Stem Cell Biology (Doetsch)Head of Research Unit Prof. Dr.Fiona DoetschOverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 8 foundShow per page10 10 20 50 Adult neural stem cells: a substrate for on-demand brain plasticity Research Project | 1 Project MembersNo Description available Regulation and diversity of adult neural stem cells Research Project | 1 Project MembersNo Description available Neural Circuit Regulation of Adult Brain Stem Cells Research Project | 1 Project MembersIn the adult mammalian brain, neural stem cells (NSCs) residing in the ventricular-subventricular zone (V-SVZ), give rise to new olfactory bulb neurons and glia throughout life. Adult V-SVZ NSC are highly heterogeneous. Stem cells co-exist in quiescent and activated states and reside in regionally-distinct V-SVZ domains and produce different subtypes of olfactory bulb neurons and glia. However, whether this heterogeneity is due to intrinsic fate commitment or whether it is dynamically responsive to external changes is still debated. Moreover, the mechanisms that modulate the balance between activation and dormancy are largely unknown. It is emerging that physiological states modulate V-SVZ cell behaviour and impact adult neurogenesis. We propose to investigate whether physiologically distinct states result in the recruitment of regionally distinct pools of adult V-SVZ neural stem cells. In Aim 1, we will map the domains of stem cell activation and cell types generated in different states in male and female mice. In Aim 2, we will perform large-scale single cell sequencing to decode stem cell heterogeneity and develop novel fate mapping strategies to selectively target different stem cell populations. We will also define the connectivity of different populations of interneuron subtypes. In Aim 3, we will define how the choroid plexus and long- range innervation differentially affect V-SVZ stem cell recruitment in different states using approaches to manipulate neuronal circuit activity. Together these experiments will providea conceptual breakthrough into illuminating the logic of adult neural stem cell heterogeneity, and howregionally distinct adult neural stem cells integrate long-range signals from remote brain areas to respond to signals for on-demand neurogenesis or gliogenesis. Regulation and lineage dynamics of adult neural stem cells Research Project | 1 Project MembersStem cells reside in specialized niches in the adult mammalian brain and generate new neurons and glia throughout life. Adult neural stem cells dynamically integrate signals from the microenvironment to remain dormant or become activated to divide and give rise to progeny. The ventricular-subventricular zone is the largest germinal niche in the adult mouse brain, and generates olfactory bulb interneurons, oligodendrocytes and astrocytes. We have recently developed strategies to purify both quiescent and activated neural stem cells and their progeny directly from their niche. We will investigate the heterogeneity and potential of adult neural stem cells and define how distinct compartments of the stem cell niche regulate their behavior. Together these will give insight into the intrinsic and extrinsic signals that regulate adult neural stem cell behavior. Choroid plexus regulation of adult neural stem cells Research Project | 1 Project MembersStem cells reside in specialized niches that support their life-long self-renewal and differentiation. Adult neural stem cells continuously generate neurons in restricted parts of the brain that functionally integrate into neural circuits. These stem cells may represent an important source of endogenous cells that can be stimulated for brain repair. Defining the source and identity of signals from the niche that regulate adult neural stem cell behavior is essential to eventually harnessing these cells for brain repair, as well as understanding how changes in niche contribute to the decline in stem cell function that occurs with aging and disease. The ventricular-subventricular zone (V-SVZ) is the largest germinal region in the adult brain and is located adjacent to the cerebrospinal fluid (CSF)-filled lateral ventricles. The stem cells in the V-SVZ niche are continuously bathed by CSF. The CSF is produced by the choroid plexus, which floats in the brain ventricles. Although the lateral ventricle choroid plexus (LVCP) is in close proximity to the V-SVZ, its role in the niche has largely been ignored. We propose that in addition to important homeostatic functions, the LVCP is a key component of the adult V-SVZ NSC niche. We will investigate how LVCP secreted factors affected the behavior of adult neural stem cells and their progeny. We will also determine how aging and other states influence the functional effect of the LVCP compartment on adult neural stem cells. Defining in vivo heterogeneity of adult neural stem cells at the single cell level Research Project | 1 Project MembersAdult neural stem cells continuously generate neurons in restricted parts of the brain that functionally integrate into neural circuits. These endogenous stem cells may represent an important source of cells that can be stimulated for brain repair. The in vivo stem cells exhibit many features of astrocytes, glial cells classically associated with support