在中樞神經(jīng)系統(tǒng)（CNS）中，血管和神經(jīng)腔室之間的精確通訊對(duì)于正常發(fā)育和功能至關(guān)重要。最近的研究表明，某些神經(jīng)元群體在發(fā)育過(guò)程中會(huì)分泌各種分子線(xiàn)索來(lái)調(diào)節(jié)脊髓和大腦中的血管生長(zhǎng)和模式。有趣的是，脈管系統(tǒng)正在成為調(diào)節(jié)新皮層發(fā)育以及成年期間干細(xì)胞生態(tài)位的重要組成部分。在這篇評(píng)論文章中，我們將首先概述胚胎和成年神經(jīng)源性利基血管的發(fā)育和維持。我們還將總結(jié)當(dāng)前對(duì)血管源性信號(hào)如何影響早期發(fā)育以及成年期神經(jīng)干細(xì)胞（NSC）行為的理解，
在鼠模型中，當(dāng)神經(jīng)板形成神經(jīng)管時(shí)，中樞神經(jīng)系統(tǒng)（CNS）在E7.5–E8左右開(kāi)始發(fā)育。在尾－尾軸處，神經(jīng)管開(kāi)始分配到由前腦，中腦和后腦組成的鼻小泡中，而尾小泡發(fā)育成脊髓。隨后是廣泛水平的祖細(xì)胞增殖，分化和神經(jīng)元的遷移，這些神經(jīng)元遷移到它們的特定區(qū)域并在其中連接并形成突觸。哺乳動(dòng)物新皮層（前腦源性腦末梢區(qū)域）是由單層增殖祖細(xì)胞（神經(jīng)上皮細(xì)胞）產(chǎn)生的六層神經(jīng)元定義的，這些細(xì)胞在其頂葉基底軸上呈高度極化狀態(tài)（Breunig等，2011））。這種祖細(xì)胞群稱(chēng)為radial神經(jīng)膠質(zhì)細(xì)胞（RGCs，也稱(chēng)為CNS的原代神經(jīng)干細(xì)胞（NSCs）； Rakic，2009年； Rash等人，2018年），最初（E10.5-E12.5）經(jīng)歷了大規(guī)模對(duì)稱(chēng)分裂擴(kuò)大，然后分化為神經(jīng)元或基底祖細(xì)胞（BP； Tbr2 +，E12.5起； Paridaen和Huttner，2014；圖1A）。他們后來(lái)經(jīng)歷了最終的對(duì)稱(chēng)分裂，也產(chǎn)生了錐體神經(jīng)元（Martínez-Cerde?o等，2006）。生成后，有絲分裂后神經(jīng)元使用神經(jīng)膠質(zhì)（RGC）依賴(lài)性的遷移模式，然后使用神經(jīng)膠質(zhì)非依賴(lài)性的遷移模式，最終獲得它們?cè)谄べ|(zhì)中的位置（Nadarajah等，2001）。
（一）發(fā)展中的小鼠新皮層的插圖。在E8.5到E10.5時(shí)，組織缺氧，主要帶有來(lái)自神經(jīng)上皮細(xì)胞的頂端祖細(xì)胞（RGC，灰色）。在此期間已經(jīng)建立了PNVP。PVP進(jìn)入，降低了缺氧，大約在E11.5之前發(fā)生，隨后通過(guò)RGC的不對(duì)稱(chēng)分裂生成其他細(xì)胞類(lèi)型，如Tbr2 + BP（黃色）和神經(jīng)元（藍(lán)色）。PNVP，神經(jīng)周?chē)軈玻?/span>PVP，腦室周?chē)窠?jīng)叢；RGC，放射狀膠質(zhì)細(xì)胞；BP，基礎(chǔ)祖細(xì)胞；EC，內(nèi)皮細(xì)胞。（B）在中樞神經(jīng)系統(tǒng)（CNS）發(fā)育中介導(dǎo)生存，生長(zhǎng)和增殖的血管源性提示。
最近的研究表明，中樞神經(jīng)系統(tǒng)在形成神經(jīng)室的同時(shí)被血管化。兩個(gè)獨(dú)立的血管神經(jīng)叢，即神經(jīng)周?chē)窠?jīng)叢（PNVP /皮血管）和腦室周?chē)窠?jīng)叢（PVP），有助于中樞神經(jīng)系統(tǒng)血管化。在E8.5和E10之間，中樞神經(jīng)系統(tǒng)開(kāi)始被中胚層衍生的成血管細(xì)胞產(chǎn)生的PNVP血管化（Hogan等，2004； Engelhardt和Liebner，2014）。該神經(jīng)叢通過(guò)E9覆蓋了整個(gè)中樞神經(jīng)系統(tǒng)，但是，在其發(fā)育過(guò)程中似乎缺乏任何時(shí)空梯度（Vasudevan等，2008）。當(dāng)PNVP已經(jīng)通過(guò)E9包裹中樞神經(jīng)系統(tǒng)時(shí)，血管從PVP進(jìn)入皮層發(fā)生在2天后，大約E11.5（Vasudevan等，2008）。）。PVP來(lái)源于位于基底神經(jīng)節(jié)原基的基底血管，該基底血管來(lái)自頸咽弓弓動(dòng)脈（Hiruma等，2002）。與從PNVP萌發(fā)的血管相反，PVP的萌發(fā)從E11開(kāi)始侵入新皮層，顯示出發(fā)育梯度，這是由腹側(cè)和背側(cè)同源盒轉(zhuǎn)錄因子的特定線(xiàn)索指示的（Vasudevan等人，2008年））。來(lái)自新皮層的脈管（PNVP）的芽苗也通過(guò)E12.5徑向侵入皮層，這是PVP衍生的芽已經(jīng)進(jìn)入并開(kāi)始在皮層的中間區(qū)域（腦室下區(qū)域，SVZ）分支的時(shí)間點(diǎn)。隨后，在神經(jīng)實(shí)質(zhì)內(nèi)，從PNVP和PVP分支發(fā)芽并融合以建立發(fā)育中的皮層的血管網(wǎng)絡(luò)（圖1A； Vasudevan等，2008）。
