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Within the adult central nervous system (CNS) of most mammals resides a resident stem cell population, known as neural stem cells (NSCs). NSCs are located within specific niches of the CNS and maintain a self-renewal and proliferative capacity to generate new neurons, astrocytes, and oligodendrocytes throughout adulthood. The NSC niches are dynamic and active environments that are within proximity to the systemic circulation and the cerebrospinal fluid (CSF). Therefore, NSCs respond not only to factors present in the local microenvironment of the niche but also to factors present in the systemic macroenvironment. The factors can be soluble forms such as cytokines and chemokines located in the circulation or directly from local cells, such as microglia and astrocytes. Additionally, recent evidence points towards physiological aging and its association with a progressive loss of function and a decline in the self-renewal and regenerative capacities of CNS NSCs, which can be further exacerbated by changes in the local and systemic milieu. This review will highlight the main intrinsic and extrinsic regulators of neural stem cell function under homeostatic and inflammatory conditions including those trafficked within extracellular membrane vesicles. Further, discussion will center around how intrinsic and extrinsic factors impact normal homeostatic functions within the adult brain and in aging., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The concept of a "cancer stem cell" has evolved over the past decades, and research on cancer stem cell biology has entered into a stage of remarkable progress. Cancer stem cells are a major determining factor contributing to the establishment of phenotypic and functional intratumoral heterogeneity in synchronization with their surrounding "cancer stem cell niches." They serve as the driving force for cancer initiation, metastasis, and therapeutic resistance in various types of malignancies. In verity, reciprocal interplay between ovarian cancer stem cells and their niches involves a complex but ingeniously orchestrated tumor microenvironment within the intraperitoneal milieu and especially contribute to chemotherapy resistance in patients with advanced ovarian cancer. Herein, we review the principles of our current understanding of the biological features of ovarian cancer stem cells, focusing mainly on the precise mechanisms underlying acquired chemotherapy resistance. Furthermore, we highlight the specific roles of various cancer-associated stromal and immune cells in creating possible cancer stem cell niches that regulate ovarian cancer stemness., (Copyright © 2021. Published by Elsevier Ltd.)

Hematopoiesis is responsible for the formation of all blood cells from hematopoietic stem cells (HSC) in the bone marrow (BM). It is a highly regulated process, in order to adapt its cellular output to changing body requirements. Specific microenvironmental conditions within the BM must exist in order to maintain HSC pluripotency and self-renewal, as well as to ensure appropriate differentiation of progenitor cells towards each hematopoietic lineage. Those conditions were coined "the hematopoietic niche" and their identity in terms of cell types, location and soluble molecular components has been the subject of intense research in the last decades. Infections are one of the environmental challenges to which hematopoiesis must respond, to feed the immune system with functional cell components and compensate for cellular losses. However, how infections impact the bone marrow hematopoietic niche(s) remains elusive and most of the mechanisms involved are still largely unknown. Here, we review the most recent advances on our knowledge on the hematopoietic niche composition and regulation during homeostasis and also on how the niche responds to infectious stress., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

This study sought to derive an enhanced understanding of the complex intracellular interactions that drive bone loss in postmenopausal osteoporosis. We applied an in-vitro multicellular niche to recapitulate cell-cell signalling between osteocytes, osteoblasts and osteoclasts to investigate (1) how estrogen-deficient and mechanically loaded osteocytes regulate osteoclastogenesis and (2) whether ROCK-II inhibition affects these mechanobiological responses. We report that mechanically stimulated and estrogen-deficient osteocytes upregulated RANKL/OPG and M-CSF gene expression, when compared to those treated with 10 nM estradiol. Osteoclast precursors (RAW 264.7) cultured within this niche underwent significant reduction in osteoclastogenic gene expression (CTSK), and