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Identification and Characterization of Neuroblasts in the Subventricular Zone and Rostral Migratory Stream of the Adult Human Brain

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Identification and Characterization of Neuroblasts in the Subventricular Zone and Rostral Migratory Stream of the Adult Human Brain npg Neurogenesis in the adult human SVZ Cell Research (2011) 21:1534-1550. 1534 © 2011 IBCB, SIBS, CAS All rights reserved 1001-0602/11 $ 32.00 npg ORIGINAL ARTICLE www.nature.com/cr Identification and characterization of neuroblasts in the subventricular zone and rostral migratory stream of the adult human brain Congmin Wang1, Fang Liu1, Ying-Ying Liu2, Cai-Hong Zhao2, Yan You1, Lei Wang3, Jingxiao Zhang4, Bin Wei1, Tong Ma1, Qiangqiang Zhang1, Yue Zhang1, Rui Chen1, Hongjun Song5, Zhengang Yang1 1Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China; 2Institute of Neurosciences, The Fourth Military Medical University, Xi’an 710032, China; 3Department of Human Anatomy, Hebei Medical University, Shijiazhuang 050017, China; 4Department of Obstetrics and Gynecology, The Fourth Hospi- tal of Shijiazhuang, Shijiazhuang 050011, China; 5Institute for Cell Engineering, Department of Neurology, Johns Hopkins Univer- sity School of Medicine, Baltimore, MD 21205, USA It is of great interest to identify new neurons in the adult human brain, but the persistence of neurogenesis in the subventricular zone (SVZ) and the existence of the rostral migratory stream (RMS)-like pathway in the adult human forebrain remain highly controversial. In the present study, we have described the general configuration of the RMS in adult monkey, fetal human and adult human brains. We provide evidence that neuroblasts exist continuously in the anterior ventral SVZ and RMS of the adult human brain. The neuroblasts appear singly or in pairs without forming chains; they exhibit migratory morphologies and co-express the immature neuronal markers doublecortin, polysialylated neural cell adhesion molecule and βIII-tubulin. Few of these neuroblasts appear to be actively proliferating in the anterior ventral SVZ but none in the RMS, indicating that neuroblasts distributed along the RMS are most likely derived from the ventral SVZ. Interestingly, no neuroblasts are found in the adult human olfactory bulb. Taken together, our data suggest that the SVZ maintains the ability to produce neuroblasts in the adult human brain. Keywords: human; rhesus monkey; stem cells; neurogenesis; neuroblasts; subventricular zone; rostral migratory stream Cell Research (2011) 21:1534-1550. doi:10.1038/cr.2011.83; published online 17 May 2011 Introduction tor cells (type C cells), which in turn produce neuroblasts (type A cells) that migrate along the rostral migratory Adult neural stem cells hold the potential for therapeu- stream (RMS) into the olfactory bulb (OB). In the OB, tic applications and for mediating adaptation to normal they give rise to olfactory interneurons [4, 5]. From the and pathological stimuli. In most mammals, the genera- SVZ to the OB, the majority of migrating neuroblasts tion of new neurons (neurogenesis) from neural stem move along each other forming chains [6, 7].The RMS cells persists throughout life in the subventricular zone appears more prominent in the early postnatal rodent (SVZ) of the lateral ventricle and in the subgranular zone brain than in the adult rodent brain [8]. A similar migra- of the dentate gyrus in the hippocampus [1-3]. tion has been described in the neonatal and adult monkey In the adult mouse brain, SVZ neural stem cells (type brain [9-13]. However, the general configuration of the B cells) generate rapidly dividing intermediate progeni- RMS in coronal sections of the monkey brain has not yet been unequivocally shown. Moreover, the location where adult neuroblasts in the RMS traverse the monkey brain Correspondence: Zhengang Yang parenchyma before joining the olfactory tract (olfactory Tel: +86-21-5423-7872; Fax: +86-21-5423-7643 peduncle) remains largely unknown. E-mail: [email protected] Received 20 February 2011; revised 6 April 2011; accepted 18 April 2011; Accumulating evidence has demonstrated that SVZ published online 17 May 2011 neural stem cells (type B cells) are astrocyte-like, GFAP- Cell Research | Vol 21 No 11 | November 2011 Congmin Wang et al. npg 1535 expressing cells [4, 5]. This characterization also in- of the corpus callosum and takes a path from medial to cludes humans, where SVZ astrocytes with the character- lateral to enter the anterior olfactory nucleus (Figure 1D istics of neural stem cells were identified in vitro [14-16]. and 1I). In the anterior olfactory nucleus, neuroblasts ap- Previous studies have provided evidence suggesting that pear to take a rostral turn and then migrate into the OB neurogenesis occurs in the adult human hippocampus through the olfactory tract (Supplementary information, [17]. Two studies have also indicated the presence of a Figure S1). Some proliferating Dcx+ cells are present in putative