Untersuchuchungen zum makro- und mikroglialen Differenzierungspotential muriner Knochenmarkzellenin vitro und in vivoMatthias Boentert2345671829102.111122.2131415162.31718192.42.4.120212.4.22223242.5252.5.1262.5.2272.5.3282.5.4292.6303133233344354.13637384.2394.2.1404.2.24.2.3414.2.4424.2.54.2.6434.2.7444.3454.3.14.3.24.3.346474.3.4484.3.5494.3.64.3.7504.3.8514.3.9524.3.10534.3.1154555565.1575.1.158596061625.1.25.1.364655.2665.2.1676869705.2.2717273747576777879805.2.3818283848586878889906919293949596979899100101102103104105106 Literaturverzeichnis107108109110111112113114115116117118119120121122123124 Anhang125126 Tabellarischer Lebenslauf127128 Eidesstattliche Erklärung129 Danksagung130deInhaltsverzeichnisHilfe Literaturverzeichnis Altman J, Das GD. 1965. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124 : 319-335. Aschner M. 1998. Astrocytes as mediators of immune and inflammatory response. Neurotoxicology 19 : 269-281. Aubert I, Ridet JL, Gage FH. 1995. Regeneration in the adult mammalian CNS: guided by development. Curr Opin Neurobiol 5 : 625-635. Azizi SA, Stokes D, Augelli BJ, DiGirolamo C, Prockop D. 1998. Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats - similarities to astrocyte grafts. Proc Natl Acad Sci USA 95 : 3908-13. Banati RB, Hoppe D, Gottmann K, Kreutzberg GW, Kettenmann H. 1991. A subpopulation of bone marrow derived macrophages share a unique ion channel pattern with microglia. J Neurosci Res 30: 593-600. Barber P, Lindsay R. 1982. Schwann cells of the olfactory nerves contain glial fibrillary acidic protein and resemble astrocytes. Neuroscience 7 : 3077-3090. Bartlett PF. 1982. Pluripotential hematopoietic stem cells in adult mouse brain. Proc Natl Acad Sci USA 79 : 2722-2725. Becher B, Prat A, Antel JP. 2000. Brain-immune connection: Immuno-regulatory properties of CNS-resident cells. Glia 29: 93-304. Bechmann I, Priller J, Kowac A, Böntert M, Wehner T, Fernandez Klett F, Bohsung J, Stuschke M, Dirnagl U, Nitsch R. 2001. Immune surveillance of mouse brain perivascular spaces by blood-borne macrophages. Eur J Neurosci 14: 1651-1658. Bennett JH, Joyner CJ, Triffitt JT, Owen ME. 1991. Adipocytic cells cultured from marrow have osteogenic potential. J Cell Sci 99 : 131-139 . Bernier L, Colman DR, D'Eustachio P. 1988. Chromosomal locations of genes encoding 2', 3' cyclic nucleotide 3'-phosphodiesterase and glial fibrillary acidic protein in the mouse.J Neurosci Res 20 : 497-504 . Bianco P, Costantini M, Dearde LC, Bonucci E. 1988. Alkaline phosphatase positive precursors of adipocytes in the human bone marrow. Br J Haematol 68 : 401-403. Bianco P, Riminucci M, Gronthos S, Robey PG. 2001. Bone marrow stromal stem cells: Nature, biology and potential applications. Stem Cells 19 : 180-192 . Bierhuizen M, Westerman Y, Visser TP, Wognum AW, Wagemaker G. 1997. Enhanced green fluorescent protein as a selectable marker of retroviral-mediated gene transfer in immature hematopoietic bone marrow cells. Blood 90 : 3304-3315 . Björklund H, Dahl D. 1985. Glial fibrillary acidic protein immunoreactivity in the rodent eye. Comparison between peripheral glia of the anterior uvea and central glia of the retina. J Neuroimmunol 8 : 331-345 . Bjornson CRR, Rietze RL Reynolds BA, Magli MC, Vescovi AL. 1999. Turning brain into blood: a hematopoietic fate adopte by adult neural stem cells in vivo. Science 283 : 534-37 . Bodine DM, Karlsson S, Nienhuis AW. 1989. Combination of interleukins 3 and 6 preserves stem cell function in culture and enhances retrovirus-mediated gene transfer into hematopoietic stem cells. Proc Natl Acad Sci USA 86 : 8897-901 . Bodine DM, McDonagh KT. 1991. Survival and retrovirus infection of murine hematopoietic stem cells in vitro: Effects of 5-FU and method of infection. Exp