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Neuroimmunol Neuroinflamm. Author manuscript; available in PMC 2017 July 10. Published in final edited form as: Neuroimmunol Neuroinflamm. 2016 ; 3: 204–206. doi:10.20517/2347-8659.2016.32.
Emerging roles of microglia cells in the regulation of adult neural stem cells Eduardo Lira-Diaz1,2 and Oscar Gonzalez-Perez1 1Laboratory 2Medical
of Neuroscience, School of Psychology, University of Colima, Colima 28040, Mexico
Sciences PhD Program, School of Medicine, University of Colima, Colima Mexico 28040
Author Manuscript
Abstract Microglia cells were first described as a component for the brain with few beneficial functions. The classical point of view implied that these cells had inflammatory properties more than benefits for brain homeostasis. To date, this assumption has changed and new roles of microglia cells are continuously discovered. Although, the main function of microglia cells is to provide a cellular defense against harmful or pathogen agents (bacteria, viruses, fungi, toxins, etc.), recent evidence indicates that microglial cells are dynamic modulators of synaptic pruning, brain development and neurogenesis by maintaining a balance of local cell population. In this commentary, we summarized the emerging role of the relationship between microglia cells and the neural stem cells resident in the ventricular-subventricular zone (V-SVZ), the largest neurogenic niche in the adult brain.
Author Manuscript
Keywords Microglia cells; neurogenesis; neural stem cells; ventricular-subventricular zone (V-SVZ); niche
Microglia cells
Author Manuscript
Microglia cells are antigen presenting cells with myeloid origin that integrate the mononuclear phagocyte system into the brain [1]. These cells are considered the resident macrophages of the adult central nervous system (CNS). In the adult rodent brain, microglia cells constituted approximately 10% of all glial cells [1]. In the early embryo, the microglial precursors are located in the yolk sac and progressively migrate throughout the primitive brain [2]. In the adult brain, some of microglial cells derive from the bone marrow, but this process can only take place when the brain is lesioned [1]. Microglial cells can display four morphological and functional stages: 1) resting microglia, 2) active microglia, 3) phagocytic microglia, and 4) senescent microglia [3]. One of the functions of microglia is to provide the
Corresponding author: Oscar Gonzalez-Perez, M.D., Ph.D., Facultad de Psicologia, Universidad de Colima, Av. Universidad 333, Colima, COL 28040, Mexico, Tel: +52 (312) 316-1091, [email protected]. Contribution details Eduardo Lira-Díaz: literature search, manuscript preparation and manuscript editing. Óscar Gonzalez-Perez: concept definition of intellectual content, manuscript editing and manuscript review. Conflict of interest The authors report no conflict of interest.
Lira-Diaz and Gonzalez-Perez
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cell-mediated immunity response against pathogens by releasing chemokines or cytokines and acting as antigen presenting cells [1]. Thus, microglial cells can stimulate naïve T cells to initiate a T-cell response after the breakdown of the blood brain barrier. However, the immune response and debris removing are not the only functions of microglial cells. Recently, it has been identified that microglia cells regulate neuronal apoptosis during the early brain development [4], modulate synaptic function and control neurogenesis [5].
