1、Advances in Experimental Medicine and Biology 853MoneebEhtesham EditorStem Cell Biology in Neoplasms of the Central Nervous SystemAdvances in Experimental Medicine and BiologyVOLUME 853Series EditorsIrun R. CohenTheWeizmann Institute of Science RehovotIsraelN. S. Abel LajthaKline Institute for Psych

2、iatric Res OrangeburgNewYork USARodolfo Paoletti University of Milan MilanItalyJohn D. Lambris Univ. Of Pennsylvania Philadelphia PennsylvaniaUSAAdvances in Experimental Medicine and Biology presents multidisciplinary and dynamic findings in the broad fields of experimental medicine and biology. The

3、 wide variety in topics it presents offers readers multiple perspectives on a variety of disci- plines including neuroscience, microbiology, immunology, biochemistry, biomedical engineering and cancer research. Advances in Experimental Medicine and Biology has been publishing exceptional works in th

4、e field for over 30 years and is indexed in Medline, Scopus, EMBASE, BIOSIS, Biological Abstracts, CSA, Biological Sciences and Living Resources (ASFA-1), and Biological Sciences. The series also provides scientists with up to date information on emerging topics and techniques.2013 Impact Factor: 2.

5、012More information about this series at /series/5584Moneeb EhteshamEditorStem Cell Biologyin Neoplasms of the Central Nervous SystemEditorMoneeb Ehtesham Department of NeurosurgeryVanderbilt University Medical Center Nashville, TN, USAISSN 0065-2598ISSN 2214-8019 (electronic)A

6、dvances in Experimental Medicine and BiologyISBN 978-3-319-16536-3ISBN 978-3-319-16537-0 (eBook) DOI 10.1007/978-3-319-16537-0Library of Congress Control Number: 2015937184 Springer Cham Heidelberg New York Dordrecht London Springer International Publishing Switzerland 2015This work is subject to co

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8、orage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed.The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statem

9、ent, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the

10、 publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.Printed on acid-free paperSpringer International Publishing AG Switzerland is part of Springer Science+Business Media (w

11、)To my juniorsJ.A.M., A.M.M., S.L.Z., A.S.No man could ask for a better team in the heat of battleA volume like this is beyond the scope of one person/editors effort. There are count- less hours spent contacting authors, reviewing submissions, and cross-checking ref- erences and publi

12、cation permissionstedious work that can be draining but remains essential for a project like this to succeed. This project would have failed miserably if it were not for the tireless effort and dedication of Imad Saeed Khan, M.D., whose assistance in making this volume a reality is tremendously appr

13、eciated by me and all those involved. Thank you, Imad, for your passion in helping make this idea a real- ity. I would also like to thank Fiona Sarne, Joy Evangeline Bramble, and Sabina Ashbaugh at Springer who, together, were always available to assist and shepherd this project through, and whose h

14、elp made this volume a pleasure to work on.viixContentsImmunobiology and Immunotherapeutic Targetingof Glioma Stem Cells .Mecca Madany, Tom M. Thomas, Lincoln Edwards, and John S. YuEmerging Strategies for the Treatment of Tumor Stem Cellsin Central Nervous System Malignancies .Imad Saeed Khan and M

15、oneeb Ehtesham139167Index.189Regulation of Subventricular Zone-Derived Cells Migrationin the Adult Brain1Vivian Capilla-Gonzalez, Emily Lavell, Alfredo Quiones -Hinojosa, and Hugo Guerrero-CazaresThe SVZ and Its Relationship to Stem Cell BasedNeuro-oncogenesis23Yael Kusne and Nader SanaiIsolation an

16、d Characterization of Stem Cells from HumanCentral Nervous System Malignancies33Imad Saeed Khan and Moneeb EhteshamThe Role of Stem Cells in Pediatric Central NervousSystem Malignancies49Branavan Manoranjan, Neha Garg, David Bakhshinyan, and Sheila K. SinghLaboratory Models for Central Nervous Syste

17、m TumorStem Cell Research69Imad Saeed Khan and Moneeb EhteshamRadiation Therapy for Glioma Stem Cells85Anthony E. Rizzo and Jennifer S. YuChemoresistance and Chemotherapy Targeting Stem-Like Cellsin Malignant Glioma111Mia Dahl Srensen, Sigurd Fosmark, Sofie Hellwege, Dagmar Beier,Bjarne Winther Kris

18、tensen, and Christoph Patrick BeierixDavid Bakhshinyan McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, CanadaDepartment of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON, CanadaChristoph Patrick Beier Departmen

19、t of Neurology, University of Southern Denmark, Odense C, DenmarkInstitute of Clinical Research, University of Southern Denmark, Odense M, DenmarkDagmar Beier Department of Neurology, University of Southern Denmark, Odense C, DenmarkInstitute of Clinical Research, University of Southern Denmark, Ode

