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Open Access

The less-often-traveled surface of stem cells: caveolin-1 and caveolae in stem cells, tissue repair and regeneration

Stem Cell Research & Therapy20134:90

DOI: 10.1186/scrt276

Published: 30 July 2013

Stem cells are an important resource for tissue repair and regeneration. While a great deal of attention has focused on derivation and molecular regulation of stem cells, relatively little research has focused on how the subcellular structure and composition of the cell membrane influences stem cell activities such as proliferation, differentiation and homing. Caveolae are specialized membrane lipid rafts coated with caveolin scaffolding proteins, which can regulate cholesterol transport and the activity of cell signaling receptors and their downstream effectors. Caveolin-1 is involved in the regulation of many cellular processes, including growth, control of mitochondrial antioxidant levels, migration and senescence. These activities are of relevance to stem cell biology, and in this review evidence for caveolin-1 involvement in stem cell biology is summarized. Altered stem and progenitor cell populations in caveolin-1 null mice suggest that caveolin-1 can regulate stem cell proliferation, and in vitro studies with isolated stem cells suggest that caveolin-1 regulates stem cell differentiation. The available evidence leads us to hypothesize that caveolin-1 expression may stabilize the differentiated and undifferentiated stem cell phenotype, and transient downregulation of caveolin-1 expression may be required for transition between the two. Such regulation would probably be critical in regenerative applications of adult stem cells and during tissue regeneration. We also review here the temporal changes in caveolin-1 expression reported during tissue repair. Delayed muscle regeneration in transgenic mice overexpressing caveolin-1 as well as compromised cardiac, brain and liver tissue repair and delayed wound healing in caveolin-1 null mice suggest that caveolin-1 plays an important role in tissue repair, but that this role may be negative or positive depending on the tissue type and the nature of the repair process. Finally, we also discuss how caveolin-1 quiescence-inducing activities and effects on mitochondrial antioxidant levels may influence stem cell aging.

Caveolae Caveolin-1 Stem cells Signal transduction Cholesterol Tissue repair Regenerative medicine

Stem cells are an important resource for tissue regeneration. Much stem cell research has focused on stem cell sourcing and stem cell regulation by external stimuli (reviewed in [1]). However, relatively little is known about the composition of the stem cell membrane, the organization of which can affect cell responses to external stimuli. Specifically, membrane lipid rafts are recognized as important platforms regulating activity at the cell surface. These cholesterol-rich and sphingolipid-rich liquid-ordered phases in the cell membrane allow compartmentalization and clustering of signaling molecules [2, 3]. Concentration of signaling molecules in membrane rafts may enable amplification, cross-talk, specificity or inhibitory regulation of cell signaling. One flask-shaped subtype of membrane raft, the caveola [4, 5], is the regulation center for a plethora of cell signaling events owing to the activity of its distinguishing caveolin scaffolding proteins [6]. There are three caveolin proteins, which are essential for caveolae formation, cholesterol binding [710] and cholesterol trafficking [1012]. As shown in Figure 1, the caveolin proteins form a hairpin loop in the cell membrane with their N-termini and C-termini remaining in the cell cytoplasm [13, 14]. The cytoplasmic portion of the caveolin protein contains a caveolin scaffolding domain sequence that can bind to many different cell signaling molecules and effect cell signal transduction (reviewed in [6, 15]).
Figure 1

Structure and general activities of caveolae/caveolin-1. Structure (box): caveolae are flask-shaped invaginations in the cell membrane coated with multimers of caveolin scaffolding proteins. The N-termini and C-termini of caveolin proteins are in the cell cytoplasm, but a hairpin loop of the protein is inserted into the cell membrane. Caveolin-1 has a caveolin scaffolding domain (CSD) that can bind to and affect the activity of a variety of cell signaling molecules. Activities: various caveolae/caveolin-1 activities that have been reported in different cell types are depicted. Caveolin-1 binds to cholesterol and can regulate mitochondrial levels of cholesterol. Caveolae are rich cholesterol stores as well as membrane reservoirs that can stretch to buffer mechanical and osmotic stress at the cell surface. Caveolin-1 can regulate cellular levels of nitric oxide (NO) through regulation of NO synthase activity. Caveolin-1 can inhibit cell growth and activate cell senescence by inhibition of mitogen-activated protein (MAP) kinases and binding to the p53 inhibitor MdM2. Caveolin-1 can also regulate other growth and differentiation signaling pathways by caveolar endocytosis of cell surface receptors and sequestering secondary messengers such as β-catenin. Caveolin-1 also participates in focal adhesion signaling and internalization of integrins upon cell detachment. For references, see main text. BMP, bone morphogenetic protein; MLC, myosin light chain; PI-3-kinase, phosphatidylinositol 3-kinase; TGFβ, transforming growth factor beta.

Caveolae are particularly abundant in adipocytes, endothelial cells, pulmonary type I cells and muscle cells [10]. Assays of various mouse and rat tissues have determined that caveolin-1 is most highly expressed in fat and lung tissue [1620], but it is also expressed in many other tissues and differentiated cell types [18, 19, 2128]. Caveolin-2 is usually co-expressed with caveolin-1 and appears unable to form caveolae in the absence of caveolin-1 [17, 18, 29]. Caveolin-3, meanwhile, is highly expressed in muscle cells [19, 22, 30].

Given its expression in many cell types, the role of caveolin-1 in cell activities has been well researched. The growth factor receptors and signaling molecules that localize to caveolae and/or interact with caveolin-1 include the platelet-derived growth factor receptor and the epidermal growth factor (EGF) receptor, G-protein coupled receptors, G-protein alpha and beta subunits, Src, endothelial nitric oxide synthase, and proteins in the Ras-p42/44 mitogen-activated protein kinase and phosphatidylinositol 3-kinase–Akt pathways [6, 15]. While association of signaling molecules with caveolin-1 is usually inhibitory [6, 15], signaling can be enhanced, probably by bringing molecules in close proximity to one another [31]. Furthermore, binding to the caveolin-1 scaffolding domain may enhance the activity of some enzymes. This has been demonstrated in vitro with the insulin receptor kinase [32]. Figure 1 summarizes functions attributed to caveolae and caveolin-1 in various cell types. If present in stem cells, many of these activities could impact stem cell behavior. This review discusses current research findings that implicate caveolin-1 in the regulation of stem and progenitor cell activity, tissue repair and aging.