The ventricular-subventricular zone (V-SVZ)
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The adult mammalian brain possess specialized structures known as niches that host stem cells with neurogenic potential [6]. One of those niches is known as the V-SVZ, which is an epithelial layer located in the lateral walls of the lateral ventricles [7]. In the adulthood, the V-SVZ three cell populations have been identified: type-B cells, type-C cells and type-A cells [8]. The putative neural stem cells is the type-B cell, an astroglial cells that can be identified by the expression of the glial fibrillary acidic protein (GFAP), glutamate aspartate transporter (GLAST), brain lipid binding protein (BLBP), platelet-derived growth factor receptor alpha (PDGFRα), CD133, Id1, Tailless (Tlx), VCAM1, epidermal growth factor receptor (EGFR), and others [7, 8]. The activation of B1 cells depends of signaling pathways including sonic hedgehog (SHH), wingless-related integration site (Wnt), Notch, bone morphogenetic proteins (BMP), ephrins, retinoic acid (RA), betacellulin (BTC), stromal derived factor-1 (SDF-1), pigment epithelium-derived factor (PEDF) and some intrinsic signals (PRX1, SOX2, ARS2, ASCL1, NG2, OLIG2) [7, 8]. This myriad of chemical effectors are provided by resident cells within the niche and some of them derived for the cerebrospinal fluid [8]. After activation, type-B1 cells produce transit-amplifying progenitors (type-C cells) that express the epidermal growth factor receptor (EGFR) and the transcription factors Dlx2 and Mash1 [8, 9]. Type-C cells divide and give rise to neuroblasts (type-A cells) that migrate to the olfactory bulb (OB) through the rostral migratory stream and become mature interneurons. Besides their neurogenic potential, type-B cells and type-C cells can generate oligodendrocytes in vivo that migrate to the corpus callosum, striatum and fimbria fornix [10].
The relationship between microglia cells and the SVZ
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In the adult brain microglia cells are present all along the V-SVZ (figure 1) and remain in an intimate contact with type-B1 cells [10]. The first interaction between the V-SVZ and microglia begins when microglia cells begin to populate the embryonic brain. At the early stages of brain development an excessive number of neurons are produced. This surplus of neurons needs to be eliminated by phagocytosis and microglia cells are the responsible effectors of that function. Thus microglial cells are crucial to maintain the balance of neurons and normal postnatal brain development [11]. In the adult V-SVZ microglia cells stimulate neurogenesis by releasing soluble factors within the niche [8]. This is a very complex process that requires the molecular feedback between neural stem cells and microglia cells, which release and express a myriad of molecules, such as: CD200, VEGF, TGF-β in NSCs and CD200R, RNS/ROS, IGF-1, TNFα, TLR-9, CX3CL1, CX3CR1, KATP channel IL-1β, LIF, IFN-γ [10, 12, 13]. In the V-SVZ,
Neuroimmunol Neuroinflamm. Author manuscript; available in PMC 2017 July 10.
Lira-Diaz and Gonzalez-Perez
Page 3
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microglia cells presents certain degree of activation level and constantly release cytokines and neurotrophic factors with respect to other brain areas [14]. This phenomenon suggests that neural stem cells are regulated by microglia cells. In vitro studies reveal that microgliaderived cytokines regulate the generation of neurons and oligodendrocytes in V-SVZ cell cultures [15]. All of these events occurs under physiological conditions, but under pathological circumstances these signals can be magnified. After activation, microglia cells enter into a phagocytic state (amoeboid shape) to remove cell debris and damaged. Phagocytic microglia releases neurotrophic factors and cytokines that activate neural stem cells, thus trigger cell survival and neural regeneration after lesion. Microglial phagocytosis is one of the principal mechanisms to regulate and preserve the homeostasis in the production of neural progenitors in the postnatal brain. Microglia also eliminates aberrant cells that might later give rise to malignant cells or brain tumors.
Author Manuscript
In summary, microglial cells are important components of the V-SVZ that play key roles in neurogenesis, neural protection and cell differentiation. Studying the relationship between NSCs and microglia cells is important for understanding the homeostatic mechanism that control the V-SVZ neurogenenic niche. Nonetheless, this neural-immune interaction is still not well understood. Thus, further studies are needed for clarifying the molecular events implied in the neurogenic process and determining its clinical relevance.
Acknowledgments OGP was financed by grants from Consejo Nacional de Ciencia y Tecnologia (CONACyT-268062) and NIH/ NINDS; R01-NS070024). ELD by CONACyT’s Fellowhip grant (No. 736004).