在生長(zhǎng)和再生過(guò)程中，來(lái)自不同組織（例如胰腺，肝臟，脂肪組織和中樞神經(jīng)系統(tǒng)）的干細(xì)胞在靠近血管的地方生長(zhǎng)，這些血管提供氧氣和營(yíng)養(yǎng)，以滿(mǎn)足干細(xì)胞的高代謝需求（Rafii等。 ，2016年）。另外，血管源性分子除了充當(dāng)氧氣和營(yíng)養(yǎng)的行為外，還可以調(diào)節(jié)干細(xì)胞的特性。它被很好地描述內(nèi)皮細(xì)胞（EC）和造血干細(xì)胞（HSC）的直接關(guān)聯(lián)調(diào)節(jié)造血干細(xì)胞的自我更新和分化經(jīng)由 angiocrine導(dǎo)出的信號(hào)（Rafii等人，2016）。造血干細(xì)胞和胚胎造血干細(xì)胞具有相似的分子和遺傳特征（Ivanova et al。，2002），表明它們對(duì)不同血管內(nèi)分泌線(xiàn)索的反應(yīng)也很常見(jiàn)。雖然成年神經(jīng)發(fā)生中充分描述了EC調(diào)節(jié)NSC的血管分泌潛力（見(jiàn)下文），但在發(fā)育過(guò)程中知之甚少。下面，我們描述了在發(fā)育中的小鼠大腦中針對(duì)該主題的一些研究。
盡管特征不如成人NSC，但多項(xiàng)體外研究已經(jīng)確定了胚胎NSC與脈管系統(tǒng)的關(guān)聯(lián)。ECs與胚胎神經(jīng)祖細(xì)胞（NPC）共培養(yǎng)時(shí)，可通過(guò)未知的可溶性因子促進(jìn)干細(xì)胞的維持（Gama Sosa等，2007； Vissapragada等，2014）。還顯示了類(lèi)似的ECs與胚胎小鼠脊髓干細(xì)胞共培養(yǎng)系統(tǒng)可增強(qiáng)NSC存活并保持其多能性（Lowry等，2008）。一項(xiàng)有趣的研究使用了與腦EC共同培養(yǎng)的新生兒NSC，揭示了這些細(xì)胞通過(guò) NSC表達(dá)的整聯(lián)蛋白α6β1和EC表達(dá)的層粘連蛋白的物理相互作用（Rosa等，2016）。這種相互作用部分通過(guò) Notch和雷帕霉素（mTOR）信號(hào)轉(zhuǎn)導(dǎo)級(jí)聯(lián)的哺乳動(dòng)物靶標(biāo)促進(jìn)了NSC的增殖（Rosa et al。，2016）。
對(duì)發(fā)育中的后腦的研究表明，RC2陽(yáng)性的NPC過(guò)程與生發(fā)區(qū)脈管系統(tǒng)發(fā)生物理相互作用（Tata等，2016）。與后腦相比，在新皮質(zhì)中，PVP模式與Tbr2 + BP的產(chǎn)生相吻合，并且這些祖細(xì)胞與傳入的PVP緊密相關(guān)（Javaherian和Kriegstein，2009年）。有趣的是，在由于異位表達(dá)血管內(nèi)皮生長(zhǎng)因子（VEGF）而導(dǎo)致脈管系統(tǒng)異常的情況下，Tbr2 +細(xì)胞仍然緊密相連并與發(fā)育中的脈管系統(tǒng)保持一致（Javaherian和Kriegstein，2009年）），因此進(jìn)一步強(qiáng)調(diào)了血管系統(tǒng)對(duì)祖細(xì)胞增殖的需求。然而，描述它們的締合的分子機(jī)制仍有待闡明。
中樞神經(jīng)系統(tǒng)被包括硬腦膜，蛛網(wǎng)膜和硬腦膜的腦膜覆蓋并保護(hù)。這些層富含血液和淋巴管以及神經(jīng)供應(yīng)。有趣的是，在對(duì)比的是神經(jīng)前體棲息的實(shí)質(zhì)組織的一般概念，越來(lái)越多的證據(jù)表明，腦膜也含有具有神經(jīng)源性簽名和向CNS形成（Bifari等人，多能干細(xì)胞。2009年，2015年，2017年 ; Decimo等人，2011 ; Nakagomi等人，2012 ; Ninomiya等人，2013 ; Kumar等人，2014）。這些靜止的放射狀神經(jīng)膠質(zhì)樣，巢蛋白陽(yáng)性干細(xì)胞在E13.5–E16.5期間產(chǎn)生，在出生后早期便遷移到新皮層，并分化為功能性皮層神經(jīng)元和投射神經(jīng)元（Bifari等人，2017年）。腦膜血液和淋巴管是否調(diào)節(jié)這些干細(xì)胞的性質(zhì)尚不清楚。
值得一提的是，少突膠質(zhì)前體細(xì)胞（OPC）是一種會(huì)產(chǎn)生成熟少突膠質(zhì)細(xì)胞的神經(jīng)膠質(zhì)細(xì)胞，在發(fā)育過(guò)程中也會(huì)與血管結(jié)合（Seo等，2014 ; Maki等，2015 ; Tsai等。 。，2016）。在存在細(xì)胞外信號(hào)提示的情況下，培養(yǎng)物中的OPC可以重新編程為多能CNS干細(xì)胞，可以自我更新并產(chǎn)生少突膠質(zhì)細(xì)胞，星形膠質(zhì)細(xì)胞和神經(jīng)元（Kondo和Raff，2000； Gaughwin等，2006）。試圖推測(cè)這些細(xì)胞外信號(hào)可能是由局部脈管系統(tǒng)響應(yīng)生長(zhǎng)組織的特定需求而引發(fā)的。
血管來(lái)源的細(xì)胞外基質(zhì)（ECM）對(duì)于for骨神經(jīng)膠質(zhì)末端的正確附著和NSC與血管的相互作用是必需的。最近的一份報(bào)告顯示，內(nèi)皮Dab1信號(hào)調(diào)節(jié)發(fā)育中的大腦中層粘連蛋白和整聯(lián)蛋白介導(dǎo)的RGC和星形膠質(zhì)細(xì)胞的締合（Segarra等，2018）。內(nèi)皮細(xì)胞Dab1的丟失會(huì)減少層粘連蛋白-α4的沉積，從而導(dǎo)致徑向膠質(zhì)神經(jīng)末梢從基底膜上脫離。隨后，這導(dǎo)致了大腦發(fā)育過(guò)程中神經(jīng)膠質(zhì)依賴(lài)性神經(jīng)元遷移和體細(xì)胞移位的缺陷，從而表明EC衍生的ECM對(duì)神經(jīng)發(fā)育很重要。