20、nse M, DenmarkVivian Capilla-Gonzalez Stem Cells Department, Andalusian Molecular Biology and Regenerative Medicine Centre, Seville, SpainDepartment of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USALincoln Edwards Maxine Dunitz Neurosurgical Institute, Ced

21、ars-Sinai Medical Center, Los Angeles, CA, USAMoneeb Ehtesham Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN, USASigurd Fosmark Department of Pathology, Odense University Hospital, Odense C, DenmarkInstitute of Clinical Research, University of Southern Denmar

22、k, Odense M, DenmarkNeha Garg McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, CanadaHugo Guerrero-Cazares Department of Neurosurgery, Johns Hopkins University School, Baltimore, MD, USAxixiiContributorsSofie Hellwege Department of Pathology, Odense University Hos

23、pital, Odense C, DenmarkInstitute of Clinical Research, University of Southern Denmark, Odense M, DenmarkImad Saeed Khan Section of Neurosurgery, Geisel School of Medicine at Dartmouth, Lebanon, NH, USABjarne Winther Kristensen Department of Pathology, Odense University Hospital, Odense C, DenmarkIn

24、stitute of Clinical Research, University of Southern Denmark, Odense M, DenmarkYael Kusne Barrow Brain Tumor Research Center, Phoenix, AZ, USAEmily Lavell Department of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USAMecca Madany Maxine Dunitz Neurosurgical

25、Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USAGraduate Program in Biological Science & Translational Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USABranavan Manoranjan McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, CanadaMichael G. DeGr

26、oote School of Medicine, McMaster University, Hamilton, ON, CanadaDepartment of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON, CanadaAlfredo Quiones -Hinojosa Department of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, B

27、altimore, MD, USAAnthony E. Rizzo Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USANader Sanai Barrow Brain Tumor Research Center, Phoenix, AZ, USASheila K. Singh McMaster Stem Cell and Cancer Research Institute, McMaster Unive

28、rsity, Hamilton, ON, CanadaMichael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, CanadaDepartment of Biochemistry and Biomedical Sciences, Faculty of Health Sciences, McMaster University, Hamilton, ON, CanadaDepartment of Surgery, Faculty of Health Sciences, McMaster University,

29、 Hamilton, ON, CanadaMia Dahl Srensen Department of Pathology, Odense University Hospital, Odense C, DenmarkInstitute of Clinical Research, University of Southern Denmark, Odense M, DenmarkContributorsxiiiTom M. Thomas Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles,

30、CA, USAGraduate Program in Biological Science & Translational Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USAJennifer S. Yu Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH, USADepartment of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Clevelan

31、d Clinic, Cleveland, OH, USAJohn S. Yu Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USARegulation of Subventricular Zone-Derived Cells Migration in the Adult BrainVivian Capilla-Gonzalez, Emily Lavell, Alfredo Quiones -Hinojosa, and Hugo Guerrero-CazaresAbstra

32、ct The subventricular zone of the lateral ventricles (SVZ) is the largest source of neural stem cells (NSCs) in the adult mammalian brain. Newly generated neuroblasts from the SVZ form cellular chains that migrate through the rostral migratory stream (RMS) into the olfactory bulb (OB), where they be

33、come mature neurons. Migration through the RMS is a highly regulated process of intrinsic and extrinsic factors, orchestrated to achieve direction and integration of neuroblasts into OB circuitry. These factors include internal cytoskeletal and volume regulators, extracellular matrix proteins, and c

34、hemoattractant and chemorepellent proteins. All these molecules direct the cells away from the SVZ, through the RMS, and into the OB guaranteeing their correct integration. Following brain injury, some neuroblasts escape the RMS and migrate into the lesion site to participate in regeneration, a phen

35、omenon that is also observed with brain tumors. This review focuses on factors that regulate the migration of SVZ precursor cells in the healthy and pathologic brain. A better understanding of the factors that control the movement of newly generated cells may be crucial for improving the use of NSC-

36、replacement therapy for specific neurological diseases.Keywords Neural stem cells Subventricular zone Rostral migratory stream Neuroblasts Neuronal migration Regulation of migration Adult neurogenesis Brain tumorsV. Capilla-GonzalezStem Cells Department, Andalusian Molecular Biology and Regenerative

37、 Medicine Centre, Seville, SpainDepartment of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USAE. Lavell A. Quiones-HinojosaDepartment of Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USAH. Guerrero-Cazares, M.D., Ph.D

38、. (*)Department of Neurosurgery, Johns Hopkins University,1550 Orleans St, CRBII, Room 247B, Baltimore, MD 21201, USA e-mail: Springer International Publishing Switzerland 20151M. Ehtesham (ed.), Stem Cell Biology in Neoplasms of the Central Nervous System, Advances in Experimental Medi

39、cine and Biology 853, DOI 10.1007/978-3-319-16537-0_1SVZ Cell Migration21IntroductionAdult neurogenesis mainly occurs in two regions of the mammalian brain, the subgranular zone of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles 1. In rodents adult SVZ, highly migratory n