References Author Manuscript Author Manuscript
1. Greter M, Merad M. Regulation of microglia development and homeostasis. Glia. 2013; 61(1):121– 7. [PubMed: 22927325] 2. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010; 330(6005):841–5. [PubMed: 20966214] 3. Streit WJ, Xue Q-S. Life and death of microglia. Journal of neuroimmune pharmacology. 2009; 4(4):371–9. [PubMed: 19680817] 4. Olejniczak M, Urbanek MO, Krzyzosiak WJ. The role of the immune system in triplet repeat expansion diseases. Mediators of inflammation. 2015; 2015:873860. [PubMed: 25873774] 5. Casano AM, Peri F. Microglia: multitasking specialists of the brain. Developmental cell. 2015; 32(4):469–77. [PubMed: 25710533] 6. Doetsch F. The glial identity of neural stem cells. Nature neuroscience. 2003; 6(11):1127–34. [PubMed: 14583753] 7. Lim DA, Alvarez-Buylla A. Adult neural stem cells stake their ground. Trends in neurosciences. 2014; 37(10):563–71. [PubMed: 25223700] 8. Lim DA, Alvarez-Buylla A. The Adult Ventricular-Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis. Cold Spring Harbor perspectives in biology. 2016; 8(5) 9. Doetsch F, Petreanu L, Caille I, Garcia-Verdugo J-M, Alvarez-Buylla A. EGF converts transitamplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron. 2002; 36(6):1021–34. [PubMed: 12495619] 10. Gonzalez-Perez O, Gutierrez-Fernandez F, Lopez-Virgen V, Collas-Aguilar J, Quinones-Hinojosa A, Garcia-Verdugo JM. Immunological regulation of neurogenic niches in the adult brain. Neuroscience. 2012; 226:270–81. [PubMed: 22986164]
Neuroimmunol Neuroinflamm. Author manuscript; available in PMC 2017 July 10.
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11. Morrens J, Van Den Broeck W, Kempermann G. Glial cells in adult neurogenesis. Glia. 2012; 60(2):159–74. [PubMed: 22076934] 12. Su P, Zhang J, Zhao F, Aschner M, Chen J, Luo W. The interaction between microglia and neural stem/precursor cells. Brain research bulletin. 2014; 109:32–8. [PubMed: 25245208] 13. Shigemoto-Mogami Y, Hoshikawa K, Goldman JE, Sekino Y, Sato K. Microglia enhance neurogenesis and oligodendrogenesis in the early postnatal subventricular zone. The Journal of Neuroscience. 2014; 34(6):2231–43. [PubMed: 24501362] 14. Goings GE, Kozlowski DA, Szele FG. Differential activation of microglia in neurogenic versus non-neurogenic regions of the forebrain. Glia. 2006; 54(4):329–42. [PubMed: 16862532] 15. Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, et al. Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/ progenitor cells. Molecular and Cellular Neuroscience. 2006; 31(1):149–60. [PubMed: 16297637]
Author Manuscript Author Manuscript Author Manuscript Neuroimmunol Neuroinflamm. Author manuscript; available in PMC 2017 July 10.
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Figure 1.
Microglia cells in the adult V-SVZ of mouse brain. Schematic bran section: The adult VSVZ is the neurogenic niche lining the lateral walls of the lateral ventricles (LV). Photomicrography: Microglia cells labeled with anti-Iba1 antibodies and revealed with 3,3'Diaminobenzidine (DAB) technique. At resting stage, these cells exhibit a ramified cell morphology and numerous thin processes. Note that microglia cells are more abundant in the
Neuroimmunol Neuroinflamm. Author manuscript; available in PMC 2017 July 10.
Lira-Diaz and Gonzalez-Perez
Page 6
Author Manuscript
V-SVZ as compared to adjacent brain regions: corpus callosum (CC) and striatum (Str). These cells are also in close contact with blood vessels (BV). Bar = 20 µm.
Author Manuscript Author Manuscript Author Manuscript Neuroimmunol Neuroinflamm. Author manuscript; available in PMC 2017 July 10.
Neuroimmunol Neuroinflamm. Author manuscript; available in PMC 2017 July 10. Published in final edited form as: Neuroimmunol Neuroinflamm. 2016 ; 3: 204–206. doi:10.20517/2347-8659.2016.32.
