期刊论文详细信息
BMC Cell Biology
Differentiation of mouse bone marrow derived stem cells toward microglia-like cells
Alexandra Stolzing1  Arnd Hinze1 
[1]Fraunhofer Institute for Cell Therapy and Immunology (IZI), Perlickstrasse 1, 04103, Leipzig, Germany
关键词: differentiation;    neurodegeneration;    GM-CSF;    Flt3L;    microglia;    bone marrow stem cells;   
Others  :  857096
DOI  :  10.1186/1471-2121-12-35
 received in 2011-02-17, accepted in 2011-08-19,  发布年份 2011
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【 摘 要 】

Background

Microglia, the macrophages of the brain, have been implicated in the causes of neurodegenerative diseases and display a loss of function during aging. Throughout life, microglia are replenished by limited proliferation of resident microglial cells. Replenishment by bone marrow-derived progenitor cells is still under debate. In this context, we investigated the differentiation of mouse microglia from bone marrow (BM) stem cells. Furthermore, we looked at the effects of FMS-like tyrosine kinase 3 ligand (Flt3L), astrocyte-conditioned medium (ACM) and GM-CSF on the differentiation to microglia-like cells.

Methods

We assessed in vitro-derived microglia differentiation by marker expression (CD11b/CD45, F4/80), but also for the first time for functional performance (phagocytosis, oxidative burst) and in situ migration into living brain tissue. Integration, survival and migration were assessed in organotypic brain slices.

Results

The cells differentiated from mouse BM show function, markers and morphology of primary microglia and migrate into living brain tissue. Flt3L displays a negative effect on differentiation while GM-CSF enhances differentiation.

Conclusion

We conclude that in vitro-derived microglia are the phenotypic and functional equivalents to primary microglia and could be used in cell therapy.