在培養(yǎng)的新生兒NPC中進(jìn)行的基因表達(dá)研究強(qiáng)調(diào)了不同NPC命運(yùn)期間代謝途徑調(diào)節(jié)劑的差異基因表達(dá)（Karsten等，2003），暗示了祖細(xì)胞在增殖和細(xì)胞命運(yùn)決定過(guò)程中的動(dòng)態(tài)代謝需求。有趣的是，導(dǎo)致高血糖的妊娠代謝變化導(dǎo)致胚胎新皮層RGC分化潛能受損，并導(dǎo)致RGC支架缺陷（Rash等人，2018年），表明血管的能量供應(yīng)對(duì)于適當(dāng)?shù)纳窠?jīng)發(fā)育至關(guān)重要。神經(jīng)祖細(xì)胞的那些變化是否受血管源性因子或差異運(yùn)輸?shù)恼{(diào)節(jié)，這一可能性尚待探索。
由于缺乏脈管系統(tǒng)，早期的胚胎腦缺氧。這種低氧組織是攜帶增殖NPC的理想生境（Lee等，2001； Zhu等，2005； Lange等，2016）。Studer等人的體外研究。（2000）確定了氧在中腦前體細(xì)胞培養(yǎng)物中的生理作用。低O 2濃度（約3％）有利于這些前體細(xì)胞的增殖，并最終加速了多巴胺能神經(jīng)元的總產(chǎn)生。進(jìn)一步研究，以了解底層的氧的作用的分子機(jī)制在體外和體內(nèi)結(jié)果表明，轉(zhuǎn)錄因子Hif1α充當(dāng)了NPC 體內(nèi)存活，生長(zhǎng)和分化的正調(diào)控因子（Tomita等，2003； Milosevic等，2007）。Hif1α在神經(jīng)細(xì)胞中的條件性敲除導(dǎo)致神經(jīng)元通過(guò)細(xì)胞凋亡而大量喪失，而新皮層表現(xiàn)出腦積水（Tomita等，2003）。在類(lèi)似的觀點(diǎn)，蘭格等。（2016）最近證明了體內(nèi)通過(guò)緩解缺氧，新皮層中的血管進(jìn)入調(diào)節(jié)了從初始RGC（新皮層發(fā)育過(guò)程中的頂端NPC）向分化模式的轉(zhuǎn)換。以更詳細(xì)的方式，首次顯示了脈管系統(tǒng)對(duì)干細(xì)胞的代謝調(diào)節(jié)。作者使用GPR124基因敲除的小鼠胚胎，其在中樞神經(jīng)系統(tǒng)中表現(xiàn)出的血管網(wǎng)絡(luò)明顯減少，從而導(dǎo)致缺氧率更高，作者描述了穩(wěn)定NPC中的Hif1α?xí)?dǎo)致糖酵解基因（如pfkfb3）的表達(dá)增加，同時(shí)伴隨RGC的增加擴(kuò)張。他們還表明Pfkfb3阻止了RGC分化，從而維持了祖細(xì)胞的增殖位（Lange等人，2016）。因此，祖先啟動(dòng)分化所需的代謝轉(zhuǎn)換需要通過(guò)血管緩解缺氧。
對(duì)發(fā)育中的小鼠后腦的研究表明，NPC有絲分裂的峰值與血管生成發(fā)芽呈正相關(guān)。有趣的是，EC所表達(dá)的Neuropilin1（NRP1）被證明可以正向調(diào)節(jié)NPC的有絲分裂行為，因?yàn)镋C特異性的NRP1缺失導(dǎo)致NPC的早熟細(xì)胞周期退出，而與組織的氧合水平無(wú)關(guān)（Tata等，2016）。）。這些結(jié)果表明，組織氧合和缺氧可能不是唯一的調(diào)節(jié)機(jī)制經(jīng)由該容器的NPC調(diào)節(jié)并建議有源angiocrine信令也可能參與。圖1B突出了中樞神經(jīng)系統(tǒng)發(fā)育過(guò)程中從進(jìn)入的脈管系統(tǒng)獲得的已知線(xiàn)索。有趣的是，最近來(lái)自發(fā)育中的前腦在不同階段的EC的RNA測(cè)序揭示了基因表達(dá)的動(dòng)態(tài)變化，包括可能充當(dāng)潛在血管分泌分子的基因以及參與代謝的基因（Hupe et al。，2017）。盡管這些代謝標(biāo)志物可能是EC代謝本身所必需的，但仍很容易推測(cè)，并且有待證明，CNS ECs在發(fā)育過(guò)程中的代謝調(diào)節(jié)會(huì)導(dǎo)致EC衍生的血管分泌因子可能影響NPC功能。
多年來(lái)，人們一直認(rèn)為新神經(jīng)元的產(chǎn)生是胚胎和出生后早期中樞神經(jīng)系統(tǒng)組織的特權(quán)。然而，新的神經(jīng)元和神經(jīng)膠質(zhì)的誕生也發(fā)生在成年哺乳動(dòng)物的大腦中，并在整個(gè)生命中持續(xù)下去，這一過(guò)程被稱(chēng)為“成人神經(jīng)發(fā)生”（Ming and Song，2011）。已在成年腦內(nèi)的不同位置鑒定出產(chǎn)生神經(jīng)元和神經(jīng)膠質(zhì)的NSC，例如海馬齒狀回（DG）的顆粒下亞區(qū)（SGZ），側(cè)腦室SVZ和與第三腦室壁相鄰的下丘腦（ Kokoeva等人，2007； Lin和Iacovitti，2015）。與中樞神經(jīng)系統(tǒng)發(fā)育的胚胎階段相似，最近的研究也強(qiáng)調(diào)了成年大鼠腦和脊髓中軟腦膜的想法，認(rèn)為其潛在潛伏位點(diǎn)具有具有神經(jīng)源性潛能的干細(xì)胞/前體細(xì)胞，并且可以在脊髓過(guò)程中功能性參與實(shí)質(zhì)反應(yīng)（Bifari等，2009； Decimo等，2011； Nakagomi等，2012）。