Emerging roles of microglia cells in the regulation of adult neural stem cells Eduardo Lira-Diaz1,2 and Oscar Gonzalez-Perez1 1Laboratory 2Medical
of Neuroscience, School of Psychology, University of Colima, Colima 28040, Mexico
Sciences PhD Program, School of Medicine, University of Colima, Colima Mexico 28040
Author Manuscript
Abstract Microglia cells were first described as a component for the brain with few beneficial functions. The classical point of view implied that these cells had inflammatory properties more than benefits for brain homeostasis. To date, this assumption has changed and new roles of microglia cells are continuously discovered. Although, the main function of microglia cells is to provide a cellular defense against harmful or pathogen agents (bacteria, viruses, fungi, toxins, etc.), recent evidence indicates that microglial cells are dynamic modulators of synaptic pruning, brain development and neurogenesis by maintaining a balance of local cell population. In this commentary, we summarized the emerging role of the relationship between microglia cells and the neural stem cells resident in the ventricular-subventricular zone (V-SVZ), the largest neurogenic niche in the adult brain.
Author Manuscript
Keywords Microglia cells; neurogenesis; neural stem cells; ventricular-subventricular zone (V-SVZ); niche
Microglia cells
Author Manuscript
Microglia cells are antigen presenting cells with myeloid origin that integrate the mononuclear phagocyte system into the brain [1]. These cells are considered the resident macrophages of the adult central nervous system (CNS). In the adult rodent brain, microglia cells constituted approximately 10% of all glial cells [1]. In the early embryo, the microglial precursors are located in the yolk sac and progressively migrate throughout the primitive brain [2]. In the adult brain, some of microglial cells derive from the bone marrow, but this process can only take place when the brain is lesioned [1]. Microglial cells can display four morphological and functional stages: 1) resting microglia, 2) active microglia, 3) phagocytic microglia, and 4) senescent microglia [3]. One of the functions of microglia is to provide the
Corresponding author: Oscar Gonzalez-Perez, M.D., Ph.D., Facultad de Psicologia, Universidad de Colima, Av. Universidad 333, Colima, COL 28040, Mexico, Tel: +52 (312) 316-1091, [email protected]. Contribution details Eduardo Lira-Díaz: literature search, manuscript preparation and manuscript editing. Óscar Gonzalez-Perez: concept definition of intellectual content, manuscript editing and manuscript review. Conflict of interest The authors report no conflict of interest.
Lira-Diaz and Gonzalez-Perez
Page 2
Author Manuscript
cell-mediated immunity response against pathogens by releasing chemokines or cytokines and acting as antigen presenting cells [1]. Thus, microglial cells can stimulate naïve T cells to initiate a T-cell response after the breakdown of the blood brain barrier. However, the immune response and debris removing are not the only functions of microglial cells. Recently, it has been identified that microglia cells regulate neuronal apoptosis during the early brain development [4], modulate synaptic function and control neurogenesis [5].
The ventricular-subventricular zone (V-SVZ)
Author Manuscript Author Manuscript
The adult mammalian brain possess specialized structures known as niches that host stem cells with neurogenic potential [6]. One of those niches is known as the V-SVZ, which is an epithelial layer located in the lateral walls of the lateral ventricles [7]. In the adulthood, the V-SVZ three cell populations have been identified: type-B cells, type-C cells and type-A cells [8]. The putative neural stem cells is the type-B cell, an astroglial cells that can be identified by the expression of the glial fibrillary acidic protein (GFAP), glutamate aspartate transporter (GLAST), brain lipid binding protein (BLBP), platelet-derived growth factor receptor alpha (PDGFRα), CD133, Id1, Tailless (Tlx), VCAM1, epidermal growth factor receptor (EGFR), and others [7, 8]. The activation of B1 cells depends of signaling pathways including sonic hedgehog (SHH), wingless-related integration site (Wnt), Notch, bone morphogenetic proteins (BMP), ephrins, retinoic acid (RA), betacellulin (BTC), stromal derived factor-1 (SDF-1), pigment epithelium-derived factor (PEDF) and some intrinsic signals (PRX1, SOX2, ARS2, ASCL1, NG2, OLIG2) [7, 8]. This myriad of chemical effectors are provided by resident cells within the niche and some of them derived for the cerebrospinal fluid [8]. After activation, type-B1 cells produce transit-amplifying progenitors (type-C cells) that express the epidermal growth factor receptor (EGFR) and the transcription factors Dlx2 and Mash1 [8, 9]. Type-C cells divide and give rise to neuroblasts (type-A cells) that migrate to the olfactory bulb (OB) through the rostral migratory stream and become mature interneurons. Besides their neurogenic potential, type-B cells and type-C cells can generate oligodendrocytes in vivo that migrate to the corpus callosum, striatum and fimbria fornix [10].