40、euroblasts arise from neural stem cells (NSCs). These neuroblasts move tangentially through a special- ized path called the rostral migratory stream (RMS) to reach their final destination, the olfactory bulb (OB) 210. Once in the OB, SVZ-derived neuroblasts incorpo- rate into the OB circuitry and di

41、fferentiate into interneurons 6, 1114. The exis- tence of a similar migratory pathway in the adult human brain remains highly controversial. However, there is prominent neuroblast migration from the ventricu- lar walls into the olfactory tract in the human fetal brain that appears to decrease with d

42、evelopment 1522.The regulation of SVZ-derived cells migration in the adult brain involves mul- tiple processes including dynamic cellcell communication, cellextracellular matrix interactions, as well as chemo repellent and chemo attractant signals 2326. Under certain pathological conditions, these p

43、rocesses are modified to redirect the migration of SVZ-derived cells and provide support in damaged areas 2631. We review the roles of the different mechanisms that regulate the migration of newly generated cells from the SVZ into the OB, as well as their migration into damaged brain areas and brain

44、 tumors. A more complete understanding of the mechanisms regulating this migratory capacity could provide valuable insight in the possible use of NSCs in treatment of neurological disorders.Adult Neurogenic Niche: The Subventricular ZoneThe SVZ is the major source of NSCs in the adult brain of mamma

45、ls, including humans. In this region, NSCs have been identified as a subpopulation of astroglial cells that are able to differentiate into any of the main cell types of the central ner- vous system, i.e., neurons, oligodendrocytes, or astrocytes 32, 33. These cells organize in the SVZ to confer a un

46、ique cytoarchitecture, which presents remarkable differences between rodents and humans 21.RodentsThe SVZ is found behind a layer of ependymal cells (type E cells) that separates it from the ventricle cavity. The NSCs within the rodent SVZ correspond to a sub- population of astrocytes called B1 cell

47、s. These cells display a primary cilium in the apical surface that extends into the ventricle cavity, which has been related to the proliferative activity of B1 cells 3439. Typically, B1 astrocytes divide asym- metrically, maintaining their population and giving rise to the highly proliferative, tra

48、nsient amplifying progenitors (type C cells), which then become migratoryFig. 1 Cytoarchitecture of the subventricular zone (SVZ) in rodents. Biciliated (E2) and multicili- ated (E1) cells form a monolayer on the ventricular wall. E1 and E2 cells are organized in a pin- wheel fashion surrounding B1

49、cell cilia. B1 cells extend one apical process that maintains contact with the ventricle and another process that contacts blood vessels. Type B2 cells are not in contact with the ventricular wall and surround the migratory A cells. Type C cells are highly proliferative and separated from the E1 and

50、 E2 cells by astrocytic processes. Type A cells organize in chains to migrate tangentially while surrounded by astrocytic cellsneuroblasts (type A cells). Additionally, the SVZ contains a subpopulation of non- neurogenic astrocytes (B2 astrocytes) that are located at the underlying striatal parenchy

51、ma and do not make contact with the ventricle. These cells function as support for neuroblasts migration toward the OB (Fig. 1) 26.All SVZ cell types can be distinguished from each other by their ultrastructural characteristics and specific molecular markers (Table 1). Briefly, B1 astrocytes have li

52、ght cytoplasm with abundant intermediate filaments, and express glial fibrillary acidic protein (GFAP), nestin and vimentin. Type C cells are large cells with dark cytoplasm and many mitochondria. This cell type expresses the molecular markers Mash1, DLX-2, and nestin. Neuroblasts (Type A cells) are

53、 small, elongated cells that typically express nestin, Doublecortin (Dcx), polysialylated-neural cell adhe- sion molecule (PSA-NCAM), and Neuron-specific class III beta-tubulin (Tuj1). In the SVZ, neuroblasts form large chains that are surrounded by astrocytes. The B2 astrocytes are similar to B1 as

54、trocytes but have higher number of intermediate fila- ments and do not contact the ventricle. Type E cells exhibit multiple cilia and micro- villi on their apical surface and express markers such as vimentin, nestin, S100, and CD24 10, 35, 4043.As neuroblasts migrate away from the SVZ, they form lar

55、ge cellular chains, ensheathed by processes of B2 astrocytes (Fig. 2a, b). These structures constituteTable 1 Ventricular zone cell types and characteristicsCell typeMolecular markersMicroscopic and ultrastructural characteristicsE1Multiciliated ependymal cellsCD24Vimentin S100 beta Nestin Approxima

56、te size of 115 m2 Multiciliated, comprise most of the ventricularsurface Multiple basal bodies Abundant mitochondria concentrated around the basal bodies Small GolgiE2Biciliated Ependymal cellsCD24Vimentin S100 beta Nestin Comprise 5 % of ventricular surface Two partially invaginated cilia (9 + 2) and two basal bodies Spherical nuclei with no invaginations anddispersed chromatin Abundant mitochondria concent