functions. The ventricular-subventricular zone (V-SVZ) is the largest germinal region in the adult brain and generates different subtypes of olfactory bulb neurons, as well as oligodendrocytes and astrocytes. Recent work has suggested that adult neural stem cells exhibit regional heterogeneity in terms of their progeny. However little is known about the molecular programs and diversity of neural stem cells in vivo, due to a lack of markers to isolate them. We have recently defined a combination of markers that allows the prospective purification of quiescent and activated adult neural stem cells directly from the in vivo niche. We will couple this novel purification strategy with microfluidics-based single cell transcriptional profiling to illuminate the heterogeneity of adult neural stem cells. We propose to: 1) define the heterogeneity of adult neural stem cells by performing single cell transcriptional profiling of prospectively purified quiescent and activated adult neural stem cells isolated from different regions of the V-SVZ, 2) define the in vivo distribution and functional properties of the novel adult neural stem cell subpopulations. Together these studies will yield key insight into the heterogeneity and molecular programs of adult neural stem cells. MicroRNA regulation of adult neural stem cells Research Project | 1 Project MembersIn the adult brain, neural stem cells continuously generate new neurons. The stem cells are a subset of glial cells, classically associated with support functions in the brain. This raises the possibility that glial cells elsewhere in the brain are also latent stem cells. Neural stem cells are predominantly found in a quiescent state, and occasionally become activated to divide. However the molecular mechanisms that control the dormant state are largely unknown. MicroRNAs are small, non-coding RNAs that are capable of rapidly suppressing translation of hundreds of transcripts, making them attractive mediators of rapid changes in cell state. We have found that different cohorts of microRNAs are expressed in quiescent and activated adult neural stem cells, and are important regulators of the transition of stem cells from quiescence to activation. We will define 1) the role of the miR-17~92 cluster and 2) its targets in adult neural stem cell regulation. Elucidating the regulatory networks that control stem cells in the adult mammalian brain will provide insight into the possibility of harnessing endogenous stem cells, as well as activating other cells in non-neurogenic regions, for brain repair. Prospective Purification of Adult Neural Stem Cells Research Project | 1 Project MembersStem cells continuously generate new neurons in restricted regions of the adult mammalian brain. The ventricular-subventricular zone (V-SVZ) is the largest germinal region in the adult and gives rise to both olfactory bulb neurons and glia. The in vivo stem cells are a subset of astrocytes. These endogenous stem cells potentially represent a pool of cells that can be harnessed for brain repair. A balance between intrinsic and extrinsic signals mediates the activation of quiescent stem cells. However, the ability to distinguish between quiescent and activated stem cells has been hampered by a lack of markers. We have identified a combination of markers that allow us to identify and purify quiescent and activated stem cells directly from the V-SVZ in vivo niche, and have characterized their cell cycle properties, functional properties in vitro and transcriptomes. We will use genetic approaches to 1) perform lineage tracing and 2) to determine the functional role of PDGFRb in adult neural stem cell regulation. Together these studies will yield key insights into the regulation of stem cell quiescence in the adult brain. 1 1 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 8 foundShow per page10 10 20 50 Adult neural stem cells: a substrate for on-demand brain plasticity Research Project | 1 Project MembersNo Description available Regulation and diversity of adult neural stem cells Research Project | 1 Project MembersNo Description available Neural Circuit Regulation of Adult Brain Stem Cells Research Project | 1 Project MembersIn the adult mammalian brain, neural stem cells (NSCs) residing in the ventricular-subventricular zone (V-SVZ), give rise to new olfactory bulb neurons and glia throughout life. Adult V-SVZ NSC are highly heterogeneous. Stem cells co-exist in quiescent and activated states and reside in regionally-distinct V-SVZ domains and produce different subtypes of olfactory bulb neurons and glia. However, whether this heterogeneity is due to intrinsic fate commitment or whether it is dynamically responsive to external changes is still debated. Moreover, the mechanisms that modulate the balance between activation and dormancy are largely unknown. It is emerging that physiological states modulate V-SVZ cell behaviour and impact adult neurogenesis. We propose to investigate whether physiologically distinct states result in the recruitment of regionally distinct pools of adult V-SVZ neural stem cells. In Aim 1, we will map the domains of stem cell activation and cell types generated in different states in male and female mice. In Aim 2, we will perform large-scale single cell sequencing to decode