Caveolin-1 regulation of cell proliferation

Inhibitory association of signaling molecules with caveolin-1, as well as caveolin-1 regulation of intracellular cholesterol levels [33], may be responsible for the mostly inhibitory effects of caveolin-1 on differentiated cell proliferation [29, 3438]. In the caveolin-1 null mouse, enlarged populations of cells expressing stem cell markers in the gut, mammary gland and brain have been observed [3941], suggesting that caveolin-1 may also negatively regulate stem cell proliferation. Furthermore, others have noted that the bone marrow-derived mesenchymal stem cells (MSCs) from the caveolin-1 null mouse have a higher proliferative rate in culture [42], and in mouse neural progenitor cells caveolin-1 facilitates glucocorticoid receptor signaling that leads to inhibition of proliferation [43]. Meanwhile, in human MSCs, Park and colleagues showed that caveolin-1 expression increases when cells are cultured to senescence [44], suggesting that caveolin-1 expression is inversely associated with the proliferative rate of human MSCs. In agreement, we have shown that siRNA-mediated knockdown of caveolin-1 expression in human MSCs increases their proliferation [45].

Conversely, in mouse embryonic stem cells (ESCs), caveolin-1 and caveolae structure appear to be required for cell renewal. Treatment of ESCs with caveolin-1 siRNA or with methyl-β-cyclodextrin, which depletes membrane cholesterol thus disrupting the caveolae structure, reduces the cell proliferation index [46]. Furthermore, when mouse ESCs are seeded on fibronectin, caveolin-1 phosphorylation and caveolae integrity are required in downstream events that activate DNA synthesis [47]. Caveolin-1 also mediates estradiol-17β-induced cell proliferation [48] and its expression is required for EGF-induced cell proliferation and glucose induction of DNA synthesis in ESCs [49]. Caveolin-1 may therefore negatively regulate the proliferation of adult murine and human progenitor cells, but in murine ESCs caveolin-1 may be positively involved in proliferative signaling.

Caveolin-1 effects on cell differentiation

Caveolin-1 is known to regulate Wnt/β-catenin signaling [5054], transforming growth factor beta signaling [5562] and bone morphogenetic protein (BMP) signaling [6367], all pathways that can guide stem cell fate. Meanwhile, caveolin expression typically increases upon cell differentiation in vitro[1620, 23, 30, 6872], including upon osteogenic differentiation of human MSCs [45] and neurogenesis of rat MSCs [73]. This may reflect negative feedback, where caveolin-1 expression increases as cells differentiate to stabilize the phenotype and prevent continued growth and differentiation. For example, bone marrow MSCs from the caveolin-1 null mouse have greater osteogenic potential [74], suggesting that caveolin-1 inhibits osteogenesis. This may explain the increased postnatal bone formation rate in these animals [74]. We have also shown that caveolin-1 knockdown enhances human MSC osteogenesis [45]. Caveolin-1 also inhibits murine and rat neuronal and oligodendral differentiation [73, 75, 76] and human MSC adipogenesis [44].

Caveolin-1 regulation of differentiation probably occurs within caveolae through interactions with receptors and downstream signaling molecules for differentiation stimuli. In accordance with this idea, MSC osteogenic differentiation can be promoted by the cholesterol biosynthesis inhibitor simvastatin [7779], and by oxysterols, which suppress caveolin-1 expression and cause caveolin-1 translocation out of caveolae [80, 81]. Also, bone marrow MSCs isolated from mouse models of osteoporosis or high bone mineral density have decreased and increased responsiveness to BMP2, respectively, due to dysregulated localization of the BMP receptor 1a with caveolin-1 isoforms, and dysregulated caveolae trafficking in response to BMP2 [82, 83]. Caveolae endocytosis of BMP receptors can also affect rat MSC differentiation [84] (as described further below) and active β-catenin levels are elevated in cells expressing stem cell markers in the intestinal crypts and mammary gland of the caveolin-1 null mouse [39, 40], while caveolin-1 regulation of neurogenesis may occur via effects on Notch signaling [73].

Caveolin-1/caveolae regulation of matrix-directed stem cell differentiation

Engler and colleagues showed that MSCs can differentiate according to their substratum elasticity [85]. MSCs seeded on a soft substrate with an elastic modulus similar to brain tissue differentiate into nerve cells, while MSCs seeded on a substrate with an elastic modulus similar to bone differentiate into osteoblasts, and those seeded on a substrate with an elastic modulus similar to muscle differentiate into myoblasts [85]. This phenomenon depends on nonmuscle myosin II activity [85]. As summarized in Figure 2, Du and colleagues have shown that, at least on soft substrates, the mechanism involves caveolin-1 and caveolar endocytosis [84]. In MSCs seeded on a soft substrate, there is increased activation and internalization of β1-integrin via caveolae endocytosis. BMP receptor 1a co-localized with β1-integrin is consequently also internalized, thus inhibiting pro-osteogenic BMP signaling [84]. Du and colleagues calculated that integrin adhesions to the substratum should be more easily ruptured on soft than on stiff substrates [84]. Therefore, when an adherent cell pulls on (or deforms) its matrix, more integrin contacts should be ruptured if that matrix is soft. Ruptured integrin contacts may then be endocytosed in caveolae [84]. In sum, this means tensile forces generated by nonmuscle myosin II when a cell deforms its matrix could be coupled to caveolar endocytosis to modulate availability of cell signaling platforms necessary for directing cell differentiation.
Figure 2

Caveolae endocytosis helps couple regulation of differentiation signals to culture substrate elasticity. When mesenchymal stem cells are seeded on a stiff substrate with an elastic modulus similar to bone, focal adhesions and stress fibers form and nonmuscle myosin II expression increases. Cells osteogenically differentiate on the stiff substrate. The activity of nonmuscle myosin II, which promotes the assembly of focal adhesions, is required for substrate-driven differentiation. As nonmuscle myosin II expression increases in cells seeded on a stiff substrate, it may allow cells to form more focal adhesions and generate the greater force needed to deform a stiff matrix. When cells are seeded on a soft substrate, the integrin contacts with the substrate may be easily ruptured by nonmuscle myosin II-generated forces on the cell cytoskeleton. Expression of nonmyosin II remains lower and less focal adhesions and stress fibers form than in cells seeded on a stiff substrate. Activated integrins from ruptured contacts with the substrate are internalized by caveolar endocytosis. The bone morphogenetic protein receptor 1a (BMPR1a) is co-internalized and the potential for pro-osteogenic bone morphogenetic protein (BMP)-induced Smad signaling is reduced as a result. Cells neurogenically differentiate on the soft substrate. For more information, refer to [84, 85].