RMS in the fetal human brain [18, 19]. How- the SVZ, as they express the cell proliferation markers ever, evidence for the presence of SVZ neurogenesis and MCM2 (Figure 1O-1S’) and Ki67 [9]. Interestingly, in an RMS-like pathway in the adult human brain remains the adult monkey olfactory tract and OB, nearly all Dcx+ highly controversial [14, 20-23]. cells express PSA-NCAM and βIII-tubulin (Tuj1), but In the present study, we have described the configura- many PSA-NCAM+ and Tuj1+ cells do not express Dcx tion of the RMS in adult monkey, fetal human and adult (Supplementary information, Figure S1). human brains. In the adult human brain, we find that there are neuroblasts in the anterior ventral SVZ and The RMS is prominent in the fetal human brain RMS, but not OB. Interestingly, these neuroblasts appear To identify and characterize neuroblasts in the hu- singly or in pairs without forming chains. Few of these man brain, we first tested the specificity of the antibodies neuroblasts appear to be actively proliferating in vivo. used in this study by immunostaining human material. This work suggests that the generation of neuroblasts Previous studies have clearly shown that there is a novel from neural stem and progenitor cells in the SVZ occurs population of Dcx+ cells in the adult human temporal in the adult human brain. cortex [24]. Moreover, a fixation delay of up to 12 h has no significant difference in the pattern of Dcx immunore- Results activity and the number of Dcx+ cells in the brain section [24]. Consistent with this report, using both goat and rab- The general configuration of the RMS in the adult mon- bit polyclonal Dcx antibodies, we observed many Dcx+ key brain cells in layer II of the inferior temporal gyrus of the adult Every day, new neurons (neuroblasts) are generated human brain (Supplementary information, Figure S2A- in the adult monkey SVZ, and they migrate through an S2C). These Dcx+ cells co-expressed PSA-NCAM and RMS to the OB [9-13]. To characterize the distribution Tuj1 (Supplementary information, Figure S2B and S2C). of neuroblasts in the SVZ and RMS of the adult rhesus We also evaluated the immunoreactivity of the MCM2 monkey, we performed double immunostaining for dou- and Ki67 antibodies on cryostat sections of the human blecortin (Dcx) and polysialylated neural cell adhesion jejunum and glioblastoma multiforme (as a positive con- molecule (PSA-NCAM) in coronal brain sections. Neu- trol from the central nervous system). The nuclei within roblasts in the monkey SVZ and RMS are Dcx+/PSA- the dividing cells of these tissues uniformly showed NCAM+, and they form chain-like structures (Figure 1) strong MCM2 and Ki67 double-labeling (Supplementary [9-11, 13]. In the SVZ, neuroblasts are mainly found in information, Figure S2D and S2E). the lateral and ventral regions (Figure 1D). Occasionally, Having established that the antibodies are compat- Dcx+/PSA-NCAM+ cells are detected in the dorsal, me- ible with human tissues, we then used these hallmarks dial and caudal SVZ, but they are sparse. to identify neuroblasts in the human fetal and adult The shape of the RMS in the primate brain differs brain. In serial coronal sections of the fetal brain (22- from that of rodents. As shown in Figure 1, the RMS in 24 weeks of gestation), 4′,6′-diamidino-2-phenylindole the adult monkey brain extends from the ventral horn (DAPI) staining and double-labeling for Dcx and Tuj1 of the lateral ventricle to the olfactory tract [9-13]. It is revealed that the RMS is prominent. The migratory surprising that the anatomical location of the RMS in the stream characterized by high cell density (demonstrated adult monkey brain can be observed in a coronal brain by DAPI staining) was observed from the lateral SVZ section (Figure 1). As in rodents, the monkey RMS is to the olfactory tract and OB (Figure 2). As expected, mainly composed of migrating neuroblasts and astro- a huge number of Dcx+ cells were observed along the cytes (Figure 1) [9, 10]. Indeed, SVZ neuroblasts in the stream (Figure 2B-2J). These Dcx+ cells co-expressed floor of the anterior horn of the lateral ventricle start to Tuj1 and PSA-NCAM (Figure 2B-2J), suggesting that form the RMS (Figure 1D). In the monkey forebrain, they are migrating neuroblasts. We also recognized that the RMS is located between the caudate nucleus and the some neuroblasts formed chains within the RMS (Figure rostrum of the corpus callosum (Figure 1D). Beneath the 2E), much like chains of migrating neuroblasts in the caudate nucleus, the RMS directly traverses the rostrum SVZ and RMS of the rodent and monkey brain (Figure 1 www.cell-research.com | Cell Research npg Neurogenesis in the adult human SVZ 1536 Figure 1 Neuroblasts in the SVZ and RMS of the adult rhesus monkey brain co-express Dcx and PSA-NCAM. (A) Photo- graph of the adult rhesus monkey brain (bottom view) showing the olfactory tract and OB. (B) The brain was cut coronally into 1.0-2.0 cm slabs. (C) DAPI staining of the coronal section shows the RMS.
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