stem cell heterogeneity and develop novel fate mapping strategies to selectively target different stem cell populations. We will also define the connectivity of different populations of interneuron subtypes. In Aim 3, we will define how the choroid plexus and long- range innervation differentially affect V-SVZ stem cell recruitment in different states using approaches to manipulate neuronal circuit activity. Together these experiments will providea conceptual breakthrough into illuminating the logic of adult neural stem cell heterogeneity, and howregionally distinct adult neural stem cells integrate long-range signals from remote brain areas to respond to signals for on-demand neurogenesis or gliogenesis. Regulation and lineage dynamics of adult neural stem cells Research Project | 1 Project MembersStem cells reside in specialized niches in the adult mammalian brain and generate new neurons and glia throughout life. Adult neural stem cells dynamically integrate signals from the microenvironment to remain dormant or become activated to divide and give rise to progeny. The ventricular-subventricular zone is the largest germinal niche in the adult mouse brain, and generates olfactory bulb interneurons, oligodendrocytes and astrocytes. We have recently developed strategies to purify both quiescent and activated neural stem cells and their progeny directly from their niche. We will investigate the heterogeneity and potential of adult neural stem cells and define how distinct compartments of the stem cell niche regulate their behavior. Together these will give insight into the intrinsic and extrinsic signals that regulate adult neural stem cell behavior. Choroid plexus regulation of adult neural stem cells Research Project | 1 Project MembersStem cells reside in specialized niches that support their life-long self-renewal and differentiation. Adult neural stem cells continuously generate neurons in restricted parts of the brain that functionally integrate into neural circuits. These stem cells may represent an important source of endogenous cells that can be stimulated for brain repair. Defining the source and identity of signals from the niche that regulate adult neural stem cell behavior is essential to eventually harnessing these cells for brain repair, as well as understanding how changes in niche contribute to the decline in stem cell function that occurs with aging and disease. The ventricular-subventricular zone (V-SVZ) is the largest germinal region in the adult brain and is located adjacent to the cerebrospinal fluid (CSF)-filled lateral ventricles. The stem cells in the V-SVZ niche are continuously bathed by CSF. The CSF is produced by the choroid plexus, which floats in the brain ventricles. Although the lateral ventricle choroid plexus (LVCP) is in close proximity to the V-SVZ, its role in the niche has largely been ignored. We propose that in addition to important homeostatic functions, the LVCP is a key component of the adult V-SVZ NSC niche. We will investigate how LVCP secreted factors affected the behavior of adult neural stem cells and their progeny. We will also determine how aging and other states influence the functional effect of the LVCP compartment on adult neural stem cells. Defining in vivo heterogeneity of adult neural stem cells at the single cell level Research Project | 1 Project MembersAdult neural stem cells continuously generate neurons in restricted parts of the brain that functionally integrate into neural circuits. These endogenous stem cells may represent an important source of cells that can be stimulated for brain repair. The in vivo stem cells exhibit many features of astrocytes, glial cells classically associated with support functions. The ventricular-subventricular zone (V-SVZ) is the largest germinal region in the adult brain and generates different subtypes of olfactory bulb neurons, as well as oligodendrocytes and astrocytes. Recent work has suggested that adult neural stem cells exhibit regional heterogeneity in terms of their progeny. However little is known about the molecular programs and diversity of neural stem cells in vivo, due to a lack of markers to isolate them. We have recently defined a combination of markers that allows the prospective purification of quiescent and activated adult neural stem cells directly from the in vivo niche. We will couple this novel purification strategy with microfluidics-based single cell transcriptional profiling to illuminate the heterogeneity of adult neural stem cells. We propose to: 1) define the heterogeneity of adult neural stem cells by performing single cell transcriptional profiling of prospectively purified quiescent and activated adult neural stem cells isolated from different regions of the V-SVZ, 2) define the in vivo distribution and functional properties of the novel adult neural stem cell subpopulations. Together these studies will yield key insight into the heterogeneity and molecular programs of adult neural stem cells. MicroRNA regulation of adult neural stem cells Research Project | 1 Project MembersIn the adult brain, neural stem cells continuously generate new neurons. The stem cells are a subset of glial cells, classically associated with support functions in the brain. This raises the possibility that glial cells