SVZ代表成人大腦中最大的生發(fā)區(qū)。SVZ的NSC（B型細(xì)胞）是處于靜止?fàn)顟B(tài)的星形膠質(zhì)細(xì)胞（Codega等，2014； Mich等，2014）。激活后，它們會(huì)產(chǎn)生轉(zhuǎn)運(yùn)擴(kuò)增前體（C型細(xì)胞或TAC），進(jìn)而產(chǎn)生神經(jīng)母細(xì)胞（A型細(xì)胞）或神經(jīng)膠質(zhì)細(xì)胞（圖2A； Kriegstein和Alvarez-Buylla，2009； Ming和Song，2011）。 。成神經(jīng)細(xì)胞沿著鼻尖遷移流（RMS）遷移到嗅球（OB），在那里它們分化為成熟的中間神經(jīng)元（Kriegstein和Alvarez-Buylla，2009； Ming和Song，2011年）。與SVZ相比，SGZ的NSC產(chǎn)生神經(jīng)母細(xì)胞，這些神經(jīng)母細(xì)胞短距離遷移到DG中并成熟成齒狀顆粒神經(jīng)元（Zhao等，2008； Bonaguidi等，2012）。
（A）成年小鼠大腦中腦室下區(qū)域（SVZ）神經(jīng)源壁iche的示意圖。神經(jīng)干細(xì)胞（NSC）產(chǎn)生轉(zhuǎn)運(yùn)放大細(xì)胞，繼而引起遷移的神經(jīng)母細(xì)胞。NSC位于室管膜細(xì)胞層下方。NSC的基礎(chǔ)過(guò)程與血管的EC接觸。請(qǐng)注意，周細(xì)胞以及NSC和星形膠質(zhì)細(xì)胞的末端緊密包裹了血管。NSC的過(guò)程，周細(xì)胞和利基星形膠質(zhì)細(xì)胞形成神經(jīng)血管單位（NVU），對(duì)于控制利基處的特定EC血腦屏障（BBB）特性很重要。（B）在成年的CNS中促進(jìn)NSC及其子代靜止，存活，增殖和分化的EC來(lái)源提示。
在成年神經(jīng)源性壁N中，神經(jīng)干細(xì)胞位于一個(gè)特殊的微環(huán)境中，在那里它們會(huì)與影響其行為的各種細(xì)胞相互作用。成年SVZ小生境的細(xì)胞成分包括NSC及其子代，內(nèi)襯腦脊液（CSF）的腦室的室管膜細(xì)胞，神經(jīng)元，非干細(xì)胞星形膠質(zhì)細(xì)胞，小膠質(zhì)細(xì)胞以及脈管系統(tǒng)的成分（EC和周細(xì)胞；圖） 2A； Ihrie和Alvarez-Buylla，2011； Bjornsson等，2015）。與SVZ中的B細(xì)胞不同，SGZ中的NSC位置不同，并且更深地嵌入腦實(shí)質(zhì)中，遠(yuǎn)離心室壁，周?chē)巧窠?jīng)元，神經(jīng)膠質(zhì)和血管（Fuentealba et al。，2012）。
SVZ的NSC位于室管膜細(xì)胞層下方。它們表現(xiàn)出極化的形態(tài)，使人聯(lián)想到其胚胎的前身ors狀膠質(zhì)細(xì)胞。更具體地說(shuō)，它們擴(kuò)展了一個(gè)短的頂端過(guò)程，該過(guò)程通過(guò)室間隔膜細(xì)胞層投射以直接進(jìn)入CSF（Mirzadeh等，2008）。此外，它們還延長(zhǎng)了一個(gè)較長(zhǎng)的基礎(chǔ)過(guò)程，通過(guò)特殊的腳部接觸血管（圖2A； Mirzadeh等人，2008； Fuentealba等人，2012）。）。與在SVZ NSC中觀察到的根尖基底形態(tài)相似，SGZ的星形星形膠質(zhì)細(xì)胞（用作NSC）高度極化，其近側(cè)區(qū)域面向孔，包括與血管的接觸，初級(jí)纖毛和與之接觸的側(cè)突其他星形星形膠質(zhì)細(xì)胞（Fuentealba等，2012）。遠(yuǎn)側(cè)區(qū)域是高度分支的，并與神經(jīng)元過(guò)程和其他神經(jīng)膠質(zhì)細(xì)胞接觸（Fuentealba等，2012）。因此，SVZ和SGZ中的NSC都準(zhǔn)備好接收來(lái)自血管腔的信號(hào)。
在成年海馬中，神經(jīng)元新生的血管周?chē)鷳B(tài)位首先被描述為分裂的EC與新生神經(jīng)元的解剖學(xué)聯(lián)系（Palmer等，2000）。自那時(shí)以來(lái)，大量研究集中于脈管系統(tǒng)在干細(xì)胞壁ches中的重要作用，并確定了涉及干細(xì)胞穩(wěn)態(tài)的EC分泌以及膜結(jié)合信號(hào)分子的令人印象深刻的庫(kù)（圖2B）。重要研究的主要發(fā)現(xiàn)將在下面的段落中描述。