there was an increasing trend in the area covered by TRAP + osteoclasts (24% vs. 19.4%, p = 0.06). Most interestingly, upon treatment with the ROCK-II inhibitor, RANKL/OPG and M-CSF gene expression by estrogen-deficient osteocytes were downregulated. Yet, this inhibition of the pro-osteoclastogenic factors by osteocytes did not ultimately reduce the differentiation of osteoclast precursors. Indeed, TRAP and CTSK gene expressions in osteoclast precursors were upregulated, and there was an increased trend for osteoclast area (30.4% vs. 24%, p = 0.07), which may have been influenced by static osteoblasts (MC3T3-E1) that were included in the niche. We conclude that ROCK-II inhibition can attenuate bone loss driven by osteocytes during estrogen deficiency., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The Drosophila male stem cell niche is a well characterized structure in which a small cluster of somatic cells send self-renewal signals to neighbouring germ cells. Although the molecular information involved in the stem cell fate have been identified, much less is understand on the mechanisms driving their short-range specific release. Our ultrastructural analysis reveals distinct protrusions of the stem cell plasma membrane that interdigitate with membrane protrusions of the facing hub cells. Some of these protrusions are very elongated and extend into the hub and could correspond to the Mt-Nanotubes. Therefore, the interface between the stem cells and the hub appears more complex than previously reported and the membrane protrusions of the stem cells might represent specialized surface areas involved in the niche-stem cell communication. We also noticed the presence of clathrin-coated vesicles in the germline plasma membrane that might be also involved in delivering information from the hub., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Diabetes mellitus (DM) is reaching epidemic conditions worldwide and increases the risk for cognition impairment and dementia. Here, we postulated that progenitors in adult neurogenic niches might be particularly vulnerable. Therefore, we evaluated the different components of the mouse subventricular zone (SVZ) during the first week after chemical induction of type 1 and type 2 diabetes-like (T1DM and T2DM) conditions. Surprisingly, only T2DM mice showed SVZ damage. The initial lesions were localized to ependymal cilia, which appeared disorientated and clumped together. In addition, they showed delocalization of the ciliary membrane protein prominin-1. Impairment of neuroprogenitor proliferation, neurogenic marker abnormalities and ectopic migration of neuroblasts were found at a later stage. To our knowledge, our data describe for the first time such an early impact of T2DM on the SVZ. This is consistent with clinical data indicating that brain damage in T2DM patients differs from that in T1DM patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Neural stem cells (NSCs) are multipotent, self-renewing progenitors that generate progeny that differentiate into neurons and glia. NSCs in the adult mammalian brain are generally quiescent. Environmental stimuli such as learning or exercise can activate quiescent NSCs, inducing them to proliferate and produce new neurons and glia. How are these behaviours coordinated? The neurovasculature, the circulatory system of the brain, is a key component of the NSC microenvironment, or 'niche'. Instructive signals from the neurovasculature direct NSC quiescence, proliferation, self-renewal and differentiation. During ageing, a breakdown in the niche accompanies NSC dysfunction and cognitive decline. There is much interest in reversing these changes and enhancing NSC activity by targeting the neurovasculature therapeutically. Here we discuss principles of neurovasculature-NSC crosstalk, and the implications for the design of NSC-based therapies. We also consider the emerging contributions to this field of the model organism Drosophila melanogaster., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Neurogenesis in the subventricular zone (SVZ) of the adult brain may contribute to tissue repair after brain injuries. Whether SVZ neurogenesis can be upregulated by specific neuronal activity in vivo and promote functional recovery after stroke is largely unknown. Using the spatial and cell type specific optogenetic technique combined with multiple approaches of in vitro, ex vivo and in vivo examinations, we tested the hypothesis that glutamatergic activation in the striatum could upregulate SVZ neurogenesis in the normal and ischemic brain. In transgenic mice expressing the light-gated channelrhodopsin-2 (ChR2) channel in glutamatergic neurons, optogenetic stimulation of the