Intriguingly, culture of muscle stem cells on substrates with a similar rigidity to muscle improves their viability and proliferation in culture and maintains their stemness and regenerative potential [86]. Thus, stem cells possibly respond to changes in matrix elasticity only when it is different to their tissue of origin [85]. The mechanism behind this and the potentially important role of caveolae is a very interesting topic that deserves further exploration.

Meanwhile, it is interesting to note that caveolin-1 may promote astroglial differentiation [87] and is required for human microvascular endothelial cell tubule formation in a Matrigel differentiation assay [70]. Perhaps this observation indicates that caveolin-1 inhibition of some signaling pathways protects or promotes activation of other pathways. We have found that knockdown of caveolin-1 expression in MSCs decreases mRNA expression of the pluripotency marker POU5F1/Oct4 (unpublished observations), and others have found that caveolin-1 expression and caveolae structure are important for maintaining mouse ESC expression of pluripotency markers (Oct4, Sox2, FoxD3, Rex1) [46]. One could hypothesize that caveolin-1 may act to maintain the stemness of MSCs by holding growth factor receptors and signaling molecules in an inhibited state in caveolae, and/or committing them to caveolar endocytosis. Meanwhile, alterations to caveolin-1 expression or activity may release inhibition of signaling molecules to allow MSCs to be more responsive to other growth and differentiation stimuli. Then, as MSCs differentiate, caveolin-1 expression may increase dramatically to stabilize the new phenotype and prevent continued differentiation. This idea is schematically summarized in Figure 3A. Coupling the activity of caveolin-1 and caveolae to cell–matrix interactions would be one way to couple caveolin-1/caveolae regulatory activity on differentiation signals to a cell’s environment. Another way caveolin-1/caveolae activity may be controlled is via cholesterol, which is discussed later.
Figure 3

Caveolin-1 stabilization of cell phenotype. (A) Hypothesized role for caveolin-1 and caveolae in contributing to the control of cell growth and differentiation. In undifferentiated quiescent stem cells, low levels of caveolin-1 are expressed. Caveolin-1 binding to growth and differentiation receptors and their secondary messengers within caveolae may suppress signaling. A decrease in caveolin-1 expression at the cell surface (perhaps triggered by chemical signals and/or nonmuscle myosin II activity) leads to receptor and signaling protein redistribution. Consequently, stem cells enter a pre-differentiation state more able to respond to growth and differentiation cues. Upon cell differentiation, caveolin-1 expression increases dramatically. Receptors and their secondary messengers are re-captured by caveolae to confine or internalize them and prevent continued growth. MSC, mesenchymal stem cell. (B) Proposed role for caveolin-1 in the control of mammary gland development based on in vitro and in vivo observations [88, 89]. Prolactin, estrogen and progesterone compete to control caveolin-1 expression. Caveolin-1 inhibits prolactin signaling by binding to the prolactin receptor-associated kinase Jak2. At birth, levels of prolactin are high and levels of estrogen and progesterone drop. Prolactin is thus able to suppress caveolin-1 expression, positively feeding back on its own signaling pathway by releasing Jak2 from caveolin-1 inhibition. The elevation in prolactin signaling triggers mammary gland development.

In cells where caveolin-1 activity inhibits growth and differentiation, a transient decrease in caveolin-1 expression or low caveolin-1 activity should be required for cell proliferation and differentiation to be activated. Studies investigating mammary gland development support this idea (Figure 3B). The hormone prolactin, which activates the growth and differentiation of the mammary epithelium during pregnancy and lactation, suppresses caveolin-1 expression during lactation in mice [88]. In HC11 cells (used as a model of mammary epithelial cell differentiation), caveolin-1 inhibits prolactin signaling by binding and retaining the prolactin receptor-associated kinase Jak2 in caveolae [89]. Caveolin-1 inhibition of prolactin signaling may also occur in vivo, as during pregnancy the caveolin-1 null mouse mammary gland shows dramatically accelerated lobuloalveolar development, early milk production and a premature lactation phenotype [89]. Furthermore, in immortalized primary human mammary epithelial cells, estrogen and progesterone together upregulate caveolin-1 expression, and the authors of these findings have proposed that in vivo the drop in these hormones upon birth (when prolactin levels are high) is responsible for de-repression of prolactin signaling and decreased caveolin-1 expression during lactation [89]. In summary, this hypothesis is an example where transient, carefully timed regulation of caveolin-1 expression is important for cell differentiation (summarized in Figure 3B).

Caveolin-1 effects on tissue repair

If transient downregulation of caveolin-1 expression/activity is required for cell proliferation and differentiation, it may also be required for tissue repair. Volonte and colleagues have shown that such temporal changes in caveolin expression occur during tissue regeneration in skeletal muscle [90]. Caveolin-1 is expressed in muscle satellite cells in mice and in myogenic precursor cells in vitro[90]. Downregulation of caveolin-1 expression in these cells was shown to be a pre-requisite for their proliferation, migration and differentiation to repair muscle wounds in vivo and in vitro[90]. Following myogenic differentiation, caveolin-3 is expressed in mature multinucleated myotubes, and caveolin-1 is re-expressed in undifferentiated myogenic precursor cells that surround myotubes after wound healing is complete [90] (summarized in Figure 4A). This event agrees with a requirement for transient downregulation in caveolin expression for progenitor cell proliferation and differentiation to mediate tissue repair. Further supporting this idea, muscle regeneration is delayed in caveolin-1 overexpressing mice [90] and caveolin-1-overexpressing myogenic precursor cells fail to differentiate, to migrate and to proliferate to repair wounds in vitro[90].
Figure 4

Temporal regulation of caveolin-1 during repair processes. (A) Muscle satellite cells. Studies by Volonte and colleagues suggest a decrease in caveolin-1 expression is required for satellite cells to proliferate and migrate to damaged muscle fibers and initiate repair [90]. Once migrated, satellite cells form myotubes and muscle-specific caveolin-3 is expressed. (B) Schwann cells. When Schwann cells de-differentiate in response to injury, caveolin-1 expression decreases [92], possibly allowing cell proliferation to repair injury to the myelin sheath.