與非神經(jīng)源性大腦區(qū)域相比，成人SGZ和SVZ中的脈管系統(tǒng)都具有獨(dú)特的高度組織性（Shen等人，2008； Tavazoie等人，2008； Sun等人，2015）。更具體地說(shuō)，這兩個(gè)神經(jīng)源性壁are的特征是密集的平面，相互連接且相對(duì)不曲折（筆直）的血管網(wǎng)絡(luò)，為NSC及其后代提供了底物（Shen等人，2008； Tavazoie等人，2008； Wang等，2008）。 Culver等，2013； Sun等，2015）。但是，即使SVZ和SGZ的血管床均支持成人神經(jīng)發(fā)生，SVZ的脈管系統(tǒng)似乎也具有獨(dú)特的特征（Tavazoie等人，2008）。與大腦的其他區(qū)域相反，在大腦的其他區(qū)域，通過(guò)EC緊密連接和粘附連接，周細(xì)胞覆蓋和星形膠質(zhì)細(xì)胞的尾端來(lái)嚴(yán)格維持血腦屏障（BBB）的完整性，有人提出在大腦中存在一種具有特殊功能的改良BBB。 SVZ（Tavazoie et al。，2008）。有趣的是，小的示蹤分子研究表明，SVZ具有部分可滲透的血腦屏障，可讓血液進(jìn)入血液中（Tavazoie等，2008）。）。這些源自血液的信號(hào)影響NSC的行為并調(diào)節(jié)命運(yùn)規(guī)范，分化，靜止和增殖。此外，NSC及其直接后代（C細(xì)胞）分別在缺乏周細(xì)胞和星形膠質(zhì)細(xì)胞完全覆蓋的專(zhuān)門(mén)部位，直接與EC與其基礎(chǔ)過(guò)程和細(xì)胞體接觸，這表明直接進(jìn)行NSC-EC交流也可能很重要用于調(diào)節(jié)NSC行為（Tavazoie等，2008）。
大量研究表明，EC如何通過(guò)分泌因子調(diào)節(jié)NSC行為。BDNF是第一個(gè)經(jīng)EC分泌的分子，被證明能增加成年鳴禽大腦中的神經(jīng)發(fā)生（新生成的功能神經(jīng)元的數(shù)量）（Louissaint等，2002）。在體外，據(jù)報(bào)道，EC來(lái)源的BDNF支持SVZ外植體中神經(jīng)突的生長(zhǎng)，新生神經(jīng)母細(xì)胞的存活和遷移（Leventhal等人，1999）。從那時(shí)起，該領(lǐng)域從使用NSC / EC跨孔培養(yǎng)的體外研究中獲得了進(jìn)一步的見(jiàn)識(shí)，其中EC釋放的可溶性因子刺激自我更新，抑制分化并增強(qiáng)NSC的神經(jīng)發(fā)生（Shen等人，2004年）。內(nèi)皮細(xì)胞和室管膜細(xì)胞釋放的色素上皮衍生因子（PEDF）是第一個(gè)可溶的因子，可通過(guò)增強(qiáng)Notch依賴(lài)性轉(zhuǎn)錄選擇性增加SVZ中B細(xì)胞的自我更新，并隨后增強(qiáng)神經(jīng)發(fā)生（Ramírez-Castillejo等等人，2006；Andreu-Agulló等人，2009）。同樣，毛細(xì)血管內(nèi)皮細(xì)胞和脈絡(luò)叢神經(jīng)表達(dá)的EGF家族成員βcellulin（BTC）通過(guò)分別通過(guò)位于NSC和神經(jīng)母細(xì)胞上的EGF和ErbB4受體的作用，誘導(dǎo)NSC和神經(jīng)母細(xì)胞的擴(kuò)增（Gómez-Gaviro等，2012）。血管叢和室管膜細(xì)胞表達(dá)的趨化因子基質(zhì)衍生因子（SDF1；也稱(chēng)為CXCL12）也顯示出通過(guò)結(jié)合CXCR4受體對(duì)NSC譜系的不同階段具有不同的作用將活性NSC（aNSC）和TAC歸巢到血管中（Kokovay et al。，2010）。最近的一項(xiàng)研究進(jìn)一步表明，SDF1的表達(dá)在毛細(xì)管中受到特定限制，并且aNSC及其后代優(yōu)先與它們相關(guān)。相比之下，qNSC在SDF1陰性血管附近最為普遍（Zhu等，2019）。一種在體外研究已經(jīng)確定胎盤(pán)生長(zhǎng)因子2（PlGF-2）是VEGF受體1（VEGFR1）的配體，是EC衍生的因子，可以促進(jìn)SVZ干細(xì)胞及其后代的增殖（Crouch et al。，2015）。最近的研究也表明，可擴(kuò)散信號(hào)會(huì)強(qiáng)制靜止并促進(jìn)干細(xì)胞身份。更具體地說(shuō)，EC分泌神經(jīng)營(yíng)養(yǎng)蛋白3（NT-3）以支持表達(dá)原肌球蛋白相關(guān)激酶C（TrkC）受體的NSC的靜止（Delgado等，2014）。此外，已證明兩種鞘氨醇-1-磷酸（S1P）和前列腺素-D 2（兩種EC衍生的GPCR配體）可積極維持NSC的靜止（Codega等人，2014年）。總而言之，這些研究表明，EC衍生的因子可以同時(shí)強(qiáng)制靜止并促進(jìn)增殖，這取決于NSC的激活狀態(tài)，因此暗示了沿譜系的雙重調(diào)控。
如上所述，NSCs通過(guò)其長(zhǎng)期的基礎(chǔ)過(guò)程和專(zhuān)門(mén)的末端與血管直接接觸。一些研究調(diào)查了EC和NSC之間這些直接細(xì)胞間相互作用的重要性，并顯示了它們?nèi)绾螐?qiáng)制靜止并促進(jìn)干細(xì)胞特性。更具體地說(shuō)，ECs在其膜中分別通過(guò)激活Eph和Notch信號(hào)表達(dá)ephrinB2和Jagged1，它們促進(jìn)了通過(guò)其基礎(chǔ)過(guò)程與之接觸的NSC中的靜止（Ottone等，2014）。）。除這項(xiàng)研究外，整合素介導(dǎo)的信號(hào)傳導(dǎo)還顯示出在其利基體內(nèi)結(jié)合SVZ干細(xì)胞的功能。更具體地，成年NSC表達(dá)層粘連蛋白受體α6β1整聯(lián)蛋白，從而使這些細(xì)胞能夠結(jié)合血管周?chē)缓瑢诱尺B蛋白的環(huán)境。該α6β1整聯(lián)蛋白信號(hào)傳導(dǎo)對(duì)于NSC與EC結(jié)合非常重要，因?yàn)?/span>體內(nèi)阻斷α6β1 導(dǎo)致SVZ祖細(xì)胞從脈管系統(tǒng)遷移出去（Shen等，2008）。