【 授权许可】

   
2011 Hinze and Stolzing; licensee BioMed Central Ltd.

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【 参考文献 】
  • [1]Simard AR, Rivest S: Neuroprotective effects of resident microglia following acute brain injury. J Comp Neurol 2007, 504(6):716-729.
  • [2]Ford AL, Goodsall AL, Hickey WF, Sedgwick JD: Normal adult ramified microglia separated from other central nervous system macrophages by flow cytometric sorting. Phenotypic differences defined and direct ex vivo antigen presentation to myelin basic protein-reactive CD4+ T cells compared. J Immunol 1995, 154(9):4309-4321.
  • [3]Slepko N, Levi G: Progressive activation of adult microglial cells in vitro. Glia 1996, 16(3):241-246.
  • [4]Leone C, Le Pavec G, Meme W, Porcheray F, Samah B, Dormont D, Gras G: Characterization of human monocyte-derived microglia-like cells. Glia 2006, 54(3):183-192.
  • [5]Almolda B, Gonzalez B, Castellano B: Activated microglial cells acquire an immature dendritic cell phenotype and may terminate the immune response in an acute model of EAE. J Neuroimmunol 2010, 223(12):39-54.
  • [6]Kreutzberg GW: Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996, 19(8):312-318.
  • [7]Stence N, Waite M, Dailey ME: Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia 2001, 33(3):256-266.
  • [8]Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman DM, Bacskai BJ, Hyman BT: Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease. Nature 2008, 451(7179):720-724.
  • [9]McGeer PL, McGeer EG: The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995, 21(2):195-218.
  • [10]Stolzing A, Sethe S, Grune T: Chronically active: activation of microglial proteolysis in ageing and neurodegeneration. Redox Rep 2005, 10(4):207-213.
  • [11]Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, et al.: Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010, 330(6005):841-845.
  • [12]Lawson LJ, Perry VH, Gordon S: Turnover of resident microglia in the normal adult mouse brain. Neuroscience 1992, 48(2):405-415.
  • [13]Rodriguez M, Alvarez-Erviti L, Blesa FJ, Rodriguez-Oroz MC, Arina A, Melero I, Ramos LI, Obeso JA: Bone-marrow-derived cell differentiation into microglia: a study in a progressive mouse model of Parkinson's disease. Neurobiol Dis 2007, 28(3):316-325.
  • [14]Dobrenis K: Microglia in cell culture and in transplantation therapy for central nervous system disease. Methods 1998, 16(3):320-344.
  • [15]Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM: Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 2007, 10(12):1538-1543.
  • [16]Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Bruck W, Priller J, Prinz M: Microglia in the adult brain arise from Ly-6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 2007, 10(12):1544-1553.
  • [17]Schwarting S, Litwak S, Hao W, Bahr M, Weise J, Neumann H: Hematopoietic stem cells reduce postischemic inflammation and ameliorate ischemic brain injury. Stroke 2008, 39(10):2867-2875.
  • [18]Sievers J, Parwaresch R, Wottge HU: Blood monocytes and spleen macrophages differentiate into microglia-like cells on monolayers of astrocytes: morphology. Glia 1994, 12(4):245-258.
  • [19]Stolzing A, Widmer R, Jung T, Voss P, Grune T: Tocopherol-mediated modulation of age-related changes in microglial cells: turnover of extracellular oxidized protein material. Free Radic Biol Med 2006, 40(12):2126-2135.
  • [20]Streit WJ: Microglial senescence: does the brain's immune system have an expiration date? Trends Neurosci 2006, 29(9):506-510.
  • [21]Streit WJ, Braak H, Xue QS, Bechmann I: Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer's disease. Acta Neuropathol 2009, 118(4):475-485.
  • [22]Conde JR, Streit WJ: Effect of aging on the microglial response to peripheral nerve injury. Neurobiol Aging 2006, 27(10):1451-1461.
  • [23]Flanary BE, Streit WJ: Progressive telomere shortening occurs in cultured rat microglia, but not astrocytes. Glia 2004, 45(1):75-88.
  • [24]Zhao C, Li WW, Franklin RJ: Differences in the early inflammatory responses to toxin-induced demyelination are associated with the age-related decline in CNS remyelination. Neurobiol Aging 2006, 27(9):1298-1307.
  • [25]Flanary BE, Sammons NW, Nguyen C, Walker D, Streit WJ: Evidence that aging and amyloid promote microglial cell senescence. Rejuvenation Res 2007, 10(1):61-74.
  • [26]Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K: Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 2007, 55(4):412-424.
  • [27]Sawada M, Sawada H, Nagatsu T: Effects of aging on neuroprotective and neurotoxic properties of microglia in neurodegenerative diseases. Neurodegener Dis 2008, 5(3-4):254-256.
  • [28]Neumann H, Kotter MR, Franklin RJ: Debris clearance by microglia: an essential link between degeneration and regeneration. Brain 2009, 132(Pt 2):288-295.
  • [29]Tsuchiya T, Park KC, Toyonaga S, Yamada SM, Nakabayashi H, Nakai E, Ikawa N, Furuya M, Tominaga A, Shimizu K: Characterization of microglia induced from mouse embryonic stem cells and their migration into the brain parenchyma. J Neuroimmunol 2005, 160(1-2):210-218.