Hematol 19 : 206-12 . Bongcam-Rudloff E, Nistér M, Betsholtz C, Wang JL, Stenman G, Huebner K, Croce CM, Westermark B. 1991. Human glial fibrillary acidic protein: complementary DNA cloning, chromosome localization, and messenger RNA expression in human glioma cell lines of various phenotypes. Cancer Res 51 : 1553-1560 . Boya J, Calvo JL, Carbonell AL, Borregon A. 1991. A lectin histochemistry study on the development of rat microglial cells. J Anat 175 : 229-236 . Boyes BE, Kim SU, Lee V, Sung SC. 1986. Immunohistochemical co-localization of S100 β and the glial fibrillary acidic protein in rat brain. Neuroscience 17 : 857-865 . Braun JS, Jander S, Schroeter M, Witte OW, Stoll G. 1996. Spatiotemporal relationship of apoptotic cell death to lymphomonocytic infiltration in photochemically induced focal ische-mia of the rat cerebral cortex. Acta Neuropath 92 : 255-263 . Brazelton T, Rossi FMV, Keshet GI, Blau HM. 2000. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290 : 1775-79 . Brenner M. 1994. Structure and transcriptional regulation of the GFAP gene. Brain Pathol 4 : 245-57 . Brenner M, Kisseberth WC, Su Y, Besnard F, Messing A. 1994. GFAP promoter directs astrocyte-specific expression in transgenic mice. J Neurosci 14 : 1030-1037 . Bressler JP, Grotendorst GR, Levitov C, Hjelmeland LM. 1985. Chemotaxis of rat brain astrocytes to platelet derived growth factor. Brain Res 344 : 249-254 . Caday CG, Klagsbrun M, Fanning PJ, Mirzabegian A, Finklestein SP. 1990. Fibroblast growth factor (FGF) in the developing rat brain. Brain Res Dev Brain Res 52 : 241-246 . Carmignoto G. 2000. Reciprocal communication systems between astrocytes and neurons. Prog Neurobiol 62 : 561-581 . Chalfie M, Tu Y, Euskirchen G, Ward WW, Prasher DC. 1994. Green fluorescent protein as a marker for gene expression. Science 263 : 802-805 . Chauvet N et al. 1997. Mab22C11 antibody to amyloid precursor protein recognizes a protein associated with specific astroglial cells of the rat central nervous system characterized by their capacity to support axonal outgrowth. J Comp Neurol 377 : 550-564 . Chen H, Chopp M, Schultz L, Bodzin G, Garcia JH. 1993. Sequential neuronal and astrocytic changes after transient middle cerebral artery occlusion in the rat. J Neurol Sci 118 : 109-116 . Chen J, Li Y, Chopp M. 2000. Intracerebral transplantation of bone marrow with BDNF after MCAO in rat. Neuropharmacology 39 : 711-716 . Chen J, Li Y, Wang L, Zhang Z, Dunyue L, Lu M, Chopp M. 2001. Therapeutic benefit of intravenous andministration of bone marow stromal cells after cerebral ischemia in rats. Stroke 32 : 1005-1011 . Cheng L, Fu J, Tsukamoto A, Hawley RG. 1996. Use of green fluorescent protein variants to monitor gene transfer and expression in mammalian cells. Nature Biotech 14 : 606-609 . Cheshier S, Morrison SJ, Liao X, Weissman I. 1999. In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. Proc Natl Acad Sci USA 96 : 3120-3125 . Chopp M, Zhang RL, Chen H, Li Y, Jiang N, Rusche JR. 1994. Postischemic administration of an anti-Mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats. Stroke 25 : 869-876 . Chu VT, Gage FH. 2001. Chipping away at stem cells. Proc Natl Acad Sci USA 98 : 7652-7653 . Clarke DL, Johansson CB, Wilbertz J, Veress B, Nilsson E, Karlstrom H, Lendahl U, Frisen J. 2000. Generalized potential of adult neural stem cells. Science 288 : 1660-63 . Colter DC, Sekiya I, Prockop DJ. 2001. Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proc Natl Acad Sci USA 98 : 7841-7845 . Cramer SC, Chopp M. 2000. Recovery recapitulates ontogeny. Trends Neurosci 23 : 265-271 . De Groot CJ, Huppes W, Sminia T, Kraal G, Dijkstra CD. 1992. Determination of the origin and nature of brain macrophages and microglial cells in mouse central nervous system, using non-radioactive in situ hybridization and immunoperoxidase techniques. Glia 6 : 301-309 . Del Zoppo GJ, Ginis I, Hallenbeck JM, Iadecola C, Wang X, Feuerstein GZ. 2000. Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol 10 : 95-112 . Devitt A, Moffatt OD, Raykundalia C, Capra JD, Simmons DL, Gregory CD. 1998. Human CD14 mediates recognition and phagocytosis of apoptotic cells. Nature 392 : 505-509 . Donelly DS, Krause DS. 2001. Hematopoietic stem cells can be CD34+ or CD34-. Leuk Lymphoma 40 : 221-234 . Dorf ME, Berman MA, Tanabe S, Heesen M, Luo Y. 2000. Astrocytes express functional chemokine receptors. J Neuroimmunol 111 : 109-121 . Eddleston M, al Torre JC, Campbell IL, Oldstone MB. 1996. The M22 antibody identifies highly acivated reactive astrocytes responding to central nervous system diesease. Acta Neuropathologica 91 : 298-308 . Eglitis MA, Dawson D, Park KW, Mouradian MM. 1999. Targetig of marrow-derived astrocytes to the ischemic brain. Neuro Report 10 : 1289-1292 . Eglitis M, Mezey É. 1997. Hematopoietic cells differentiate into both microglia and macroglia in the brains of adult mice. Proc Natl Acad Sci USA 94 : 4080-4085 . Eng LF, Gerstl B, Vanderhaeghen JJ. 1970. A study of proteins in old multiple sclerosis plaques. Trans Am Soc Neurochem. 1 : 42 . Eng LF, Ghirnikar RS, Lee YL. 2000. Glial fibrillary acidic protein: GFAP thirty-one years (1969-2000). Neurochem Res 25 : 1439-1451 . Fawcett J. 1994. Astrocytes and axon regeneration in the central nervous system. J Neurol 242 (1 Suppl 1): S25-S28 . Ferrari G, Cusella-DeAngelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, Mavilio F. 1998. Muscle regeneration by bone marrow-derived myogenic progenytors. Science 279 : 1528-1530 . Feuerstein GZ, Wang X, Barone FC. 1999. Inflammatory gene expression in cerebral ischemia and trauma. Potential new therapeutic targets. Ann N Y Acad Sci 825 : 179-193 . Finklestein SP, Caday CG, Kano M, Berlove DJ, Hsu CY, Moskowitz M, Klagsbrun M. 1990. Growth factor expression after stroke. Stroke 21 (11 Suppl): III 122-124 . Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. 1968. Heterotopic transplants of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 6 : 230-247 . Friedenstein AJ et al. 1974. Precursors for fibroblasts in different populations of hematopoietic cells as detected by in vitro colony assay method. Exp Hematol 2 : 83-92 . Furukawa Y. 1998. Cell cycle regulation of hematopoietic stem cells. Hum Cell 11 : 81-92 . Fuss B, Mallon B, Phan T, Ohlemeyer C, Kirchhoff F, Nishiyama A, Macklin WB. 2000. Purification and analysis of in vivo differentiated oligodendrocytes expressing the green fluorescent protein. Dev Biol 218(2): 259-274 . Garcia JH. 1984. Experimental ischemic stroke: a review. Stroke 15 : 5-14 . Garcia JH, Liu KF, Yoshida Y, Liao J, Chen S, del Zoppo GJ. 1994. Influx of leukocytes and platelets in an evolving brain infarct. Am J Pathol 144 : 188-199 . Gard AL, White FP, Dutton G. 1985. Extra-neural glial fibrillary acidic protein immunoreacitvity in persinusoidal stellate cells of rat liver. J Neuroimmunol 8 : 359-375 . Gates MA, Thomas LB, Howard EM, Laywell ED, Sajon B, Faissner A, Gotz B, Silver J, Steindler DA. 1995. Cell and molecular analysis of the developing and adult mouse subventricular zone of the cerebal hemispheres. J Comp Neurol 361 : 249-266 . George R, Griffin JW. 1994. Delayed macrophage responses and myelin clearance during Wallerian degeneration in the central nervous system. Exp Neurol 129 : 225-236 . Goodell MA, Rosenzweig M, Kim H, Marks DF, DeMaria M, Paradis G, Grupp SA, Sieff CA, Mulligan RC, Johnson RP. 1997. Efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med 3 : 1337-1345 . Gould E, Reeves AJ, Graziano MSA, Gross CG. 1999. Neurogenesis in the neocortex of adult primates. Science 286 : 548-552 . Gussoni E, Soneoka Y, Strickland CD, Buzney EA, Khan MK, Flint AF, Kunkel LM, Mulligan RC. 1999. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401 : 390-394 . Hajdantonakis AK, Gertsenstein M, Ikawa M, Okabe M, Nagy A. 1998. Generating green fluorescent mice by germline transmission of green fluorescent ES cells. Mech Dev 76 : 79-90 . Hailer NP, Heppner FL, Haas D, Nitsch R. 1997. Fluorescent dye prelabelled microglial cells migrate into organotypic hippocampal slice cultures and ramify. Eur J Neurosci 9 : 863-866 . Hailer NP, Jarhult JD, Nitsch R. 1996. Resting microglial cells in vitro: analysis of morphology and adhesion molecule expression in organotypic hippocampal slice cultures. Glia 18 , 319-331 . Hara H, Huang PL, Panahian N, Fishman MC, Moskowitz MA. 1996. Reduced brain edema and infarction in mice lacking the neuronal isoform of nitric oxide synthase after transient MCA occlusion. J Cereb Blood Flow Metab 16 : 605-611 . Harrison DE, Stone M, Astle CM. 1990. Effects of transplantation on the primitive immunohematopoietic stem cell. J Exp Med 172 : 431-437 . Hayashi T et al. 1997. Rapid induction of vascular endothelial growth factor gene expression after transient middle cerebral artery occlusion in rats. Stroke 28 : 2039-2044 . Hess DC, Hill WD, Martin-Studdard A, Carroll J, Brailer J, Carothers J. 2002. Bone marrow as a source of endothelial cells and NeuN-expressing cells after stroke. Stroke 33 : 1362-1368 . Hickey WF, Vass K, Lassmann H. 1992. Bone marrow-derived elements in the central nervous system: an immunohistochemical and ultrastructural survey of rat chimeras. J Neuropath Exp Neurol 51 : 246-256 . Holland EC, Varmus HE. 1998. Basic fibroblast growth factor induces cell migration and proliferation after glia-specific gene transfer in mice. Proc Natl Acad Sci USA 95 : 1218-1223 . Hossmann KA. 1995. Viability thresholds and the penumbra of focal ischemia. Ann Neurol 36 : 557-565 . Imai Y, Ibata I, Ito D, Ohsawa K, Kohsaka S. 1996. A novel gene iba1 in the major histocompatibility complex class III region encoding an EF hand protein expressed in a monocytic lineage. Biochem Biophys Res Commun 224 : 855-862 . Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y. 1998. Microglia-specific localisation of a novel calcium binding protein, Iba 1. Brain Res Mol Brain Res 57 : 1-9 . Jackson KA, Mi T, Goodell MA. 1999. Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc Natl Acad Sci USA 96 : 14482-14486 . Jessen KR, Mirsky R. 1985. Glial fibrillary acidic polypeptides in peripheral glia. Molecular weight, heterogeneity and distribution. J Neuroimmunol 8(4-6) : 377-393 . Kalman M, Hajos F. 1989. Distribution of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in the rat brain. I. Forebrain. Exp Brain Res 78 : 147-163. Kato H, Kogure K, Liu XH, Araki T, Itoyama Y. 1996. Progressive expression of immunomolecules on activated microglia and invading leukocytes following focal cerebral ischemia in the rat. Brain Res 734 : 203-212 . Kato H, Walz H. 2000. The initiation of the microglial response. Brain Pathol 10 : 137-143 . Kawakami N, Sakane N, Nishizawa F, Iwao M, Fukada SI, Tsujikawa K, Kohama Y, Ikawa M, Okabe M, Yamamoto H. 1999. Green fluorescent protein-transgenic mice: immune functions and their application to studies of lymphocyte development. Immunol Lett 70(3): 165-171 . Kennedy DW, Abkowitz JL. 1997. Kinetics of central nervous system microglial and macrophage engraftment: Analysis using a transgenic bone marrow transplantation model. Blood 90: 986-993 . Kennedy DW, Abkowitz JL. 1998. Mature monocytic cells enter tissues and engraft. Proc Natl Acad Sci USA 95 : 14944-14949 . Kessinger A. 1995. Circulating stem cells - waxing hematopoietic. N Engl J Med 333 : 315-317 . Kniss DA, Burry RW. 1988. Serum and fibroblast growth factor stimulate quiescent astrocytes to re-enter the cell cycle. Brain Res 439 : 281-288. Kopen GC, Prockop DJ, Phinney DG. 1999. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA 96 : 10700-10716 . Korr H. 1994. Problems encountered when immunocytochemistry is used for quantitative glial cell identification in autoradiographic studies of cell proliferation in the brain of the unlesioned mouse. Cell Tissue Res 278 : 85-95 . Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Neutzel S, Sharkis SJ. 2001. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105 : 369-377 . Lagasse E, Connors H, Al-Dhalimy, Reitsma M, Dohse M, Osborne L, Wang X, Finegold M, Weissmann IL, Grompe M. 2000. Purified hematopoietic stem cells can differentiate to hepatocytes in vivo. Nature Med 6 : 1229-1234. Lassmann H, Schmied M, Vass K, Hickey WF. 1993. Bone marrow-derived elements and resident microglia in brain inflammation. Glia 7 : 19-24 . Lawson LJ, Perry VH, Gordon S. 1992. Turnover of resident micorglia in the normal adult mouse brain. Neuroscience 48 : 405-415 . Lawson LJ, Perry VH, Gordon S. 1990. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39 : 151-170 . Lee JC, Mayer-Proschel M, Rao MS. 2000. Gliogenesis in the central nervous system. Glia 30 : 105-121 . Lemischka I. 1999. The power of stem cells reconsidered? Proc Natl Acad Sci USA 96 : 14293-14195 . Lerner C, Harrison DE. 1990. 5-Fluorouracil spares hematopoetic stem cells responsible for long-term repopulation. Exp Hematol 18 : 114 . Lewis SA, Balcarek JM, Krek V, Shelanski M, Cowan NJ. 1984. Sequence of a cDNA encoding mouse glial fibrillary acidic protein: structural conservation of intermediate filaments. Proc Natl Acad Sci USA 81 : 2743-2746 . Li Y, Chen J, Chopp M. 2001. Adult bone marrow transplantation after stroke in adult rats. Cell Transplant 10 : 31-40 . Li Y, Sharov VG, Jiang N, Zaloga C, Sabbah HN, Chopp M. 1995. Ultrastructural and ligt microscopic evidence of apoptosis after middle cerebral artery occlusion in the rat. Am J Pathol 146 : 1045-1051 . Li Y, Chopp M, Zhang ZG, Zhang RL. 1995. Expression of glial fibrillary acidic protein in areas of focal cerebral ischemia accompanies neuronal expression of 72-kDa heat shock protein. J Neurol Sci 128 : 134-142 . Li Y, Chopp M, Powers C, Jiang N. 1997. Apoptosis and protein expression after focal cerebral ischemia in rat. Brain Res 765 : 301-312 . Li Y, Chen J, Wang L, Lu M, Chopp M. 2001b. Treatment of stroke in rat with intracarotid administration of marrow stromal cells. Neurology 56 : 1666-1672 . Li Y, Chopp M. 1999. Temporal profile of nestin expression after focal cerebral ischemia in the adult rat. Brain Res 838 : 1-10 . Li Y, Chopp M, Chen J, Wang L, Gautam SC, Xu YX, Zhang Z. 2000. Intrastriatal transplantation of nonhematopoietic bone marrow cells improves functional recovery after stroke in adult mice. J Cereb Blood Flow Metab 20 (9): 1311-1319 . Ling EA. 1979. Transformation of monocytes into ameboid microglia in the corpus callosum of postnatal rats, as shown by labelling monocytes by carbon particles. J Anat 128 : 847 Ling EA, Wong WC. 1993. The origin and nature of ramified and amoeboid microglia: A historical review and current concepts. Glia 7 : 9-18 . Linnik MD, Zobrist RH, Hatfield MD. 1993. Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats. Stroke 24 : 2002-2009 . Lipton P. 1999. Ischemic cell death in brain neurons. Phys Rev 79 : 1431-1568 . Lois C, Alvarez-Buylla A. 1994. Long distance neuronal migration in the adult mammalian brain. Science 264 : 1145-1148. McCarthy KD, De Vellis J. 1980. Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol 85 : 890-902 . McAuley MA. 1995. Rodent models of focal ischemia. Cerebrovasc Brain Metabol Rev 7 : 153-180 . McCall MA, Gregg RG, Behringer RR, Brenner M, Delaney CL, Galbreath EJ, Zhang CL, Pearce RA, Chiu SY, Messing A. 1996. Targeted deletion in astrocyte intermediate filament (GFAP) alters neuronal physiology. Proc Natl Acad Sci USA 93 : 6361-6366 . McLendon RE, Bigner DD. 1994. Immunohistochemistry of the glial fibrillary acidic protein: Basic and applied considerations. Brain Pathol 4 : 221-228 . Mezey E, Chandross KJ. 2000a. Bone marrow: a possible altervative source of cells in the adult nervous system. Eur J Pharmacol 405 : 297-302 . Mezey È, Chandross KJ, Harta G, Maki RA, McKercher SR. 2000. Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 290 : 1779-1782. Morganti-Kossmann MC, Kossmann T, Wahl SM. 1992. Cytokines and neuropathology. Trends Pharm Sci 13 : 286-291 . Morrison SJ. 2000. Stem cell potential: Can anything make anything? Curr Biol 11 : R7-R9 . Morshead CM, Benveniste P, Iscove NN, van der Kooy D. 2002. Hematopoietic competence is a rare property of neural stem cells that may depend on genetic and epigenetic alterations. Nature Medicine 8(3) : 268-273 . Nagy A, Rossant J, Nagy R, Abramow-Newerly W, Roder JC. 1993. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci USA 90 : 8424-8428 . Nakano K, Migita M, Mochizuki H, Shimada T. 2001. Differentiation of transplanted bone marrow cells in the adult mouse brain. Transplantation 71 : 1735-1740 . Nichols NR, Day JR, Laping NJ, Johnson SA, Finch CE. 1993. GFAP mRNA increases with age in rat and human brain. Neurobiol Aging 14 : 421-429 . Nolte C, Matyash M, Pivneva T, Schipke CG, Ohlemeyer C, Hanisch UK, Kirchhoff F, Kettenmann H. 2001. GFAP promoter-controlled EGFP-expressing transgenic mice: a tool to visualize astrocytes and astrogliosis in living brain tissue. Glia 33 : 72-86 . Okabe M, Ikawa M, Kominami K, Nakanishi T, Nishimune Y. 1997. Green mice as a source of ubiquitous green cells. FEBS Lett 407(3 ): 313-319 . Okada S, Nakauchi H, Nagayoshi K, Nishikawa S, Miura Y, Suda T. 1992. In vivo and in vitro stem cell function of c-kit- and Sca-1-positive murine hematopoietic cells. Blood 80 : 3044-3050 . Ono K, Takii T, Onozaki K, Ikawa M, Okabe M, Sawada M. 1999. Migration of exogenous immature hematopoietic cells into adult mouse brain parenchyma under GFP-expressing bone marrow chimera. Biochem Biophys Res Commun 262 : 610-614 . Patterson GH, Knobel SM, Sharif WD, Kain SR, Piston DW. 1997. Use of the green fluorescent protein and its mutants in quantitative fluorescence microscopy. Biophys J 73 : 2782-2790 . Perry VH, Andersson PB, Gordon S. 1993. Macrophages and inflammation in the central nervous system. Trends Neurosci 16 : 268-273 . Persons DA, Allay JA, Allay ER, Smeyne RJ, Ashmun RA, Sorrentino BP, Nienhuis AW. 1997. Retroviral-mediated transfer of the green fluorescent protein into murine hematopoietic cells facilitates scoring and selection of transduced progenitors in vitro and indentification of genetically modified cells in vivo. Blood 90 : 1777-1786 . Persons DA, Mehaffey MG, Kaleko M, Nienhuis AW, Vanin EF. 1998. An improved method for generating retroviral producer clones for vectors lacking a selectable marker gene. Blood Cells Mol Dis 24 : 167-182. Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, Boggs SS, Greenberger JS, Goff JP. 1999. Bone marrow as a potential source of hepatic oval cells. Science 284 : 1168-1170 . Polli E. 2000. Transplanting bone-marrow stem cells into the central nervous system. Haematologica 85 : 1009-1010 . Prasher DC, Eckenrode VK, Ward WW, Prendergast FG, Cormier MJ. 1992. Primary structure of the Aequorea victoria green-fluorescent protein. Gene 111 : 229-233 . Priller J, Flügel A, Wehner T, Boentert M, Haas CA, Prinz M, Fernandez Klett F, Prass K, Bechmann I, de Boer B, Frotscher M, Kreutzberg GW, Persons DA, Dirnagl U. 2001. Targeting gene-modified hematopoetic cells to the central nervous system: Use of green fluorescent protein uncovers microglial engraftment. Nature Medicine 7 (12) : 1356-1361 . Priller J, Persons DA, Fernandez-Klett F, Kempermann G, Kreutzberg GW, Dirnagl U. 2001.Neogenesis of cerebellar Purkinje neurons from gene-marked bone marrow cells in vivo. J Cell Biol, 155 (5 ): 733–738 . Rao MS, Noble M, Mayer-Proschel M. 1998. A tripotential glial precursor is present in the developing spinal cord. Proc Natl Acad Sci USA 95 : 3996-4001 Reilly JF, Kumari VG. 1996. Alterations in fibroblast growth factor receptor expression following brain injury. Exp Neurol 140 : 139-150 . Ridet JL, Malhotra SK, Privat A, Gage FH. 1997. Reactive astrocytes: cellular and molecular cues to biological function. Trends Neursci 20: 570-577 . Rio Hortega del P. 1932. Microglia. In: Penfield W (ed.), Cytology and cellular pathology of the nervous system. Vol. 2, 481-584. Ritter LS, Orozco JA, Coull BM, McDonagh PF, Rosenblum WI. 2000. Leukocyte accumulation and hemodynamic changes in the cerebral microcirculation during early reperfusion after stroke. Stroke 31: 1153-1161. Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, Freeman TB, Saporta S, Janssen W, Patel N, Cooper DR, Sanberg PR. 2000. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 164: 247-256. Savaskan NE, Eyupoglu IY, Brauer AU, Plaschke M, Ninnemann O, Nitsch R, Skutella T. 2000. Entorhinal cortex lesion studied with the novel dye fluoro-jade. Brain Research 864: 44-51. Scheffler B, Horn M, Blumcke I, Langwell ED, Coomes D, Kukekov VG, Steindler DA. 1999. Marrow-mindedness: a perspective on neuropoiesis. Trends Neurosci 22: 348-357. Schmidtmayer J, Jacobsen C, Miksch G, Sievers J. 1994 . Blood monocytes and spleen macrophages differentiate into microglia-like cells on monolayers of astrocytes: membrane currents. Glia 12: 259-267. Schroeter M, Jander S, Huitinga I, Witte OW, Stoll G. 1997. Phagocytic response in photochemically induced infarction of the rat cerebral cortex: the role of resident microglia. Stroke 28: 382-386. Shimomura O, Johnson FH, Saiga Y. 1962. J Cell Comp Physiol 59: 223-239. Sievers J, Parwaresch R. 1994. Blood monocytes and spleen macrophages differentiate into microglia-like cells when cultured on astrocytes. Ann Anat 176: 45-51. Sievers J, Parwaresch R, Wottge HU. 1994. Blood monocytes and spleen macrophages differentiate into microglia-like cells on monolayers of astrocytes: morphology. Glia 12: 245-258. Smart I. 1961. The subependymal layer of the mouse brain and its cell production as shown by radioautography after thymidine-H3 injection. J Comp Neurol 116: 325-338. Smith GH, Hale JH. 1997. Macrophage/microglia regulation of astrocytic tenascin: synergistic action of transforming growth factor beta and basic fibroblast growth factor. J Neurosci 17: 9624-9633. Spangrude GJ. 1994. Biological and clinical aspects of hematopoietic stem cells. Annu Rev Med 45: 93-104. Spangrude GJ, Heimfeld S, Weissman IL. 1988. Purification and characterization of mouse hematopoietic stem cells. Science 241: 58-62. Spangrude GJ, Klein J, Heimfeld S, Aihara Y, Weissman IL. 1989. Two monoclonal antibodies identify thymic-repopulating cells in mouse bone marrow. J Immunol 142 : 425-430 . Stoll G, Jander S, Schroeter M. 1998. Inflammation and glial responses in ischemic brain lesions. Progress in Neurobiology 56: 149-171. Streit WJ, Graeber MB, Kreutzberg GW. 1988. Functional plasticity of microglia: a review. Glia 1: 301-307. Stroemer R et al. 1998. Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats. Stroke 29: 2381-2395. Sturrock RR, Smart I. 1980. A morphological study of the mouse subependymal layer from embryonic life to old age. J Anat 130: 391-415. Tanaka J, Maeda N. 1996. Microglial ramification requires nondiffusible factors derived from astrocytes. Exp Neurol 137(2): 367-375. Tanaka J, Toku K, Sakanaka M, Maeda N. 1999. Morphological differentiation of microglial cells in culture: involvement of insoluble factors derived from astrocytes. Neurosci Res 34: 207-215. Terskikh A, Easterday MC, Li L, Hood L, Kornblum HI, Geschwind DH, Weissman IL. 2001. From hematopoiesis to neuropoiesis: Evidence of overlapping genetic programs. Proc Natl Acad Sci USA 98: 7934-7939. Thomson JA, Kalishman J, Golos TG, Durning M, Harris CP, Becker RA, Hearn JP. 1995. Isolation of a primate embryonic stem cell line. Proc Natl Acad Sci USA 92: 7844-7848. Thomson JA, Kalishman J, Golos TG, Durning M, Harris CP, Hearn JP. 1996. Pluripotent cell lines derived from common marmoset (Callithrix jacchus) blastocysts. Biol Reprod 55: 254-259. Tsien RY. 1998. The green fluorescent protein. Annu Rev Biochem 67: 509-544. Ulvestad E, Williams K, Mork S, Antel J, Nyland H. 1994. Phenotypic differences between human monocytes/macrophages and microglial cells studied in situ and in vitro. J Neuropathol Exp Neurol 53: 492-501. Unger ER, Sung JH, Manivel JC, Chenggis ML, Blazar BR, Krivit W. 1993. Male donor-derived cells in the brains of female sex-mismatched bone marrow transplant redipients: A Y-chromosome specific in situ hybridization study. J Neuropathol Exp Neurol 52: 460-470. Van de Rijn M, Heimfeld S, Spangrude GJ, Weissmann IL. 1989. Mouse hematopoietic stem-cell antigen Sca-1 is a member of the Ly-6 antigen family. Proc Natl Acad Sci USA 86: 4634-4638. Vesce S, Bezzi P, Volterra A. 1999 . The active role of astrocytes in synaptic transmission. Cell Mol Life Sci 56: 991-1000. Vijayan VK, Lee YL, Eng LF. 1990. Increase in glial fibrillary acidic protein following neural trauma. Mol Chem Neuropathol 13: 107-118. Wang X, Feuerstein GZ. 1995.Induced expression of adhesion molecules following brain i-schemia. J Neurotrauma 12: 825-832. Wehner T, Böntert M, Eyuepoglu I, Prass K, Prinz M, Fernandez Klett F, Heinze M, Bechmann I, Nitsch R, Kirchhoff F, Kettenmann H, Dirnagl U, Priller J. 2003. Bone marrow-derived cells expressing green fluorescent protein under the control of the glial fibrillary acidic protein promoter do not differentiate into astrocytes in vitro and in vivo. J Neuroscience 23(12): 5004-5011. Weinstein DE, Shelanski ML, Liem RK. 1991. Suppresion by antisense mRNA demonstrates a requirement for the glial fibrillary acidic protein in the formation of stable astrocytic processes in response to neurons. J Cell Biol 112: 1205-1213. Wilms H, Hartmann D, Sievers J. 1997. Ramification of microglia, monocytes and macrophages in vitro: Influences of various epithelial and mesenchymal cells and their conditioned media. Cell Tissue Res 287: 447-458. Woodbury D, Schwarz EJ, Prockop DJ, Black IB. 2000. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 61: 364-370. Yang F, Moss LG, Phillips GN. 1996. The molecular structure of green fluorescent protein. Nat Biotechnol 14: 1246-1251. Yu AC, Lau LT. 2000 . Expression of interleukin-1 alpha, tumor necrosis factor alpha and interleukin-6 genes in astrocytes under ischemic injury. Neurochem Int 36: 369-377. Zenker W. Feinstruktur des Nervengewebes. In: Benninghoff. Anatomie. hrsg. von D. Drenckhahn und W. Zenker.

München

1994. Zhang ZG, Chopp M, Powers C. 1997. Temporal profile of microglial response following transient (2h) middle cerebral artery occlusion. Brain Res 744: 189-198. Zhuo L, Sun B, Zhang CL, Fine A, Chiu SY, Messing A. 1997. Live astrocytes visualized by green fluorescent protein in transgenic mice. Dev Biol 187: 36-42.