There are other examples of drops in caveolin expression during reparative processes. For example, in the corneal epithelium, levels of caveolin-1 expression are inversely related to wound healing capacity [91]. In the rat sciatic nerve, caveolin-1 expression also increases as Schwann cells differentiate into a myelinating phenotype, but decreases upon their de-differentiation in response to injury [92]. This may occur because caveolin-1 is only present in the differentiated Schwann cell, with a functional role in cholesterol transport, and/or occur because the drop in caveolin-1 expression allows cells to proliferate in response to injury [92] (Figure 4B). Meanwhile, caveolin-1 appears to inhibit rat fetal neural progenitor cell neuronal differentiation, and downregulation in caveolin-1 occurs in these cells upon hypoxia-induced neuronal differentiation [76].

Caveolin-1 expression is also reduced in mouse hearts 3 days following cryoinjury [93]. The return of caveolin-1 expression to normal levels is important for later stages of cardiac repair, however, suggestive of a positive role for caveolin-1 in part of the process [93]. Also, in rat heart tissue, translocation of caveolin-3 and the caveolin-1α isoform out of caveolae upon aging or infarction may contribute to tissue degeneration/disease pathology [94], while the caveolin-1 scaffolding domain can protect against polymorphonuclear neutrophil reperfusion injury [95]. Caveolin proteins may thus be positively involved in the maintenance of healthy heart tissue. Caveolin-1 may be particularly important for repair in the cardiovascular system, because it is required for the formation of new blood vessels [21, 96]. In contrast to its anti-proliferative role in most other cell types, caveolin-1 is needed for the induction of mouse pulmonary microvascular endothelial cell proliferation in response to a disruption in laminar flow [97]. The requirement for caveolin-1 in new blood vessel formation may be a reason why caveolin-1 is vital for collateralization following ischemia in tissues such as the hindlimb [98] and why caveolin-1 deficiency can lead to an increased infarction volume upon cerebral ischemia [99].

Liver regeneration is another example where caveolin-1 may actually be required for cell proliferation and tissue repair. Caveolin-1 null mice have reduced survival after partial hepatectomy [100], and those that survive have a greatly reduced liver regeneration index compared with controls [100]. Caveolin-1 appears to be required for lipid droplet formation, a crucial step in the proliferative response of hepatocytes during liver regeneration [100]. A lack of caveolin-1 regulation of mitochondrial cholesterol levels in these mice has also been suggested to impair metabolism (and thus affect proliferation) to contribute to the phenotype [12]. However, others have found that caveolin-1 is dispensable for liver regeneration in mice [101] and that caveolin-1 deficiency even accelerates liver regeneration [102]. This discrepancy in results could be due to the use of two different knockout animals [100, 101]. Meanwhile, caveolin-1 may also have a positive role in regeneration in the kidney; it is expressed in regenerating proximal tubules after gentamicin-induced acute renal failure in rats and may have a role in the regenerative process by modulating EGF and platelet-derived growth factor signaling [103]. Indeed, perhaps in cases where caveolin-1 is required for repair and regeneration, caveolin-1 inhibition of other pathways is beneficial for signal pathways that activate repair.

Caveolin-1 may also have a positive role in cutaneous wound healing. Endocytosis of β1-integrins in fibroblasts occurs via a pathway involving syndecan-4, protein kinase C alpha, RhoG and caveolin-1, and this process is crucial for fibroblast recruitment and migration during wound healing [104]. Indeed, caveolin-1 null mice have significantly slower skin wound healing than wild-type mice [105]. Caveolin-1 may also have a positive role in regulating the formation of the lipid-rich outermost layer of the epidermis following injury by promoting keratinocyte terminal differentiation (programmed cell death) into corneocytes [106].

In summary, caveolin-1 may positively or negatively contribute to tissue repair depending on the tissue. This context dependence is possibly due to caveolin-1-negative and caveolin-1-positive regulation of different cell signaling pathways, but much further research is required to understand the role of caveolin-1 in tissue repair.

Caveolin-1 regulation of stem cell homing and mobilization

Migration is an important aspect of stem cell function. Caveolin-1 has an important role in promoting directional cell migration in other cell types (reviewed in [107]), and may also be involved in stem cell migration. Caveolin-1 expression is required for EGF and fibronectin-induced migration of ESCs [49, 108] and may also affect stem cell mobilization and homing. Caveolin-1 expression appears to enhance murine renal MSC adhesion to post-ischemic renal tissue [109]. This adhesion occurs via interaction of stem cell CXCR4 receptors with stromal cell-derived factor-1 on the target cell, and α4β1(VLA4)–vascular cell adhesion molecule-1 interactions [109]. Caveolin-1 may be required for CXCR4 interactions (Figure 5A), because membrane rafts are important for CXCR4–stromal cell-derived factor-1 interactions in human CD34+ hematopoietic stem/progenitor cells [110]. Meanwhile, as summarized in Figure 5B, studies by Sbaa and colleagues suggest caveolin-1 expression is required for mobilization of progenitor cells from bone marrow reserves in mice [111]. In vitro experiments suggest this may be because caveolar internalization of CXCR4 receptors in response to soluble stromal cell-derived factor-1 may be important for progenitor cell mobilization [111].
Figure 5

Caveolin-1 regulation of progenitor cell homing and mobilization. (A) Renal stem cell homing. Caveolin-1 may positively contribute to renal stem cell adhesion to ischemic tissue [109], possibly by promoting CXCR4 clustering in caveolae and allowing its interaction with stromal cell-derived factor-1 (SDF-1) in the ischemic tissue. (B) Bone marrow stem cell mobilization. In the bone marrow, caveolar internalization of CXCR4 may be important for progenitor cell de-adhesion to marrow stromal cells. Upon tissue ischemia, endothelial progenitor cells from the bone marrow may be recruited to the ischemic site to form new vasculature to restore blood flow. Caveolin-1 null mice (Cav−/−), unlike wild-type (WT) mice, fail to restore perfusion when ischemia is induced in their hind limbs. However, this phenotype can be rescued by direct intravenous infusion of Cav−/− or WT progenitor cells in the affected area, or by transplanting WT bone marrow into irradiated Cav−/− mice [111]. These results suggest that caveolin-1 is involved in the process of progenitor cell mobilization from the bone marrow in response to soluble SDF-1, which normally triggers progenitor cell mobilization. HSPC, hematopoietic stem/progenitor cell; MSC, mesenchymal stem cell.