glutamatergic activity in the striatum triggered glutamate release into SVZ region, evoked membrane currents, Ca 2+ influx and increased proliferation of SVZ neuroblasts, mediated by AMPA receptor activation. In ChR2 transgenic mice subjected to focal ischemic stroke, optogenetic stimuli to the striatum started 5days after stroke for 8days not only promoted cell proliferation but also the migration of SVZ neuroblasts into the peri-infarct cortex with increased neuronal differentiation and improved long-term functional recovery. These data provide the first morphological and functional evidence showing a unique striatum-SVZ neuronal regulation via a semi-phasic synaptic mechanism that can boost neurogenic cascades and stroke recovery. The benefits from stimulating endogenous glutamatergic activity suggest a novel regenerative strategy after ischemic stroke and other brain injuries., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Although the existence of the limbal stem cell (LSC) niche is accepted, precise knowledge of its three-dimensional (3D) architecture remains incomplete. The LSC niche was explored on freshly excised and organ-cultured corneoscleral rims from human donors (n = 47), pigs (n = 15) and mice (n = 27) with full-field optical coherence microscopy (FFOCM). Limbal crypt features were detected in 90% of organ-cultured human corneoscleral rims, extending between the palisades of Vogt as radially oriented rectangular (74% of eyes) and/or rounded (23% of eyes) forms, often branching off to, or becoming interconnected by, sub-scleral radially or circumferentially oriented crypts (in 56% of eyes). Mean crypt volume represented 16% of sampled limbal volume on the vertical axis and 8% on the horizontal axis. In pigs, palisades were finer and crypts wider with relatively uniform distribution around the eye, and radial orientation, connecting to numerous narrow criss-crossing invaginations beneath the scleral surface. In mice, only a circumferential limbal trough was detected. Mean crypt volume represented 13% of sampled limbal volume in humans and 9% in pigs. FFOCM combined with fluorescence, and confocal fluorescence microscopy, showed presence of p63-α+ cells and cytokeratin-3+ cells in the limbal crypts. To assess colony forming efficiency (CFE), limbal epithelial cells were cultured at low density with mitomycin-arrested 3T3 feeders. CFE increased with limbal crypt volume and was not significantly decreased in organ-cultured cornea, despite degradation of the epithelial roof, suggesting that stem cells remain protected at the base of crypts during organ culture. CFE in human samples was significantly greater than in pig, and CFE in mouse was zero. Crypt architecture in the three species appears associated with eye exposure to light. LSC density increased with percentage limbal volume occupied by crypts., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neurogenesis impairment starting from early developmental stages is a key determinant of intellectual disability in Down syndrome (DS). Previous evidence provided a causal relationship between neurogenesis impairment and malfunctioning of the mitogenic Sonic Hedgehog (Shh) pathway. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain), a cleavage product of the trisomic gene APP (amyloid precursor protein) up-regulate transcription of Ptch1 (Patched1), the Shh receptor that keeps the pathway repressed. Since AICD results from APP cleavage by γ-secretase, the goal of the current study was to establish whether treatment with a γ-secretase inhibitor normalizes AICD levels and restores neurogenesis in trisomic neural precursor cells. We found that treatment with a selective γ-secretase inhibitor (ELND006; ELN) restores proliferation in neurospheres derived from the subventricular zone (SVZ) of the Ts65Dn mouse model of DS. This effect was accompanied by reduction of AICD and Ptch1 levels and was prevented by inhibition of the Shh pathway with cyclopamine. Treatment of Ts65Dn mice with ELN in the postnatal period P3-P15 restored neurogenesis in the SVZ and hippocampus, hippocampal granule cell number and synapse development, indicating a positive impact of treatment on brain development. In addition, in the hippocampus of treated Ts65Dn mice there was a reduction in the expression levels of various genes that are transcriptionally regulated by AICD, including APP, its origin substrate. Inhibitors of γ-secretase are currently envisaged as tools for the cure of Alzheimer's disease because they lower βamyloid levels. Current results provide novel evidence that γ-secretase inhibitors may represent a strategy for the rescue of neurogenesis defects in DS., (Copyright © 2015. Published by Elsevier Inc.)

