborgT, MiharadaK, PadelT, EnglundE, GenoveG and PaulG. (2014). Brain pericytes acquire a microglial phenotype after stroke. Acta Neuropathol, 128:381–396.
113.
ChengL, HuangZ, ZhouW, WuQ, DonnolaS, LiuJK, FangX, SloanAE, MaoY, LathiaJD, MinW, et al. (2013). Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell, 153:139–152.
114.
KaukuaN, ShahidiMK, KonstantinidouC, DyachukV, KauckaM, FurlanA, AnZ, WangL, HultmanI, Ahrlund-RichterL, BlomH, et al. (2014). Glial origin of mesenchymal stem cells in a tooth model system. Nature, 513:551–554.
115.
TavazoieM, Van der VekenL, Silva-VargasV, LouissaintM, ColonnaL, ZaidiB, Garcia-VerdugoJM and DoetschF. (2008). A specialized vascular niche for adult neural stem cells. Cell Stem Cell, 3:279–288.
116.
ReynoldsBA and WeissS. (1992). Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science, 255:1707–1710.
117.
KriegsteinA and Alvarez-BuyllaA. (2009). The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci, 32:149–184.
118.
DoetschF, Garcia-VerdugoJM and Alvarez-BuyllaA. (1999). Regeneration of a germinal layer in the adult mammalian brain. Proc Natl Acad Sci U S A, 96:11619–11624.
119.
ShimadaIS, PetersonBM and SpeesJL. (2010). Isolation of locally derived stem/progenitor cells from the peri-infarct area that do not migrate from the lateral ventricle after cortical stroke. Stroke, 41:e552–e560.
120.
BelachewS, ChittajalluR, AguirreAA, YuanX, KirbyM, AndersonS and GalloV. (2003). Postnatal NG2 proteoglycan-expressing progenitor cells are intrinsically multipotent and generate functional neurons. J Cell Biol, 161:169–186.
121.
RichardsonWD, YoungKM, TripathiRB and McKenzieI. (2011). NG2-glia as multipotent neural stem cells: fact or fantasy?. Neuron, 70:661–673.
122.
KondoT and RaffM. (2000). Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science, 289:1754–1757.
123.
YokoyamaA, SakamotoA, KamedaK, ImaiY and TanakaJ. (2006). NG2 proteoglycan-expressing microglia as multipotent neural progenitors in normal and pathologic brains. Glia, 53:754–768.
124.
YokoyamaA, YangL, ItohS, MoriK and TanakaJ. (2004). Microglia, a potential source of neurons, astrocytes, and oligodendrocytes. Glia, 45:96–104.
125.
SainoO, TaguchiA, NakagomiT, Nakano-DoiA, KashiwamuraS, DoeN, NakagomiN, SomaT, YoshikawaH, et al. (2010). Immunodeficiency reduces neural stem/progenitor cell apoptosis and enhances neurogenesis in the cerebral cortex after stroke. J Neurosci Res, 88:2385–2397.
126.
TakataM, NakagomiT, KashiwamuraS, Nakano-DoiA, SainoO, NakagomiN, OkamuraH, MimuraO, TaguchiA and MatsuyamaT. (2012). Glucocorticoid-induced TNF receptor-triggered T cells are key modulators for survival/death of neural stem/progenitor cells induced by ischemic stroke. Cell Death Differ, 19:756–767.
127.
NakagomiT, TaguchiA, FujimoriY, SainoO, Nakano-DoiA, KuboS, GotohA, SomaT, YoshikawaH, et al. (2009). Isolation and characterization of neural stem/progenitor cells from post-stroke cerebral cortex in mice. Eur J Neurosci, 29:1842–1852.
128.
OkadaS, NakamuraM, MikamiY, ShimazakiT, MiharaM, OhsugiY, IwamotoY, YoshizakiK, KishimotoT, ToyamaY and OkanoH. (2004). Blockade of interleukin-6 receptor suppresses reactive astrogliosis and ameliorates functional recovery in experimental spinal cord injury. J Neurosci Res, 76:265–276.
129.
NakashimaK, YanagisawaM, ArakawaH, KimuraN, HisatsuneT, KawabataM, MiyazonoK and TagaT. (1999). Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science, 284:479–482.
130.
ShenQ, GoderieSK, JinL, KaranthN, SunY, AbramovaN, VincentP, PumigliaK and TempleS. (2004). Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science, 304:1338–1340.
131.
SongH, StevensCF and GageFH. (2002). Astroglia induce neurogenesis from adult neural stem cells. Nature, 417:39–44.
132.
JiaoJ and ChenDF. (2008). Induction of neurogenesis in nonconventional neurogenic regions of the adult central nervous system by niche astrocyte-produced signals. Stem Cells, 26:1221–1230.
133.
BechmannI, PrillerJ, KovacA, BontertM, WehnerT, KlettFF, BohsungJ, StuschkeM, DirnaglU and NitschR. (2001). Immune surveillance of mouse brain perivascular spaces by blood-borne macrophages. Eur J Neurosci, 14:1651–1658.
134.
HutchingsM and WellerRO. (1986). Anatomical relationships of the pia mater to cerebral blood vessels in man. J Neurosurg, 65:316–325.
135.
PieperC, MarekJJ, UnterbergM, SchwerdtleT and GallaHJ. (2014). Brain capillary pericytes contribute to the immune defense in response to cytokines or LPS in vitro. Brain Res, 1550:1–8.
136.
KovacA, EricksonMA and BanksWA. (2011). Brain microvascular pericytes are immunoactive in culture: cytokine, chemokine, nitric oxide, and LRP-1 expression in response to lipopolysaccharide. J Neuroinflammation, 8:139
137.
LiJ, TangY, WangY, TangR, JiangW, YangGY and GaoWQ. (2014). Neurovascular recovery via co-transplanted neural and vascular progenitors leads to improved functional restoration after ischemic stroke in rats. Stem Cell Reports, 3:101–114.