Traditionally, reactive oxygen species-mediated damage to cellular components has been thought to cause aging [112]. Caveolin-1 can protect against oxidative stress by regulating mitochondrial cholesterol levels, which affect the levels of the antioxidant glutathione in mitochondria [113] (Figure 1). Accordingly, the accumulation of mitochondrial cholesterol and reactive oxygen species in the liver and brain of caveolin-1 null mice contributes to disease progression in degenerative disease models (steatohepatitis, Huntington’s disease, Alzheimer’s disease) [113], and these animals demonstrate some signs of accelerated aging, particularly in the brain [114, 115]. This aging may be due to decreased brain mitochondrial glutathione levels [113]. However, the aging may also or solely be due to increased production of amyloid-β protein from amyloid precursor protein, the processing of which is normally regulated in membrane rafts [114]. Meanwhile, it is now clear that reactive oxygen species do not initiate aging and that, although they may have damaging effects on macromolecules, they may have beneficial effects on age-related cell signaling [116].

A positive role for caveolin-1 in aging agrees more with the mostly quiescent effects of caveolin-1 on cell biology discussed above. Also, caveolin-1 promotes insulin signaling and adipocyte lipid droplet storage [117119]. Caveolin-1 could therefore have a general role in inhibiting continued growth and differentiation and slowing metabolism, perhaps as a response to completion of tissue formation and aging. In turn, this may mean that reducing caveolin-1 expression/activity could reverse aging effects in certain cells/tissues. Indeed, caveolin-1 expression increases with age in a number of rat tissues and in human diploid fibroblasts [120], and reducing caveolin-1 expression in the latter restores responsiveness to EGF [121]. Moreover, caveolin-1 null mice are lean, resistant to diet-induced obesity [119], insulin resistant [118] and have decreased levels of the adipokine leptin [119]. Conversely, plasma levels of leptin are increased in aged mice [122] and reducing the activity of nutrient sensing pathways (for example, insulin signaling) is known to increase longevity in several species [123]. In humans, insulin resistance is a side effect of treatment with rapamycin, the inhibitor of mammalian target of rapamycin [124], which is known to slow aging in mice [125, 126]. Whether rapamycin’s anti-aging effects could be partly attributed to inhibition of caveolin-1/caveolae activity remains to be elucidated and warrants further investigation; one would not be surprised if caveolin-1 could affect stem cell aging, which rapamycin has been shown to do [126].

The activation of stem cells is dysregulated with age in mouse muscle [127129] and, as Volonte and colleagues have shown that caveolin-1 expression delays murine skeletal muscle regeneration [90], one could hypothesize that an age-related increase in caveolin-1 expression may be responsible for an age-related decline in mouse muscle regenerative potential. Interestingly, aged satellite cells have impaired activation of Notch-Delta signaling [128], and premature activation of Wnt signaling in these cells causes fibrosis [129]. Caveolin-1 can affect the propagation of both Wnt and Notch signaling pathways in other progenitor cells [39, 40, 73, 87]. Furthermore, parabiotic pairings of old rats with young rats increases aortal and muscle cholesterol uptake in the older animals [130]. An increase in intracellular cholesterol levels promotes caveolin-1-directed cholesterol efflux and caveolae formation, and free cholesterol promotes caveolin-1 expression [33, 80]. Perhaps older tissues thus have a greater tendency to absorb cholesterol, which in turn increases caveolin-1 activity and caveolae formation. Meanwhile, systemic factors released by young mice can reactivate resident stem cells in aged mice and replenish their reparative capacity [128]. One would therefore be interested to determine whether factors in young plasma affect cholesterol metabolism and caveolae activity in old cells.

Mechanical stimulation and focal adhesion signaling can regulate stem cell differentiation [131], including fluid shear forces at the surface of the cell [132]. Caveolae and caveolin-1 are important for mechanosensing and the propagation of mechanotransduction pathways in many cell types, particularly cells exposed to shear forces [133144]. The actual structure of caveolae even provides a membrane reserve that can buffer stresses on the cell membrane caused by mechanical stretch and osmotic swelling [145147] (as shown in Figure 1). The role of caveolae and caveolin-1 in stem cell mechano-responses may therefore also be worth investigation. Perhaps it is possible that mechanical perturbations to caveolae can activate differentiation and proliferation and repair pathways in quiescent stem cells.

In summary, caveolin-1 affects several aspects of stem cell biology, including proliferation, differentiation, substrate-driven differentiation, homing and mobilization. We predict that alteration to caveolin-1/caveolar activity is a prerequisite for stem cell activation and differentiation, and that increased caveolin-1 expression with age may implicate the protein in age-related declines in tissue regenerative potential. However, because of the multiple (and probably context-dependent) effects of caveolin-1, this will not apply to all cells and tissues. Promotion of caveolin-1 activity may be desirable for some areas of regenerative medicine (for example, mobilization of bone marrow stores of progenitor cells), while inhibition may be desirable in others (for example, to reverse muscle aging, increase bone density, or improve in vitro expansion of adult stem cell harvests). Manipulation of caveolin-1 expression/activity may be possible in specific tissues in vivo; for example, via siRNA approaches or modulation of cholesterol biosynthesis. However, much research is required to define caveolin-1 function in different stem cells and to determine whether manipulation of membrane signaling platforms such as caveolae could be beneficial in stem cell therapies and regenerative medicine.

Bone morphogenetic protein

Epidermal growth factor

Embryonic stem cell

Mesenchymal stem cell

Small interfering RNA.

Supported in part by a grant from the Commonwealth of Pennsylvania Department of Health (SAP 4100050913).

Authors’ Affiliations

Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine

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Loney Lovin’

Great game tonight! I’m not sure wtup with Randy Wolf in the beginning. D-back’s grand slam–not so fun. Dodgers were down 5 to 2 after Hudson walked in a run. But then Loney came through as he does with the bases loaded (Vin Scully tells me he’s currently ML’s top hitter in this situation) and tied the game! MARRY ME.