The relationship between microglia cells and the SVZ
Author Manuscript
In the adult brain microglia cells are present all along the V-SVZ (figure 1) and remain in an intimate contact with type-B1 cells [10]. The first interaction between the V-SVZ and microglia begins when microglia cells begin to populate the embryonic brain. At the early stages of brain development an excessive number of neurons are produced. This surplus of neurons needs to be eliminated by phagocytosis and microglia cells are the responsible effectors of that function. Thus microglial cells are crucial to maintain the balance of neurons and normal postnatal brain development [11]. In the adult V-SVZ microglia cells stimulate neurogenesis by releasing soluble factors within the niche [8]. This is a very complex process that requires the molecular feedback between neural stem cells and microglia cells, which release and express a myriad of molecules, such as: CD200, VEGF, TGF-β in NSCs and CD200R, RNS/ROS, IGF-1, TNFα, TLR-9, CX3CL1, CX3CR1, KATP channel IL-1β, LIF, IFN-γ [10, 12, 13]. In the V-SVZ,
Neuroimmunol Neuroinflamm. Author manuscript; available in PMC 2017 July 10.
Lira-Diaz and Gonzalez-Perez
Page 3
Author Manuscript
microglia cells presents certain degree of activation level and constantly release cytokines and neurotrophic factors with respect to other brain areas [14]. This phenomenon suggests that neural stem cells are regulated by microglia cells. In vitro studies reveal that microgliaderived cytokines regulate the generation of neurons and oligodendrocytes in V-SVZ cell cultures [15]. All of these events occurs under physiological conditions, but under pathological circumstances these signals can be magnified. After activation, microglia cells enter into a phagocytic state (amoeboid shape) to remove cell debris and damaged. Phagocytic microglia releases neurotrophic factors and cytokines that activate neural stem cells, thus trigger cell survival and neural regeneration after lesion. Microglial phagocytosis is one of the principal mechanisms to regulate and preserve the homeostasis in the production of neural progenitors in the postnatal brain. Microglia also eliminates aberrant cells that might later give rise to malignant cells or brain tumors.
Author Manuscript
In summary, microglial cells are important components of the V-SVZ that play key roles in neurogenesis, neural protection and cell differentiation. Studying the relationship between NSCs and microglia cells is important for understanding the homeostatic mechanism that control the V-SVZ neurogenenic niche. Nonetheless, this neural-immune interaction is still not well understood. Thus, further studies are needed for clarifying the molecular events implied in the neurogenic process and determining its clinical relevance.
Acknowledgments OGP was financed by grants from Consejo Nacional de Ciencia y Tecnologia (CONACyT-268062) and NIH/ NINDS; R01-NS070024). ELD by CONACyT’s Fellowhip grant (No. 736004).