Human limbal epithelial stem cells (LESCs) are essential for the maintenance of the corneal epithelium of the ocular surface. LESCs are located within limbal crypts between the palisades of Vogt in the limbus; the interface between the peripheral cornea and conjunctiva. The limbal crypts have been proposed as a LESC niche owing to their support of epithelial cells, which can form holoclone colonies in vitro. Closely associated with the limbal crypts is a concentrated population of melanocytes. The anatomical location and close proximity to putative LESC suggests that melanocytes might play a role in maintenance of these stem cells in the niche. The aim of this study was to assess the ability of human limbal melanocytes (hLM) to support the expansion of human limbal epithelial cells (LECs) in vitro as an indicator of functional cell-cell interaction. After observing that hLM co-localize with clusters of compact epithelial cells in the native limbal crypts, hLM were isolated from crypt-rich cadaveric limbal biopsies and used as feeders for the culture of LECs. Interestingly, LECs grown on mitotically active hLM were able to generate large epithelial colonies that contained small and compact cells with morphological stem cell characteristics. Immunocytochemistry revealed that LECs expanded on hLM were positive for the expression of the putative stem cell markers CK15, Bmi-1 and p63α and negative for the marker of terminal cell differentiation CK3. LECs and hLM were finally co-cultured on RAFT (real architecture for 3D tissue) collagen tissue equivalents. In 3D co-cultures, hLM promoted multi-layering of the epithelial sheet in which basal cells were maintained in an undifferentiated state. Taken together, these observations suggest melanocytes could play an important role in the maintenance of LESCs in the native human limbal stem cell niche., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Cardiac aging is a heterogeneous process caused by a combination of stochastic events which manifests as loss of structure and function in the heart, however several recent studies draw attention to aging being primarily a stem cell problem. This review summarizes findings in support of the "stem cell hypothesis of aging" and discusses the impact of age on cardiac stem cells and the niche. This article is part of a Special Issue entitled 'CV Aging'., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Previous studies have established the subventricular (SVZ) and subgranular (SGZ) zones as sites of neurogenesis in the adult forebrain (Doetsch et al., 1999a; Doetsch, 2003a). Work from our laboratory further indicated that midline structures known as circumventricular organs (CVOs) also serve as adult neural stem cell (NSC) niches (Bennett et al., 2009, 2010). In the quiescent rat brain, NSC proliferation remains low in all of these sites. Therefore, we recently examined whether ischemic stroke injury (MCAO) or sustained intraventricular infusion of the mitogen bFGF could trigger an up-regulation in NSC proliferation, inducing neurogenesis and gliogenesis. Our data show that both stroke and bFGF induce a dramatic and long-lasting (14day) rise in the proliferation (BrdU+) of nestin+Sox2+GFAP+ NSCs capable of differentiating into Olig2+ glial progenitors, GFAP+nestin-astrocyte progenitors and Dcx+ neurons in the SVZ and CVOs. Moreover, because of the upsurge in NSC number, it was possible to detect for the first time several novel stem cell niches along the third (3V) and fourth (4V) ventricles. Importantly, a common feature of all brain niches was a rich vasculature with a blood-brain-barrier (BBB) that was highly permeable to systemically injected sodium fluorescein. These data indicate that stem cell niches are more extensive than once believed and exist at multiple sites along the entire ventricular system, consistent with the potential for widespread neurogenesis and gliogenesis in the adult brain, particularly after injury. We further suggest that because of their leaky BBB, stem cell niches are well-positioned to respond to systemic injury-related cues which may be important for stem-cell mediated brain repair., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Establishing and maintaining cell fate in the right place at the right time is a key requirement for normal tissue maintenance. Stem cells are at the core of this process. Understanding how stem cells balance self-renewal and production of differentiating cells is key for understanding the defects that underpin many diseases. Both, external cues from the environment and cell intrinsic mechanisms can control the outcome of stem cell division. The role of the orientation of stem cell division has emerged as an important mechanism for specifying cell fate decisions. Although, the alignment of cell divisions can dependent on spatial cues from the environment, maintaining stemness is not always linked to positioning of stem cells in a particular microenvironment or `niche'. Alternate mechanisms that could contribute to cellular memory include differential segregation of centrosomes in asymmetrically dividing cells., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hair follicles are appendages of the mammalian skin that have the ability to periodically and stereotypically regenerate in order to continuously produce new hair over our lifetime. The ability of the hair follicle to regenerate is due to the presence of stem cells that along with other cell populations and non-cellular components, including molecular signals and extracellular material, make up a niche microenvironment. Mounting evidence suggests that the niche is critical for regulating stem cell behavior and thus the process of regeneration. Here, we review the literature concerning past and current studies that have utilized mouse genetic models, combined with other approaches to dissect the molecular and cellular composition of the hair follicle niche. We also discuss our current understanding of how stem cells operate within the niche during the process of tissue regeneration and the factors that regulate their behavior., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Many physiologic processes during the early stages of mammalian ontogeny, particularly placental and vascular development, take place in the low oxygen environment of the uterus. Organogenesis is affected by hypoxia inducible factor (HIF) transcription factors that are sensors of hypoxia. In response to hypoxia, HIFs activate downstream target genes - growth and metabolism factors. During hematopoietic system ontogeny, blood cells and hematopoietic progenitor/stem cells are respectively generated from mesodermal precursors, hemangioblasts, and from a specialized subset of endothelial cells that are hemogenic. Since HIFs are known to play a central role in vascular development, and hematopoietic system development occurs in parallel to that of the vascular system, several studies have examined the role of HIFs in hematopoietic development. The response to hypoxia has been examined in early and mid-gestation mouse embryos through genetic deletion of HIF subunits. We review here the data showing that hematopoietic tissues of the embryo are hypoxic and express HIFs and HIF downstream targets, and that HIFs regulate the development and function of hematopoietic progenitor/stem cells., (© 2013.)