血液循環(huán)物質(zhì)可以直接通過(guò) SVZ 的部分滲透性BBB（基于Tavazoie等人，2008的結(jié)果）或通過(guò)脈絡(luò)叢/ CSF 間接訪(fǎng)問(wèn)SVZ神經(jīng)源性利基，并且已顯示會(huì)影響神經(jīng)源性利基。例如，催乳素是一種在懷孕期間被上調(diào)并由血流攜帶的激素，在增強(qiáng)懷孕期間SVZ的神經(jīng)發(fā)生中起關(guān)鍵作用（Shingo等人，2003年）。此外，循環(huán)中的促紅細(xì)胞生成素可以作為一個(gè)完整的分子穿過(guò)血腦屏障，并在胚胎發(fā)育過(guò)程中作為干細(xì)胞祖細(xì)胞的增強(qiáng)刺激物，以及大腦局部缺血的旁分泌神經(jīng)保護(hù)介質(zhì)（Ruscher等，2002）。）。使用異時(shí)共生模型，即連接年輕和年老小鼠的循環(huán)，顯示了刺激SVZ神經(jīng)發(fā)生的血液傳播循環(huán)因子的令人興奮的演示。在這項(xiàng)研究中，GDF11被確定為增加老年小鼠神經(jīng)發(fā)生所必需的因子（Katsimpardi等，2014）。循環(huán)因素也可能對(duì)神經(jīng)發(fā)生產(chǎn)生負(fù)面影響。例如，皮質(zhì)酮和趨化因子CCL11均顯示抑制神經(jīng)發(fā)生（Villeda等，2011）。
如上所述，在動(dòng)態(tài)平衡過(guò)程中，脈管系統(tǒng)在協(xié)調(diào)成人CNS中的NSC命運(yùn)方面起著重要作用。但是，其指導(dǎo)作用超出了生理?xiàng)l件，在病理性損傷（例如腦梗死）期間和之后似乎至關(guān)重要。更具體地，許多研究表明，ECs促進(jìn)中風(fēng)后皮層中神經(jīng)干/祖細(xì)胞的存活，增殖和神經(jīng)元分化（Nakagomi等，2009； Nakano-Doi等，2010）。中風(fēng)后，受傷區(qū)域的血管上調(diào)SDF1和血管生成素1（Ang1）的表達(dá)，從而將成神經(jīng)細(xì)胞吸引到梗塞周?chē)鷧^(qū)域，并促進(jìn)神經(jīng)發(fā)生和功能恢復(fù)（Ohab等人，2006年））。同樣，在缺血性紋狀體中，ECs合成BDNF，從而促進(jìn)神經(jīng)母細(xì)胞向損傷部位的募集和脈管介導(dǎo)的遷移（Grade等，2013）。這些研究突顯了血管作為將成神經(jīng)細(xì)胞遷移到梗塞區(qū)域的支架的額外作用（Kojima等，2010； Grade等，2013）。但是，該主題不在我們的討論范圍之內(nèi)，因此請(qǐng)讀者參考Saghatelyan（2009）。丁等。（2013）; 澤田等。（2014）; 阮等人。（2015）和Horgusluoglu等人。（2017）了解更多詳細(xì)信息。
成年NSC構(gòu)成了一個(gè)非?；钴S的種群，最近的NSC轉(zhuǎn)錄組分析顯示，沿神經(jīng)源性譜系的過(guò)渡與它們的代謝特征發(fā)生了變化（Llorens-Bobadilla等，2015； Shin等，2015）。更具體地說(shuō)，在處于靜止?fàn)顟B(tài)并因此處于低代謝狀態(tài)時(shí)，神經(jīng)干細(xì)胞優(yōu)先利用糖酵解和脂肪酸氧化（FAO;脂解）來(lái)滿(mǎn)足其能量需求（Ito和Suda，2014年 ; Llorens-Bobadilla等人，2015年 ; Shin等人。 ，2015 ; Stoll等人，2015 ; Xie等人，2016 ; Knobloch和Jessberger，2017 ; Knobloch等人，2017）。相反，在高度增殖的aNSC中，其分化的子代線(xiàn)粒體氧化磷酸化（OXPHOS）以及從頭脂肪形成接管細(xì)胞分裂（Knobloch等人，2013； Ito和Suda，2014； Llorens-Bobadilla等人，2015）。 ; Shin等，2015）。同樣，胚胎腦的NSC表現(xiàn)出其擴(kuò)展和/或維持所必需的高糖酵解活性，而其分化后會(huì)降低（Lange等人，2016）。這些研究表明，代謝輸入和營(yíng)養(yǎng)物質(zhì)的利用是神經(jīng)發(fā)生的關(guān)鍵調(diào)節(jié)劑，并有助于NSC的決策。因此，脈管系統(tǒng)成為NSC代謝的關(guān)鍵調(diào)節(jié)器，因?yàn)樗鼮榇竽X提供了營(yíng)養(yǎng)和氧氣，并確保滿(mǎn)足NSC的能量需求。
與它們的胚胎前代相似，成年的神經(jīng)干細(xì)胞生活在低氧水平（<1％–6％）的生態(tài)位中，因此強(qiáng)調(diào)了其在干細(xì)胞功能中的重要性（Ochocki和Simon，2013年）。大量的體外研究已經(jīng)研究了氧氣在NSC自我更新和命運(yùn)規(guī)范中的作用，并證明了低氧氣含量對(duì)NSC有利于促進(jìn)NSC的增殖和存活。NSC通過(guò)關(guān)閉OXPHOS以支持糖酵解代謝來(lái)應(yīng)對(duì)缺氧。這是由低氧誘導(dǎo)的轉(zhuǎn)錄因子（HIFs）精心策劃的，該因子在低氧氣利用率下穩(wěn)定并被激活（<9％； Majmundar等，2010）。HIF1α信號(hào)對(duì)于正常的NSC功能至關(guān)重要。例如，HIF1α的特異性缺失在成年小鼠引線(xiàn)的神經(jīng)干細(xì)胞在成人SVZ NSCs的顯著減少，從而突出在兩個(gè)調(diào)節(jié)NSCs的自我更新，增殖和分化的氧和感測(cè)機(jī)制的重要性在體外和在體內(nèi)（Li et al。，2014）。有趣的是，NSC編碼的Hif1α對(duì)維持成年SVZ的血管完整性以及穩(wěn)定腦損傷后的脈管系統(tǒng)也很重要（Roitbak等，2008； Li等，2014）。）。此外，缺氧與NSC中的Wnt /β-catenin信號(hào)傳導(dǎo)有關(guān)，這表明氧的可用性通過(guò)Wnt /β-catenin信號(hào)的Hif1α調(diào)節(jié)在NSC調(diào)控中具有直接作用（Mazumdar等，2010）。盡管有這些最初的發(fā)現(xiàn)，但成人組織中Hif1α作用的潛在分子機(jī)制仍然難以捉摸。