Casey Blake brought Loney in to break the tie. Slim Jon did wat it do. And I lived happily ever after. The end.

Unrelatedly, here is a really serious video clip featuring Loney.

(via Roberto at Vin Scully is my Homeboy)

My mind is spinning. I have so many questions…

1. Professional wiffle ball?
2. They give out Cy Young Awards in wiffle ball??
3. James Loney’s shirt?
4. How tall is this wiffle ball guy?
6. Why is Loney so sweaty?

Martin’s walk-off walk

Well-pitched game. Just what I expected from well-seasoned ace Peavy vs. the young ace-to-be Kershaw (on a good day). Wish I could’ve SEEN it! You have no idea how hard it is for my sight-loving brain to have to LISTEN to a pitchers’ duel-type game like that.

Go Dodg’s!

Finally, a solution?

Without owning any fancy sports packages, this is how I’ll be watching most Dodger games. Huh. I guess it could be worse…it’s in HD and I can watch up to 7 other games at the same time. Haha!

I missed the first several innings but I heard Bills struggled in the 1st. No news there. Fortunately, he did what he does and got the win. Russell…not sure what’s going on with him. I’ll be ready and excited to see his offense pick up soon though.

Kershaw tomorrow! He’s always fun to watch…sometimes ehhhhhhh painful…but tomorrow I’m sure they’ll win it! Also, it’s a noon game and I’m extra excited because Vin told me DeWitt is going to play.

I have a Twitter! Follow me: stephamie. I tweet about baseball sometimes (alienating most of my followers/friends). I’ll probably live-tweet whatever game I’m watching. I follow mostly comedians but there is some good baseball talk on there, too.

If you tweet here are some of my recommendations:

KF***INGP (or should he count as a baseball person? direct link censored by mlblogs)

Baseball Persons
rbaly79 (Roberto, Vin Scully is My Homeboy)
gehrig38 (Curt Schilling)
chaddurbin (Phillies…barf barf barf barf jk)
str8edgeracer (C.J. Wilson, Rangers)
BarryZito (Giants…barf…jk?)
NickSwisher (Yankees)
CC_Sabathia (Yankees)
This list is missing Dodgers😦

Onto more TV woes. Apparently I have access to SportSouth (Braves) and FSNAZ (Diamondbacks). My cable network loves to tease.

I watched as the Braves lost that 7-run lead to the Phillies in probably the worst way possible. I saw the whole thing happen in one inning and kind of wish I hadn’t. It hurt my Phillies-loathin’ heart to see the Braves’ bullpen fall apart like that. One walk at a time. Ouch.

Here is a photo of BFF activity between Manny and Ethier from Opening Day at Petco Park (from Dodgers.com).

I love the hiptag. Jump and bump. I don’t know what it’s really called but it’s adorable.

Happy Belated Opening Day!

New season, new blog photo! It is one in very few photos of me wearing
a Dodger hat and NOT looking like a man. Also, you can’t tell but I’m
wearing a zebra print jumpsuit. Just sayin’.

Anyway, I was so excited for Opening Day that I forgot to watch any games. I
“forgot” because I don’t have cable. Basically, I made myself forget
that baseball was happening because I couldn’t get any. Baseball, that

Ok…so I watched a little bit…an inning or two…but it wasn’t Dodgers so I don’t want to talk about it.

I know I haven’t updated since postseason. I thought about it but
SRSLY…off season…I can’t keep up! Hot stove this, free agent that.
I’m not there yet!

It’s been less than a year for me and baseball so I’m still getting to
know teams and players and managers and stats. I know the 2008 Dodgers
like…like characters from all my favorite Nickelodeon cartoons? (Really
well. Child of the ’90s.) But now, in the ’09, I’ve decided it’s time to acquaint
myself with the rest of the MLBsphere.

As for DeWitt, I’m sad he won’t be playing as much but still grateful
that he’s on the roster.🙂 If someone’s going to take his place on the field I guess I’m glad it’s Hudson.

Freshly groomed DeWitt from the early days of Spring Training. (From Dodgers.com, I believe.)

Good luck tomorrow to Bills and the rest. Series win! First of the season! Grab grab grab!

Recent local news interviews with Sikeston’s DeWitt

I just found this! It’s a recent interview with DeWitt from his area’s channel 12 news that takes place mostly at his parent’s house. Great offseason beard. Top notch!

I also found this written interview with DeWitt on the Sikeston Standard Democrat site.

And this news piece from the Southeast Missourian.

Good Thanksgiving, yes?

Long socks!

Still hurting

I’ve been watching the WS and it’s been really good so far… but I still hurt.

Matt Kemp says he doesn’t drink.

Thumbnail image for Dewittbeershower.pngThe NLDS! Hah! Apparently, I had nothing to worry about. The Dodgers totally killed it.

Loney’s grand slam just about made my brain explode. All over the TV. All over the dog. It was gross. Actually, my boyfriend and I leapt from our chairs and started screaming. Our hearts hugged. It was happy. Russell Martin’s reaction was really cute, too!

And when they clinched! They showed almost every player’s reaction as he raced to the mound. SO CUTE!!!!

As I said before! How sweet it is! To be me! A first-time baseball/Dodgers fan! Right now! In 2008!

Now we’re two games into the NLCS. Two games behind. But the Dodgers know what they need to do. They’ll do it–all three at home and then one more away. I know they will!!!! Games 1 and 2 were too close, too well-played for anyone to doubt that they can come back.

October FIRSTS!

My first postseason!

I am so spoiled! My first year ever following the Dodgers and I get a postseason.

Anyway, I know my blog sucks but just wait for it. The offseason will be time for my obsessive/bat-isht crazy star to shine.

What else am I going to do until Spring Training besides post pictures of Russell Martin and talk about how pretty his eyelashes are?

Anyway, tomorrow is the most excitingest thing ever.

I’ve got nothing against Milwaukee but I really wanted the Brewers to lose the NL Wild Card. You thought the same, too, right?

I’ll get back to you on that in a couple of days.

Thumbnail image for Photo 535.jpg

OK, so we’re not CHAMPIONS-champions. Yet.