Ischaemia leads to increased proliferation of progenitors in the subependymal zone (SEZ) neurogenic niche of the adult brain and to generation and migration of newborn neurons. Here we investigated the spatiotemporal characteristics of the mitotic activity of adult neural stem and progenitor cells in the SEZ during the sub-acute and chronic post-ischaemic phases. Ischaemia was induced by performing a 1h unilateral middle cerebral artery occlusion (MCAO) and tissue was collected 4/5 weeks and 1 year after the insult. Neural stem cells (NSCs) responded differently from their downstream progenitors to MCAO, with NSCs being activated only transiently whilst progenitors remain activated even at 1 year post-injury. Importantly, mitotic activation was observed only in the affected areas of the niche and specifically in the dorsal half of the SEZ. Analysis of the topography of mitoses, in relation to the anatomy of the lesion and to the position of ependymal cells and blood vessels, suggested an interplay between lesion-derived recruiting signals and the local signals that normally control proliferation in the chronic post-ischaemic phase., (© 2013.)

Background: Healing of articular cartilage has remained in question with the use of conventional treatment modalities such as subchondral drilling and microfracture. As demonstrated in the past, adult stem cells retain promising clonogenicity. Therefore, we conducted this study to elucidate the effects of cultured autologous chondrogenic satellite cells (CACSCs) compared with subchondral drilling (SCD) for the repair of full-thickness articular cartilage defects., Materials and Methods: We examined CACSCs isolated from the knee of rabbits using flow cytometry for the expression of stemness and chondrocyte-specific factors. Subsequently, we created a full-thickness cartilage defect model with a diameter of 3 mm and depth of 2 mm on the articular surface of trochlear grooves in the left knee of 24 New Zealand white rabbits. Then we drilled subchondrally through the defect in all animals and stuffed the defects with 10-μg/cm(2) collagen scaffolds. In the treatment group, we instilled CACSCs at 5 × 10(6) cells/mL in the collagen scaffold and collected samples on days 15, 30, and 45., Results: The CACSCs revealed significant expression of CD106, CD44, collagen type 2, and aggrecan. In conjunction with SCD, CACSCs improved healing of the articular cartilage defect, as evidenced by the formation of hyaline-like tissue grossly and histologically. The healed tissue also revealed a significant (P < 0.05) increase in the expression of collagen type 2 and aggrecan (by real-time polymerase chain reaction) during the experiment., Conclusions: In conjunction with SCD, CACSCs may be considered to improve articular cartilage damage., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Focal brain ischemia in adult rats rapidly and robustly induces neurogenesis in the subventricular zone (SVZ) but there are few and inconsistent reports in mice, presenting a hurdle to genetically investigate the endogenous neurogenic regulators such as ciliary neurotrophic factor (CNTF). Here, we first provide a platform for further studies by showing that middle cerebral artery occlusion in adult male C57BL/6 mice robustly enhances neurogenesis in the SVZ only under very specific conditions, i.e., 14days after a 30min occlusion. CNTF expression paralleled changes in the number of proliferated, BrdU-positive, SVZ cells. Stroke-induced proliferation was absent in CNTF-/- mice, suggesting that it is mediated by CNTF. MCAO-increased CNTF appears to act on C cell proliferation and by inducing FGF2 expression but not via EGF expression or Notch1 signaling of neural stem cells in the SVZ. CNTF is unique, as expression of other gp130 ligands, IL-6 and LIF, did not predict SVZ proliferation or showed no or only small compensatory increases in CNTF-/- mice. Expression of tumor necrosis factor-α, which can inhibit neurogenesis, and the presence of leukocytes in the SVZ were inversely correlated with neurogenesis, but pro-inflammatory cytokines did not affect