elsewhere in the brain are also latent stem cells. Neural stem cells are predominantly found in a quiescent state, and occasionally become activated to divide. However the molecular mechanisms that control the dormant state are largely unknown. MicroRNAs are small, non-coding RNAs that are capable of rapidly suppressing translation of hundreds of transcripts, making them attractive mediators of rapid changes in cell state. We have found that different cohorts of microRNAs are expressed in quiescent and activated adult neural stem cells, and are important regulators of the transition of stem cells from quiescence to activation. We will define 1) the role of the miR-17~92 cluster and 2) its targets in adult neural stem cell regulation. Elucidating the regulatory networks that control stem cells in the adult mammalian brain will provide insight into the possibility of harnessing endogenous stem cells, as well as activating other cells in non-neurogenic regions, for brain repair. Prospective Purification of Adult Neural Stem Cells Research Project | 1 Project MembersStem cells continuously generate new neurons in restricted regions of the adult mammalian brain. The ventricular-subventricular zone (V-SVZ) is the largest germinal region in the adult and gives rise to both olfactory bulb neurons and glia. The in vivo stem cells are a subset of astrocytes. These endogenous stem cells potentially represent a pool of cells that can be harnessed for brain repair. A balance between intrinsic and extrinsic signals mediates the activation of quiescent stem cells. However, the ability to distinguish between quiescent and activated stem cells has been hampered by a lack of markers. We have identified a combination of markers that allow us to identify and purify quiescent and activated stem cells directly from the V-SVZ in vivo niche, and have characterized their cell cycle properties, functional properties in vitro and transcriptomes. We will use genetic approaches to 1) perform lineage tracing and 2) to determine the functional role of PDGFRb in adult neural stem cell regulation. Together these studies will yield key insights into the regulation of stem cell quiescence in the adult brain. 1 1
Adult neural stem cells: a substrate for on-demand brain plasticity Research Project | 1 Project MembersNo Description available
Regulation and diversity of adult neural stem cells Research Project | 1 Project MembersNo Description available
Neural Circuit Regulation of Adult Brain Stem Cells Research Project | 1 Project MembersIn the adult mammalian brain, neural stem cells (NSCs) residing in the ventricular-subventricular zone (V-SVZ), give rise to new olfactory bulb neurons and glia throughout life. Adult V-SVZ NSC are highly heterogeneous. Stem cells co-exist in quiescent and activated states and reside in regionally-distinct V-SVZ domains and produce different subtypes of olfactory bulb neurons and glia. However, whether this heterogeneity is due to intrinsic fate commitment or whether it is dynamically responsive to external changes is still debated. Moreover, the mechanisms that modulate the balance between activation and dormancy are largely unknown. It is emerging that physiological states modulate V-SVZ cell behaviour and impact adult neurogenesis. We propose to investigate whether physiologically distinct states result in the recruitment of regionally distinct pools of adult V-SVZ neural stem cells. In Aim 1, we will map the domains of stem cell activation and cell types generated in different states in male and female mice. In Aim 2, we will perform large-scale single cell sequencing to decode stem cell heterogeneity and develop novel fate mapping strategies to selectively target different stem cell populations. We will also define the connectivity of different populations of interneuron subtypes. In Aim 3, we will define how the choroid plexus and long- range innervation differentially affect V-SVZ stem cell recruitment in different states using approaches to manipulate neuronal circuit activity. Together these experiments will providea conceptual breakthrough into illuminating the logic of adult neural stem cell heterogeneity, and howregionally distinct adult neural stem cells integrate long-range signals from remote brain areas to respond to signals for on-demand neurogenesis or gliogenesis.
Regulation and lineage dynamics of adult neural stem cells Research Project | 1 Project MembersStem cells reside in specialized niches in the adult mammalian brain and generate new neurons and glia throughout life. Adult neural stem cells dynamically integrate signals from the microenvironment to remain dormant or become activated to divide and give rise to progeny. The ventricular-subventricular zone is the largest germinal niche in the adult mouse brain, and generates olfactory bulb interneurons, oligodendrocytes and astrocytes. We have recently developed strategies to purify both quiescent and activated neural stem cells and their progeny directly from their niche. We will investigate the heterogeneity and potential of adult neural stem cells and define how distinct compartments of the stem cell niche regulate their behavior. Together these will give insight into the intrinsic and extrinsic signals that regulate adult neural stem cell behavior.