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SPECIAL AWESOME - stereoscopic resource

We at SPECIAL AWESOME are keeping this blog up to date with all the exciting news coming in the world of 3D with special attention to small screens, mobile, consumer devices, and of course - AUTOSTEREOSCOPIC (glasses free). Please dig deep, so much is happening that articles of monumental importance quickly fall down the list into obscurity. Interested in Apple 3D? The latest on touch-screen 3D hand-held devices? Intel 3D? Nokia 3D? ESPN? It's all here and more.

Sunday, September 18, 2011

Glasses-free 3D LCD TVs Likely out by 2015

By Dan Nystedt, IDG News May 28, 2010 2:30 am

Consumers will likely see 3D LCD TVs that don't require people to wear polarized glasses out on global markets by 2015, according to a Taiwanese research group that showed off an early version of such a device this week.

Taiwan's Industrial Technology Research Institute (ITRI) displayed a 42-inch glasses-free 3D LCD TV this week, and the company can currently make them with screens as large as 65 inches, according to Stephen Jeng, director of ITRI's 3D System & Application Division.

The technology is considered vital to getting 3D into more people's living rooms. Analysts say most people don't want to wear polarized glasses to watch 3D TV, and many balk at the price, up to $200 per pair for some of the glasses. The high price might make a person think twice about hosting a World Cup or Super Bowl party with friends.

Jeng says ITRI's technology will be used in digital signs and 3D digital photo-frames initially. The main issues for glasses-free 3D TV are broadcasting, availability of content, and eye safety, he said. Small quantities of glasses-free digital signage and 3D photo frames are already available on the market, he said, but may yet take a year or two to take off.

The glasses-free 3D LCD TV on display from ITRI this week showed pictures of objects that ITRI's software converted into a 3D image. The image was blurry and the technology appears to still be a long way from being ready.

The research group is using parallax barrier technology to create the 3D effect on the TV. The TV was branded Chi Mei, from Chimei Innolux, but Jeng said the company gave ITRI a regular LCD TV to use for the show and that ITRI added its 3D technology to the set on display. Chimei Innolux is not making glasses-free 3D TVs.

A number of companies are working on glasses-free 3D TVs, mainly in Japan and South Korea.

The 3D TV concept took off early this year at the International Consumer Electronics Show in Las Vegas as most major TV makers, including Samsung Electronics, showed off sets that are 3D-capable, meaning people can use them as regular high definition (2-dimensional) TVs or as 3D TVs.

The global 3D TV market this year will likely reach 6.2 million units, according to market researcher Displaybank, with sales growing to 33 million units by 2012.

Thursday, August 11, 2011

2 phones compete for emerging 3D mobile market share

Here's an interesting new site: 3dphonereview.com

Currently they are announcing the new HTC EVO 3D and publishing a comparison between it and the LG 3D Optimus. Both run Android OS 2.3 - what we find interesting (exciting) is that there is a growing buzz and competition in this space as more and more products emerge and more and more critics, pundits, and consumers enter the fray.

and yet another viewing option... VUZIX eyewear

Vuzix is now shipping their Wrap 1200 3Ds, a pair of $500 glasses (a headtracking model called the 1200VR is coming later this month) that displays a 75-inch virtual screen in front of your face and supports 3D content. You have separate focus settings for each each eye and these are as light and small as a standard pair of sunglasses.

The Vuzix 1200s also allow you to wear your own prescription lenses under the device.

I’ve used earlier Vuzix video glasses on flights before and, barring the dork-feel of wearing a pair of video glasses, the experience is fairly interesting and impressive. Now, however, with HD, 3D and a huge screen these things could, feasibly, replace a standard monitor in some situations.

The glasses include a pair of headphones for audio and you can buy optional DVI adapters and light shields as well as a head-position sensor for more advanced tricks like real-time VR. The future, as they say, is already here. It’s just not evenly distributed.

Wednesday, July 13, 2011

Sony HDR-TD10 hits the market

We've been watching the development of the consumer 3D camcorders for a while now. Panasonic were the first with a prototype and their entry into the market has been a long time coming now. Sony have quietly been developing their device as part of their stated commitment to 3D on all screens and platforms, now with the Sony 3d camcorder.

Sony HDR-TD10 3D camcorder

Thursday, July 7, 2011

4.5 stars for new LG 3DTV with passive display system

All I can say is: FINALLY.

At NAB when 3D was really new and all the rage there were all sorts of PASSIVE 3DTVs being shown - the models from JVC were amazing. It all looked bright and sunny for the future of 3D in the home, and then.... All the big electronics manufactures started bringing out ACTIVE 3D TV systems. Those of us in the know were aghast - the active shutter glass system is, and has always been inferior. The logic I believe, was that the active systems could be inexpensively retrofit to the new generation of high refresh sets, thus getting a jump on the 3D bandwagon without making it a vanity product with an unreasonable pricetag. This would (presumably) give them time to reduce the manufacturing costs of the superior passive system sets - passive is like you see in the RealD theaters - inexpensive lightweight plastic glasses with polarizing filters in each lens. Whatever the reasons were, we are finally emerging from the active systems days. This set of reviews show consumers' opinions of the new LG screen - and the feedback is excellent. A pricetag of $1600 is not bad either.

(link to consumer opinions) 4.5 STARS FOR LG 55LW5600

Sunday, July 3, 2011

Nintendo 3DS video content

(from the 3DS Wiki)

Video content

The system also has 3D movie and video playback capability. Nintendo has made deals with Warner Bros, Disney, and DreamWorks to deliver 3D movies.[91] Although no titles have been announced yet, the trailers for DreamWorks' How to Train Your Dragon, Warner Bros' Legend of the Guardians: The Owls of Ga'Hoole, and Disney’s film Tangled were shown on the 3DS during the E3 Expo.[92] On September 29, 2010, Nintendo of Japan announced that it will be partnering with Fuji TV and other Japanese broadcasters to distribute free 3D videos to Japanese Nintendo 3DS owners.[93][94] On January 19, 2011, Nintendo of Europe announced at their press conference that they will be partnering with EuroSport and Sky 3D to bring content to the Nintendo 3DS at a later date in 2011. Richard Goleszowski is also locked to bring exclusive 3D episodes of Shaun the Sheep to European Nintendo 3DS market by the end of the year. During the 2011 Game Developers Conference, Nintendo of America president Reggie Fils-Aime announced that the Nintendo 3DS will support live streaming from Netflix.[95] Also at the same conference, Nintendo announced a short-form video service for the Nintendo 3DS. This channel will offer a wide variety of video content, from comedy to music, all curated by Nintendo.[96] As part of an initial firmware update for the system, Nintendo 3DS systems in North America include the 3D version of the music video for "White Knuckles" from OK Go.[97]