CNTF expression in cultured astrocytes. These results suggest that slowly up-regulated CNTF in the SVZ mediates stroke-induced neurogenesis and is counteracted by inflammation. Further pharmacological stimulation of endogenous CNTF might be a good therapeutic strategy for cell replacement after stroke as CNTF regulates normal patterns of neurogenesis and is expressed almost exclusively in the nervous system., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In the bone marrow cavity, hematopoietic stem cells (HSC) have been shown to reside in the endosteal and subendosteal perivascular niches, which play specific roles on HSC maintenance. Although cells with long-term ability to reconstitute full hematopoietic system can be isolated from both niches, several data support a heterogenous distribution regarding the cycling behavior of HSC. Whether this distinct behavior depends upon the role played by the stromal populations which distinctly create these two niches is a question that remains open. In the present report, we used our previously described in vivo assay to demonstrate that endosteal and subendosteal stromal populations are very distinct regarding skeletal lineage differentiation potential. This was further supported by a microarray-based analysis, which also demonstrated that these two stromal populations play distinct, albeit complementary, roles in HSC niche. Both stromal populations were preferentially isolated from the trabecular region and behave distinctly in vitro, as previously reported. Even though these two niches are organized in a very close range, in vivo assays and molecular analyses allowed us to identify endosteal stroma (F-OST) cells as fully committed osteoblasts and subendosteal stroma (F-RET) cells as uncommitted mesenchymal cells mainly represented by perivascular reticular cells expressing high levels of chemokine ligand, CXCL12. Interestingly, a number of cytokines and growth factors including interleukin-6 (IL-6), IL-7, IL-15, Hepatocyte growth factor (HGF) and stem cell factor (SCF) matrix metalloproteases (MMPs) were also found to be differentially expressed by F-OST and F-RET cells. Further microarray analyses indicated important mechanisms used by the two stromal compartments in order to create and coordinate the "quiescent" and "proliferative" niches in which hematopoietic stem cells and progenitors reside., (Published by Elsevier Inc.)

Precursors within the subventricular zone (SVZ) exhibit regional variations in the expression of transcription factors important for the regulation of their proliferation and differentiation. In the anterior SVZ (aSVZ) the homeobox transcription factor distalless (Dlx)2 modulates both processes by promoting neural stem cell (NSC) activation as well as neurogenesis. Activated NSCs and transit-amplifying precursors (TAPs) in the aSVZ both express high levels of epidermal growth factor receptor (EGFR(high)) and form clones in response to exogenous EGF. EGF-responsive cells are also present in the hippocampal subependyma (hSVZ). However, it is not clear whether they represent NSCs or TAPs and whether their proliferation and differentiation are regulated as in the aSVZ. Here we have purified EGFR(high) cells from both the aSVZ and hSVZ at different ages. When isolated from perinatal tissue both populations were enriched in multipotent clonogenic precursors, which generated GABAergic neurons. Although they differed in absolute expression levels, activated NSCs and TAPs in both regions displayed similar signatures of transcription factor expression. However, activated NSCs were less frequent in the hSVZ than in the aSVZ. Furthermore, increasing age had a greater inhibitory effect on NSC proliferation in the hSVZ than in the aSVZ. This suggests that NSC activation is differentially regulated in the two regions. Consistent with this hypothesis, we found that in hippocampal precursors Dlx2 promoted neurogenesis but not NSC activation. Thus, most clonogenic EGFR(high) precursors in the hSVZ represent TAPs and NSC proliferation in the aSVZ and hSVZ is regulated by different mechanisms.