  • [30]Servet-Delprat C, Arnaud S, Jurdic P, Nataf S, Grasset MF, Soulas C, Domenget C, Destaing O, Rivollier A, Perret M, et al.: Flt3+ macrophage precursors commit sequentially to osteoclasts, dendritic cells and microglia. BMC Immunol 2002, 3:15. BioMed Central Full Text
  • [31]Davoust N, Vuaillat C, Cavillon G, Domenget C, Hatterer E, Bernard A, Dumontel C, Jurdic P, Malcus C, Confavreux C, et al.: Bone marrow CD34+/B220+ progenitors target the inflamed brain and display in vitro differentiation potential toward microglia. Faseb J 2006, 20(12):2081-2092.
  • [32]Lee SC, Liu W, Brosnan CF, Dickson DW: GM-CSF promotes proliferation of human fetal and adult microglia in primary cultures. Glia 1994, 12(4):309-318.
  • [33]Santambrogio L, Belyanskaya SL, Fischer FR, Cipriani B, Brosnan CF, Ricciardi-Castagnoli P, Stern LJ, Strominger JL, Riese R: Developmental plasticity of CNS microglia. Proc Natl Acad Sci USA 2001, 98(11):6295-6300.
  • [34]Wodnar-Filipowicz A: Flt3 ligand: role in control of hematopoietic and immune functions of the bone marrow. News Physiol Sci 2003, 18:247-251.
  • [35]Solanilla A, Grosset C, Duchez P, Legembre P, Pitard V, Dupouy M, Belloc F, Viallard JF, Reiffers J, Boiron JM, et al.: Flt3-ligand induces adhesion of haematopoietic progenitor cells via a very late antigen (VLA)-4- and VLA-5-dependent mechanism. Br J Haematol 2003, 120(5):782-786.
  • [36]Maraskovsky E, Brasel K, Teepe M, Roux ER, Lyman SD, Shortman K, McKenna HJ: Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J Exp Med 1996, 184(5):1953-1962.
  • [37]McKenna HJ, Stocking KL, Miller RE, Brasel K, De Smedt T, Maraskovsky E, Maliszewski CR, Lynch DH, Smith J, Pulendran B, et al.: Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 2000, 95(11):3489-3497.
  • [38]Fischer HG, Reichmann G: Brain dendritic cells and macrophages/microglia in central nervous system inflammation. J Immunol 2001, 166(4):2717-2726.
  • [39]Melchior B, Garcia AE, Hsiung BK, Lo KM, Doose JM, Thrash JC, Stalder AK, Staufenbiel M, Neumann H, Carson MJ: Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer's disease. ASN Neuro 2010, 2(3):e00037.
  • [40]Hailer NP, Jarhult JD, Nitsch R: Resting microglial cells in vitro: analysis of morphology and adhesion molecule expression in organotypic hippocampal slice cultures. Glia 1996, 18(4):319-331.
  • [41]Heppner FL, Skutella T, Hailer NP, Haas D, Nitsch R: Activated microglial cells migrate towards sites of excitotoxic neuronal injury inside organotypic hippocampal slice cultures. Eur J Neurosci 1998, 10(10):3284-3290.
  • [42]Bai B, Song W, Ji Y, Liu X, Tian L, Wang C, Chen D, Zhang X, Zhang M: Microglia and microglia-like cell differentiated from DC inhibit CD4 T cell proliferation. PLoS One 2009, 4(11):e7869.
  • [43]Steinman RM, Hawiger D, Nussenzweig MC: Tolerogenic dendritic cells. Annu Rev Immunol 2003, 21:685-711.
  • [44]Prodinger C, Bunse J, Kruger M, Schiefenhovel F, Brandt C, Laman JD, Greter M, Immig K, Heppner F, Becher B, et al.: CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system. Acta Neuropathol 2011, 121(4):445-458.
  • [45]Magnus T, Chan A, Grauer O, Toyka KV, Gold R: Microglial phagocytosis of apoptotic inflammatory T cells leads to down-regulation of microglial immune activation. J Immunol 2001, 167(9):5004-5010.
  • [46]Narantuya D, Nagai A, Sheikh AM, Wakabayashi K, Shiota Y, Watanabe T, Masuda J, Kobayashi S, Kim SU, Yamaguchi S: Microglia transplantation attenuates white matter injury in rat chronic ischemia model via matrix metalloproteinase-2 inhibition. Brain Res 2010, 1316:145-152.
  • [47]Neumann J, Gunzer M, Gutzeit HO, Ullrich O, Reymann KG, Dinkel K: Microglia provide neuroprotection after ischemia. Faseb J 2006, 20(6):714-716.
  • [48]Takata K, Kitamura Y, Yanagisawa D, Morikawa S, Morita M, Inubushi T, Tsuchiya D, Chishiro S, Saeki M, Taniguchi T, et al.: Microglial transplantation increases amyloid-beta clearance in Alzheimer model rats. FEBS Lett 2007, 581(3):475-478.
  • [49]Schloendorn J, Sethe S, Stolzing A: Cellular therapy using microglial cells. Rejuvenation Res 2007, 10(1):87-99.
  • [50]Floden AM, Combs CK: Microglia repetitively isolated from in vitro mixed glial cultures retain their initial phenotype. J Neurosci Methods 2007, 164(2):218-224.
  • [51]Chan HT, Kedzierska K, O'Mullane J, Crowe SM, Jaworowski A: Quantifying complement-mediated phagocytosis by human monocyte-derived macrophages. Immunol Cell Biol 2001, 79(5):429-435.
  • [52]Yu WH, Go L, Guinn BA, Fraser PE, Westaway D, McLaurin J: Phenotypic and functional changes in glial cells as a function of age. Neurobiol Aging 2002, 23(1):105-115.
  • [53]Stoppini L, Buchs PA, Muller D: A simple method for organotypic cultures of nervous tissue. J Neurosci Methods 1991, 37(2):173-182.
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