We have purified and characterized a factor, from the conditioned medium of neural stem cell cultures, which is required for fibroblast growth factor 2's (FGF-2) mitogenic activity on neural stem cells. This autocrine/paracrine cofactor is a glycosylated form of cystatin C (CCg), whose N-glycosylation is required for its activity. We further demonstrated that, both in vitro and in vivo, neural stem cells undergoing cell division are immunopositive for cystatin C. Finally, we showed in vivo functional activity of CCg by demonstrating that the combined delivery of FGF-2 and CCg to the adult dentate gyrus stimulated neurogenesis. We propose that the process of neurogenesis is controlled by the cooperation between trophic factors and autocrine/paracrine cofactors, of which CCg is a prototype.
"Cystatin C, a 13 kDa basic protein, is secreted by all nucleated cells, present in all human biological fluids, and is a physiological inhibitor of cysteine proteases . The concentration of cystatin C in the cerebrospinal fluid (CSF) of adults is normally about six times higher than that of blood plasma   and cystatin C seems to promote neural stem-cell growth  in addition to being a protease inhibitor. Cystatin C has been found to colocalize with Ab in several disease states. "
"Various growth factors such as PEDF, EGF, FGF2, and BDNF as well as extracellular matrix components, such as Tenascin-C, have also been demonstrated as niche signals , –. In an attempt to search for autocrine/paracrine factors produced by niche cells, several studies examined the conditioned medium of neurosphere cultures by mass spectrometry and identified molecules such as Cystatin C, Apolipoprotein E, and DSD-1-proteoglycan , . Another recent study utilized a co-culture system of a human NSC line and human umbilical cord endothelial cells to investigate the communication between endothelial cells and NSCs via soluble factors . "
[Show abstract][Hide abstract] ABSTRACT: Neural stem cells (NSCs) reside in a unique microenvironment called the neurogenic niche and generate functional new neurons. The neurogenic niche contains several distinct types of cells and interacts with the NSCs in the subventricular zone (SVZ) of the lateral ventricle. While several molecules produced by the niche cells have been identified to regulate adult neurogenesis, a systematic profiling of autocrine/paracrine signaling molecules in the neurogenic regions involved in maintenance, self-renewal, proliferation, and differentiation of NSCs has not been done. We took advantage of the genetic inducible fate mapping system (GIFM) and transgenic mice to isolate the SVZ niche cells including NSCs, transit-amplifying progenitors (TAPs), astrocytes, ependymal cells, and vascular endothelial cells. From the isolated cells and microdissected choroid plexus, we obtained the secretory molecule expression profiling (SMEP) of each cell type using the Signal Sequence Trap method. We identified a total of 151 genes encoding secretory or membrane proteins. In addition, we obtained the potential SMEP of NSCs using cDNA microarray technology. Through the combination of multiple screening approaches, we identified a number of candidate genes with a potential relevance for regulating the NSC behaviors, which provide new insight into the nature of neurogenic niche signals.
PLoS ONE 11/2012; 7(11):e50501. DOI:10.1371/journal.pone.0050501 · 3.23 Impact Factor
"CysC is highly abundant in brain tissue (Hakansson et al., 1996), expressed by neurons, astrocytes, and microglial cells in the brains of different species (Yasuhara et al., 1993; Palm et al., 1995; Miyake et al., 1996). CysC plays a variety of biological roles, ranging from anti-viral and anti-bacterial properties (Bobek and Levine, 1992), bone resorption (Lerner and Grubb, 1992), tumor metastasis (Huh et al., 1999; Taupin et al., 2000), modulation of inflammatory responses (Warfel et al., 1987; Bobek and Levine, 1992), cell proliferation and growth (Sun, 1989; Tavera et al., 1992), and astrocytic differentiation during mouse brain development (Kumada et al., 2004). Involvement of CysC has been shown in various diseases ranging from cancer to neurodegenerative disorders. "
[Show abstract][Hide abstract] ABSTRACT: Changes in expression and secretion levels of cystatin C (CysC) in the brain in various neurological disorders and in animal models of neurodegeneration underscore a role for CysC in these conditions. A polymorphism in the CysC gene (CST3) is linked to increased risk for Alzheimer's disease (AD). AD pathology is characterized by deposition of oligomeric and fibrillar forms of amyloid β (Aβ) in the neuropil and cerebral vessel walls, neurofibrillary tangles composed mainly of hyperphosphorylated tau, and neurodegeneration. The implication of CysC in AD was initially suggested by its co-localization with Aβ in amyloid-laden vascular walls, and in senile plaque cores of amyloid in the brains of patients with AD, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), and cerebral infarction. CysC also co-localizes with Aβ amyloid deposits in the brains of non-demented aged individuals. Multiple lines of research show that CysC plays protective roles in AD. In vitro studies have shown that CysC binds Aβ and inhibits Aβ oligomerization and fibril formation. In vivo results from the brains and plasma of Aβ-depositing transgenic mice confirmed the association of CysC with the soluble, non-pathological form of Aβ and the inhibition of Aβ plaques formation. The association of CysC with Aβ was also found in brain and in cerebrospinal fluid (CSF) from AD patients and non-demented control individuals. Moreover, in vitro results showed that CysC protects neuronal cells from a variety of insults that may cause cell death, including cell death induced by oligomeric and fibrillar Aβ. These data suggest that the reduced levels of CysC manifested in AD contribute to increased neuronal vulnerability and impaired neuronal ability to prevent neurodegeneration. This review elaborates on the neuroprotective roles of CysC in AD and the clinical relevance of this protein as a therapeutic agent.
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