除了氧氣之外，營(yíng)養(yǎng)素還包括成人神經(jīng)發(fā)生的重要調(diào)節(jié)劑。如前所述，營(yíng)養(yǎng)素，生長(zhǎng)因子和循環(huán)激素可以通過(guò)脈管系統(tǒng)通過(guò)擴(kuò)散或通過(guò)轉(zhuǎn)運(yùn)介導(dǎo)的系統(tǒng)來(lái)輸送，并影響NSC的行為。這意味著存在一些分子機(jī)制，可對(duì)營(yíng)養(yǎng)物質(zhì)的利用做出響應(yīng)，并協(xié)調(diào)NSC對(duì)能量變化的響應(yīng)（例如，熱量限制，運(yùn)動(dòng)，病理，衰老等）。在這些機(jī)制中，sirtuins，CREB，AMPK和胰島素/ IGF途徑是最典型的機(jī)制。在本文中，我們將重點(diǎn)關(guān)注后者，因?yàn)樗ㄒ粋€(gè)通過(guò)激活大量下游信號(hào)級(jí)聯(lián)反應(yīng)來(lái)中樞神經(jīng)系統(tǒng)的發(fā)展和功能的中央調(diào)節(jié)器。有關(guān)其他途徑的更多詳細(xì)信息，2010 ; Rafalski和Brunet，2011年；Houtkooper等，2012；Ochocki和Simon，2013年；伊藤和須田，2014年；Fusco et al。，2016）。
One of the brain’s mechanisms to respond to glucose and energy excess is the insulin/IGF-1 signaling pathway. Systemic IGF-1 and insulin can both cross the BBB and bind to their tyrosine kinase receptors leading to their auto-phosphorylation (Hubbard, 2013; Kavran et al., 2014). Recently, a study focusing on neurovascular coupling has demonstrated that neuronal activity can induce changes in BBB permeability thus promoting the release and entrance of IGF-1 into the CNS, and consequently leading to an increase in its availability (Nishijima et al., 2010). The receptors for insulin/IGF-1 are highly expressed in NSCs in neurogenic niches, and several studies have implicated insulin/IGF-1 signaling in NSC maintenance, proliferation and differentiation (Rafalski and Brunet, 2011). More specifically, in vivo infusion of IGF-1 induces NSC proliferation and subsequent neurogenesis in the adult rat hippocampus (Aberg et al., 2000). Similarly, IGF-1 has a direct proliferative effect in adult hippocampal NSCs in vitro (Aberg et al., 2003). Even though the role of insulin in adult NSCs in vivo has not been elucidated, in vitro studies have demonstrated that insulin can induce neurogenesis (Han et al., 2008; Yu et al., 2008; Rhee et al., 2013). The main mediator of insulin/IGF-1 signaling in NSCs is the PI3K/Akt signal transduction pathway and many downstream signaling components have been shown to be involved in NSC biology, including FoxO transcription factors and mTOR (Rafalski and Brunet, 2011).