Neural stem cells (NSCs) persist in the forebrain subventricular zone (SVZ) within a niche containing endothelial cells. Evidence suggests that endothelial cells stimulate NSC expansion and neurogenesis. Experimental stroke increases neurogenesis and angiogenesis, but how endothelial cells influence stroke-induced neurogenesis is unknown. We hypothesized intact or oxygen-glucose deprived (OGD) endothelial cells secrete factors that enhance neurogenesis. We co-cultured mouse SVZ neurospheres (NS) with endothelial cells, or differentiated NS in endothelial cell-conditioned medium (ECCM). NS also were expanded in ECCM from OGD-exposed (OGD-ECCM) endothelial cells to assess injury effects. ECCM significantly increased NS production. NS co-cultured with endothelial cells or ECCM generated more immature-appearing neurons and oligodendrocytes, and astrocytes with radial glial-like/reactive morphology than controls. OGD-ECCM stimulated neuroblast migration and yielded neurons with longer processes and more branching. These data indicate that intact and injured endothelial cells exert differing effects on NSCs, and suggest targets for stimulating regeneration after brain insults.

In the postnatal subventricular zone (SVZ) neural stem cells (NSCs) give rise to transit-amplifying precursors (TAPs) expressing high levels of epidermal growth factor receptor (EGFR) that in turn generate neuroblasts. Both TAPs and neuroblasts express distal-less (DLX)2 homeobox transcription factor but the latter proliferate less. Modulation of its expression in vivo has revealed that DLX2 affects both neurogenesis and proliferation in the postnatal SVZ. However, the mechanisms underlying these effects are not clear. To investigate this issue we have here forced the expression of DLX2 in SVZ isolated NSCs growing in defined in vitro conditions. This analysis revealed that DLX2 affects the proliferation of SVZ precursors by regulating two distinct steps of neural lineage progression. Firstly, it promotes the lineage transition from NSCs to TAPs. Secondly it enhances the proliferative response of neuronal progenitors to EGF. Thus DLX2 and EGFR signalling interact at multiple levels to coordinate proliferation in the postnatal SVZ.

Understanding the alterations of migratory activities of the endogenous neural stem/progenitor cells (NSPs) in injured developing brains is becoming increasingly imperative for curative reasons. In this study, 10-day-old neonatal rats with and without hypoxic-ischemic (HI) insult at postnatal day 7 were injected intraventricularly with micron-sized iron oxide particles (MPIOs), followed by serial high-resolution MRI at 7 T for 2 weeks. MRI findings were correlated to the histological analysis using iron staining and several immunohistochemical double staining. The results indicated that in normal and HI-injured brains the NSPs from the subventricular zone (SVZ) were labeled by MPIOs, and migrated as newly created cells (iron+/BrdU+), neuroblasts (iron+/nestin+), astrocytes or astrocytes-like progenitor cells (iron+/GFAP+), and mature neurons (iron+/NeuN+). In normal brains, the endogenous NSPs mainly exhibited a tangential pattern in both rostral and caudal directions. The NSP radial migratory pattern could be observed in some rats. In the HI-injured brains during the same developmental period, the NSPs mainly migrated towards the HI lesion sites. The tangential, rostrocaudal migrations could be observed but impaired. These findings suggest that the NSP migratory pathways in SVZ change in response to the HI insult, likely due to the self-repairing efforts known in the neonatal brains. The MRI approach demonstrated here is potentially applicable to the in vivo and longitudinal study of NSP cell activities in developing brains under normal and pathological conditions and in therapeutic interventions.

Vagus nerve stimulation (VNS), used in the treatment of epilepsy, was approved recently for treatment-resistant depression. The mechanisms of action of the VNS anti-depressive effects are not yet fully elucidated. Modulation of hippocampal neurogenesis has been proposed as an important factor in depression pathogenesis. We evaluated the effects of VNS on hippocampal progenitor turnover in the adult rat brain. Rats receiving VNS at the output current of 0.75 mA VNS for 2 days showed a significant 50% increase in dentate gyrus BrdU-incorporation consistent with an increase in progenitor proliferation. Output currents of 0.5 or 1.5 mA yielded non-significant trends for increased BrdU-labeling indicating an inverted U-shaped proliferative dose response to VNS as previously reported for other VNS-induced effects. Specific analysis for progenitor survival revealed no effects by VNS on dentate gyrus BrdU-labeling. These results suggest that VNS induced an increase in the number of available progenitor cells in the adult rat dentate gyrus by a mechanism presumably involving increased progenitor proliferation.