Choroid plexus regulation of adult neural stem cells Research Project | 1 Project MembersStem cells reside in specialized niches that support their life-long self-renewal and differentiation. Adult neural stem cells continuously generate neurons in restricted parts of the brain that functionally integrate into neural circuits. These stem cells may represent an important source of endogenous cells that can be stimulated for brain repair. Defining the source and identity of signals from the niche that regulate adult neural stem cell behavior is essential to eventually harnessing these cells for brain repair, as well as understanding how changes in niche contribute to the decline in stem cell function that occurs with aging and disease. The ventricular-subventricular zone (V-SVZ) is the largest germinal region in the adult brain and is located adjacent to the cerebrospinal fluid (CSF)-filled lateral ventricles. The stem cells in the V-SVZ niche are continuously bathed by CSF. The CSF is produced by the choroid plexus, which floats in the brain ventricles. Although the lateral ventricle choroid plexus (LVCP) is in close proximity to the V-SVZ, its role in the niche has largely been ignored. We propose that in addition to important homeostatic functions, the LVCP is a key component of the adult V-SVZ NSC niche. We will investigate how LVCP secreted factors affected the behavior of adult neural stem cells and their progeny. We will also determine how aging and other states influence the functional effect of the LVCP compartment on adult neural stem cells.
Defining in vivo heterogeneity of adult neural stem cells at the single cell level Research Project | 1 Project MembersAdult neural stem cells continuously generate neurons in restricted parts of the brain that functionally integrate into neural circuits. These endogenous stem cells may represent an important source of cells that can be stimulated for brain repair. The in vivo stem cells exhibit many features of astrocytes, glial cells classically associated with support functions. The ventricular-subventricular zone (V-SVZ) is the largest germinal region in the adult brain and generates different subtypes of olfactory bulb neurons, as well as oligodendrocytes and astrocytes. Recent work has suggested that adult neural stem cells exhibit regional heterogeneity in terms of their progeny. However little is known about the molecular programs and diversity of neural stem cells in vivo, due to a lack of markers to isolate them. We have recently defined a combination of markers that allows the prospective purification of quiescent and activated adult neural stem cells directly from the in vivo niche. We will couple this novel purification strategy with microfluidics-based single cell transcriptional profiling to illuminate the heterogeneity of adult neural stem cells. We propose to: 1) define the heterogeneity of adult neural stem cells by performing single cell transcriptional profiling of prospectively purified quiescent and activated adult neural stem cells isolated from different regions of the V-SVZ, 2) define the in vivo distribution and functional properties of the novel adult neural stem cell subpopulations. Together these studies will yield key insight into the heterogeneity and molecular programs of adult neural stem cells.
MicroRNA regulation of adult neural stem cells Research Project | 1 Project MembersIn the adult brain, neural stem cells continuously generate new neurons. The stem cells are a subset of glial cells, classically associated with support functions in the brain. This raises the possibility that glial cells elsewhere in the brain are also latent stem cells. Neural stem cells are predominantly found in a quiescent state, and occasionally become activated to divide. However the molecular mechanisms that control the dormant state are largely unknown. MicroRNAs are small, non-coding RNAs that are capable of rapidly suppressing translation of hundreds of transcripts, making them attractive mediators of rapid changes in cell state. We have found that different cohorts of microRNAs are expressed in quiescent and activated adult neural stem cells, and are important regulators of the transition of stem cells from quiescence to activation. We will define 1) the role of the miR-17~92 cluster and 2) its targets in adult neural stem cell regulation. Elucidating the regulatory networks that control stem cells in the adult mammalian brain will provide insight into the possibility of harnessing endogenous stem cells, as well as activating other cells in non-neurogenic regions, for brain repair.
Prospective Purification of Adult Neural Stem Cells Research Project | 1 Project MembersStem cells continuously generate new neurons in restricted regions of the adult mammalian brain. The ventricular-subventricular zone (V-SVZ) is the largest germinal region in the adult and gives rise to both olfactory bulb neurons and glia. The in vivo stem cells are a subset of astrocytes. These endogenous stem cells potentially represent a pool of cells that can be harnessed for brain repair. A balance between intrinsic and extrinsic signals mediates the activation of quiescent stem cells. However, the ability to distinguish between quiescent and activated stem cells has been hampered by a lack of markers. We have identified a combination of markers that allow us to identify and purify quiescent and activated stem cells directly from the V-SVZ in vivo niche, and have characterized their cell cycle properties, functional properties in vitro and transcriptomes. We will use genetic approaches to 1) perform lineage tracing and 2) to determine the functional role of PDGFRb in adult neural stem cell regulation. Together these studies will yield key insights into the regulation of stem cell quiescence in the adult brain.