References Author Manuscript Author Manuscript
1. Greter M, Merad M. Regulation of microglia development and homeostasis. Glia. 2013; 61(1):121– 7. [PubMed: 22927325] 2. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010; 330(6005):841–5. [PubMed: 20966214] 3. Streit WJ, Xue Q-S. Life and death of microglia. Journal of neuroimmune pharmacology. 2009; 4(4):371–9. [PubMed: 19680817] 4. Olejniczak M, Urbanek MO, Krzyzosiak WJ. The role of the immune system in triplet repeat expansion diseases. Mediators of inflammation. 2015; 2015:873860. [PubMed: 25873774] 5. Casano AM, Peri F. Microglia: multitasking specialists of the brain. Developmental cell. 2015; 32(4):469–77. [PubMed: 25710533] 6. Doetsch F. The glial identity of neural stem cells. Nature neuroscience. 2003; 6(11):1127–34. [PubMed: 14583753] 7. Lim DA, Alvarez-Buylla A. Adult neural stem cells stake their ground. Trends in neurosciences. 2014; 37(10):563–71. [PubMed: 25223700] 8. Lim DA, Alvarez-Buylla A. The Adult Ventricular-Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis. Cold Spring Harbor perspectives in biology. 2016; 8(5) 9. Doetsch F, Petreanu L, Caille I, Garcia-Verdugo J-M, Alvarez-Buylla A. EGF converts transitamplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron. 2002; 36(6):1021–34. [PubMed: 12495619] 10. Gonzalez-Perez O, Gutierrez-Fernandez F, Lopez-Virgen V, Collas-Aguilar J, Quinones-Hinojosa A, Garcia-Verdugo JM. Immunological regulation of neurogenic niches in the adult brain. Neuroscience. 2012; 226:270–81. [PubMed: 22986164]
Neuroimmunol Neuroinflamm. Author manuscript; available in PMC 2017 July 10.
Lira-Diaz and Gonzalez-Perez
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Author Manuscript
11. Morrens J, Van Den Broeck W, Kempermann G. Glial cells in adult neurogenesis. Glia. 2012; 60(2):159–74. [PubMed: 22076934] 12. Su P, Zhang J, Zhao F, Aschner M, Chen J, Luo W. The interaction between microglia and neural stem/precursor cells. Brain research bulletin. 2014; 109:32–8. [PubMed: 25245208] 13. Shigemoto-Mogami Y, Hoshikawa K, Goldman JE, Sekino Y, Sato K. Microglia enhance neurogenesis and oligodendrogenesis in the early postnatal subventricular zone. The Journal of Neuroscience. 2014; 34(6):2231–43. [PubMed: 24501362] 14. Goings GE, Kozlowski DA, Szele FG. Differential activation of microglia in neurogenic versus non-neurogenic regions of the forebrain. Glia. 2006; 54(4):329–42. [PubMed: 16862532] 15. Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, et al. Microglia activated by IL-4 or IFN-γ differentially induce neurogenesis and oligodendrogenesis from adult stem/ progenitor cells. Molecular and Cellular Neuroscience. 2006; 31(1):149–60. [PubMed: 16297637]
Author Manuscript Author Manuscript Author Manuscript Neuroimmunol Neuroinflamm. Author manuscript; available in PMC 2017 July 10.
Lira-Diaz and Gonzalez-Perez
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Figure 1.
Microglia cells in the adult V-SVZ of mouse brain. Schematic bran section: The adult VSVZ is the neurogenic niche lining the lateral walls of the lateral ventricles (LV). Photomicrography: Microglia cells labeled with anti-Iba1 antibodies and revealed with 3,3'Diaminobenzidine (DAB) technique. At resting stage, these cells exhibit a ramified cell morphology and numerous thin processes. Note that microglia cells are more abundant in the
Neuroimmunol Neuroinflamm. Author manuscript; available in PMC 2017 July 10.
Lira-Diaz and Gonzalez-Perez
Page 6
Author Manuscript
V-SVZ as compared to adjacent brain regions: corpus callosum (CC) and striatum (Str). These cells are also in close contact with blood vessels (BV). Bar = 20 µm.
Author Manuscript Author Manuscript Author Manuscript Neuroimmunol Neuroinflamm. Author manuscript; available in PMC 2017 July 10.
