Steven Artandi, Postdoctoral Faculty Sponsor
Ependyma-expressed CCN1 restricts the size of the neural stem cell pool in the adult ventricular-subventricular zone.
The EMBO journal
Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma-derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular-subventricular zone (V-SVZ). Adult ependyma-specific deletion of Ccn1 transiently enhanced NSC proliferation and reduced neuronal differentiation in mice, increasing the numbers of NSCs and NSC units. Although proliferation of NSCs and neurogenesis seen in Ccn1 knockout mice eventually returned to normal, the expanded NSC pool was maintained in the V-SVZ until old age. Inhibition of EGFR signaling prevented expansion of the NSC population observed in CCN1 deficient mice. Thus, ependyma-derived CCN1 restricts NSC expansion in the adult brain to maintain the proper niche capacity of the V-SVZ.
View details for DOI 10.15252/embj.2019101679
View details for PubMedID 32009252
ZEB1 Represses Neural Differentiation and Cooperates with CTBP2 to Dynamically Regulate Cell Migration during Neocortex Development
2019; 27 (8): 2335-+
Zinc-finger E-box binding homeobox 1 (Zeb1) is a key regulator of epithelial-mesenchymal transition and cancer metastasis. Mutation of ZEB1 is associated with human diseases and defective brain development. Here we show that downregulation of Zeb1 expression in embryonic cortical neural progenitor cells (NPCs) is necessary for proper neuronal differentiation and migration. Overexpression of Zeb1 during neuronal differentiation, when its expression normally declines, blocks NPC lineage progression and disrupts multipolar-to-bipolar transition of differentiating neurons, leading to severe migration defects and subcortical heterotopia bands at postnatal stages. ZEB1 regulates a cohort of genes involved in cell differentiation and migration, including Neurod1 and Pard6b. The interaction between ZEB1 and CTBP2 in the embryonic cerebral cortex is required for ZEB1 to elicit its effect on the multipolar-to-bipolar transition, but not its suppression of Neurod1. These findings provide insights into understanding the complexity of transcriptional regulation during neuronal differentiation.
View details for DOI 10.1016/j.celrep.2019.04.081
View details for Web of Science ID 000468426300009
View details for PubMedID 31116980
Persistent Expression of VCAM1 in Radial Glial Cells Is Required for the Embryonic Origin of Postnatal Neural Stem Cells
2017; 95 (2): 309-+
During development, neural stem cells (NSCs) undergo transitions from neuroepithelial cells to radial glial cells (RGCs), and later, a subpopulation of slowly dividing RGCs gives rise to the quiescent adult NSCs that populate the ventricular-subventricular zone (V-SVZ). Here we show that VCAM1, a transmembrane protein previously found in quiescent adult NSCs, is expressed by a subpopulation of embryonic RGCs, in a temporal and region-specific manner. Loss of VCAM1 reduced the number of active embryonic RGCs by stimulating their premature neuronal differentiation while preventing quiescence in the slowly dividing RGCs. This in turn diminished the embryonic origin of postnatal NSCs, resulting in loss of adult NSCs and defective V-SVZ regeneration. VCAM1 affects the NSC fate by signaling through its intracellular domain to regulate β-catenin signaling in a context-dependent manner. Our findings provide new insight on how stem cells in the embryo are preserved to meet the need for growth and regeneration.
View details for DOI 10.1016/j.neuron.2017.06.047
View details for Web of Science ID 000405857500010
View details for PubMedID 28728023
Transplantation of Human Neural Stem Cells in a Parkinsonian Model Exerts Neuroprotection via Regulation of the Host Microenvironment
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
2015; 16 (11): 26473-26492
Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons and consequent dopamine (DA) deficit, and current treatment still remains a challenge. Although neural stem cells (NSCs) have been evaluated as appealing graft sources, mechanisms underlying the beneficial phenomena are not well understood. Here, we investigate whether human NSCs (hNSCs) transplantation could provide neuroprotection against DA depletion by recruiting endogenous cells to establish a favorable niche. Adult mice subjected to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were transplanted with hNSCs or vehicle into the striatum. Behavioral and histological analyses demonstrated significant neurorescue response observed in hNSCs-treated animals compared with the control mice. In transplanted animals, grafted cells survived, proliferated, and migrated within the astrocytic scaffold. Notably, more local astrocytes underwent de-differentiation, acquiring the properties of NSCs or neural precursor cells (NPCs) in mice given hNSCs. Additionally, we also detected significantly higher expression of host-derived growth factors in hNSCs-transplanted mice compared with the control animals, together with inhibition of local microglia and proinflammatory cytokines. Overall, our results indicate that hNSCs transplantation exerts neuroprotection in MPTP-insulted mice via regulating the host niche. Harnessing synergistic interaction between the grafts and host cells may help optimize cell-based therapies for PD.
View details for DOI 10.3390/ijms161125966
View details for Web of Science ID 000365648300034
View details for PubMedID 26556344
View details for PubMedCentralID PMC4661825