FoxO transcription factors have been shown to be essential for both embryonic and adult stem cells (Rafalski and Brunet, 2011; Rafalski et al., 2012). Gene expression analysis in adult NSCs shows that FoxO transcription factors, and in particular FoxO3, induce a specific program of genes that preserves quiescence, and controls glucose and oxygen metabolism thus highlighting their role in NSC homeostasis (Renault et al., 2009). Accordingly, in the absence of FoxOs NSCs hyperproliferate, leading to the exhaustion of the quiescent stem cell pool (Renault et al., 2009). FoxOs are negatively regulated by the insulin/IGF-1 pathway through the PI3K/Akt branch, thus suggesting a direct link between nutrient availability and stem cell metabolism (Rafalski and Brunet, 2011).
The mTOR is a central regulator of cell homeostasis and protein synthesis. In neurogenic niches, several studies have highlighted its role in many aspects of neurogenesis as it is involved in fine-tuning the balance between stem cell self-renewal and differentiation (Magri and Galli, 2013; LiCausi and Hartman, 2018). For example, recent in vivo studies in adult mice have demonstrated that mTOR activation promotes NSC proliferation and subsequent neuronal differentiation, at the expense of quiescence and self-renewal (Paliouras et al., 2012). In contrast, sustained mTOR activation in embryonic NSCs leads to premature differentiation and apoptosis at the expense of the stem cell pool (Magri et al., 2011; Kassai et al., 2014). mTOR can be activated in response to insulin/IGF, nutrients such as glucose and amino acids, as well as pro-inflammatory cytokines (e.g., TNFα, CD95; Magri and Galli, 2013; LiCausi and Hartman, 2018). In contrast, many cellular stresses such as hypoxia and low energy act to inactivate mTOR (Magri and Galli, 2013; LiCausi and Hartman, 2018).
In the past years, significant progress has been made to support the concept of a perivascular niche that regulates stem cells, and blood vessels have emerged as an integral component of both embryonic and adult neurogenic niches. In the developing brain, current knowledge on how blood vessels regulate NSCs is limited, in part due to the limitations of working with mouse embryos. Emerging new technical approaches, such as whole tissue imaging and single cell sequencing, will rapidly pave the path towards a better understanding of cell-cell interactions and molecular signaling pathways required for proper development of the CNS, and in particular towards the vascular control of NSC properties. Accruing to this, recent sequencing data obtained from embryonic mouse CNS tissue describes an interesting list of genes expressed by ECs during development, which could act as angiocrine factors and directly regulate NPC properties (Lange et al., 2016; Hupe et al., 2017). However, their influence on the NPCs still needs to be addressed.
Similarly, in the adult SVZ and SGZ, the close interaction of blood vessels and NSCs has a substantial impact on the behavior of the latter. An important number of studies have demonstrated that EC-derived factors, as well as direct NSC-EC interactions, can affect NSC self-renewal, proliferation, differentiation, and survival. It is now recognized that this NSC lineage progression from quiescence to activation is characterized by alterations in their metabolic status. However, whether and how signals derived from the vasculature, or how physiological remodeling of the vasculature, are directly “translated” into the metabolic switches that accompany the cellular states of NSCs needs to be further explored. In this respect, nutrients are necessary for neurogenesis, and NSCs have developed a repertoire of sensing mechanisms to respond to nutrient availability. As blood vessels comprise the main conduits for nutrients and oxygen, it would be of great interest to investigate whether NSCs can “talk” back to ECs to regulate nutrient availability for their own demands.
All the authors listed contributed to the concept and design of the manuscript. AK and BS wrote the manuscript and prepared the figures. CRA wrote and critically revised the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Funding. We acknowledge financial support by Deutsche Forschungsgemeinschaft within the funding programme Open Access Publishing, by the Baden-Württemberg Ministry of Science, Research and the Arts and by Ruprecht-Karls-Universit?t Heidelberg. CRA’s research was funded by ERC grant (ERC-StG-311367), Schram Foundation, and the Deutsche Forschungsgemeinschaft (DFG)-SFB873; FOR2325 and SFB1366 (Project number 394046768-SFB 1366).
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