text:
Songwriting Sets GRAMMY Nominee Courtney Barnett ApartWhat sets Barnett apart, and earned the 28-year-old Australian a GRAMMY nomination for best new artist, is her distinctive songwriting.
GRAMMYs Best New Artist: Ariel Rechtshaid on HAIMWe feature HAIM as seen through the eyes of producer Ariel Rechtshaid, who helped craft the band's debut album, Days Are Gone.
GRAMMYs Best New Artist: Mary J. Blige on Sam SmithThe queen of hip-hop soul opens up about Best New Artist GRAMMY nominee Sam Smith and why his music is like medicine.
GRAMMYs Best New Artist: Charli XCX on Iggy AzaleaBest New Artist nominee, Iggy Azalea as seen through the eyes of her fellow nominee, collaborator and friend Charli XCX.
GRAMMYs Best New Artist: Melissa Etheridge On Brandy ClarkMelissa Etheridge, well known as a singer-songwriter, guitarist and activist, weighs in on Brandy Clark's Best New Artist GRAMMY nomination.
GRAMMYs Best New Artist: Angel Haze on BastilleAfter having spent a few months touring with the British foursome, Angel Haze, a Brooklyn born rapper/singer, has some strong opinions on why Bastille deserves some recognition.
REWIND: Picking The Best New Artist

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Whatever. Leaving this place anyway.

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2011-02-16 20:01:47 by StompySan

I am done with Newgrounds. People who don't deserve top 5 get it, everyone zero-bombs all of the new submissions, and people are, in general, a bunch of pricks. I have had it with the community here. I am leaving Newgrounds for good. I will no longer be uploading any music here. I will post later about where you can follow my music. Any place will be better than this.

Hope to never see this horrible site again,

PS: Get a real media player, and not one that distorts and causes clipping on every track.

[Chip] Cool Loop (WIP1) Video Game Loop
Resurrection (Rmx WIP) Techno Song
[Chip] Sid Stuffz Video Game Loop
Sounds like a Movie Ambient Loop


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Good morning.

  1. A book reviewed.
  2. VAT considered. The bigger problem with VAT is that the Congress critters considering VAT aren’t thinking of it as a replacement but an addition.
  3. A book list.
  4. Clunkers. A bad idea then, worse in retrospect.
  5. Oil in them thar hills.
  6. What airline I wonder?
  7. Beslan.
  8. Lies, damn lies, and statistics.
  9. Weather is not climate. Climate is not climate
  10. The Administration and yet-another-broken-promise.
  11. Another look at unemployment numbers
  12. Prayer as image.
  13. The Discovery nut as right winger meme.
  14. Statistics and schools.
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  • #: 200704
  • Price: $0.99 In Apple Store
  • Category: Health & Fitness
  • Updated: 2009-03-28
  • Current Version: 1.3
  • 1.3
  • Size: 0.30 MB
  • Language: French
  • Seller: Luc Plancon
  • Requirements: Compatible with iPhone, iPod touch, and iPad. Requires iOS 2.2.1 or later
  • © DPC Interactive 2009
  •  Add to Favorite apps

You can’t count the tries you have made to give up smoking? You would like to get assistance when trying to?StopSmoking is your support : each time you would like to light a cigarette, just launch the application, set it up with your previous habits….. Read more

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Stop smoke application designed for your iPhone and iPod touch will help to quit smoking. Just press stop button and timer will appear on the screen. This app also contain some useful facts which may… [more..]

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Ask the Dev's...

Discussion in 'UHall' started by puni666, Apr 13, 2011.

  1. puni666

    puni666 Slightly Crazed
    Stratics Veteran

    Jul 10, 2008
    Likes Received:
    Last question asked

    12-30-2010, 01:07 PM

    Responded to

    01-28-2011, 10:56 AM

    Today's date

    04-13-11, 12:00 AM

    Not one good question in that time? (this is my question btw) Hope you're working on something for the bulk of the people per server instead of 2% of the people per server. Let me guess... New Jhelom's next?
  2. claudia-fjp

    claudia-fjp Lore Master
    Stratics Veteran

    May 26, 2008
    Likes Received:
    My favorite question is:
    "A few years back, someone went around to see how many houses could be placed on a shard starting with castle and working down to the smallest plot. Could you tell me if any castles could be placed on Fire Isle? Keeps?
    thanks and enjoy"-Sellingahouse

    Responded with:
    "Yes we have been taking down these houses as we are informed of them. I ask you as our players to help us with this. We have taken down a huge number of these houses that have been reported over all the shards. So with that said.....

    If you come across these types of abandoned houses, please send me the location, shard and any other information you have so we can take down all these empty houses. My email is [email protected].

    Thanks in advance for your help."-Mesanna

    Problem is the guy was referring to the time a dev team member (I'm thinking Mr.Tact, maybe Draconi it was around that era) used an algorithm on an empty server. The algorithm attempted to place as many castles as possible, followed by keeps and so on to the smaller house sizes and came up with a list that resembled:

    So the guy was asking if any keeps or castles from the algorithm test were on fire island. In Mesannas defense she probably has no idea about this test or the results. I just thought it was funny the question and answer were about two different things.

    PS my server is still full of the houses she WAS referring to that were reported long ago...
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Selling Fire Rubble on Pac=sold

Discussion in 'UO Rares Collector' started by imported_spiderpig, Mar 12, 2008.

  1. Selling Fire Rubble on Pac. Sold another 2 monthsish ago for 75 mil. I placed this one on my vendor in luna. Vendor is located on the north side inside luna walls. All vendors dressed in blaze robes and house is 7x7. Thank you for your time.
  2. Treyster18

    Treyster18 Visitor

    Dec 1, 2005
    Likes Received:
    ill offer you 50m


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Sarnia, ON - Radio Stations on your iPhone, iPad, iPod Touch, Android, Blackberry, and other app-enabled mobile phones. Get in touch via the Contact Us below if you're interested in these apps. Also, find the top new songs, playlists, and music on our website!