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OPEN ACCESS ARTICLE
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TISSUE-SPECIFIC STEM CELLS |
Department of Cell Therapy and Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan
Key Words. Stem cell • Notch • Embryogenesis • Homeostasis
Correspondence: Shigeru Chiba, M.D., Ph.D., Department of Cell Therapy and Transplantation Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Telephone: 81-3-5800-6421; Fax: 81-3-5689-7286; e-mail: schiba-tky{at}umin.ac.jp
Received December 30, 2005;
accepted for publication July 11, 2006.
First published online in STEM CELLS EXPRESS August 3, 2006.
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ABSTRACT |
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 Top Abstract IntroductionHistorical Background of NotchNotch Signaling Pathway and...Notch Signaling in Stem...Roles of Notch Signaling...ConclusionDisclosuresAcknowledgmentsReferences |
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INTRODUCTION |
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TopAbstractIntroductionHistorical Background of NotchNotch Signaling Pathway and...Notch Signaling in Stem...Roles of Notch Signaling...ConclusionDisclosuresAcknowledgmentsReferences |
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HISTORICAL BACKGROUND OF NOTCH |
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TopAbstractIntroductionHistorical Background of NotchNotch Signaling Pathway and...Notch Signaling in Stem...Roles of Notch Signaling...ConclusionDisclosuresAcknowledgmentsReferences |
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Although such a concept was established in lower animals such as Drosophila and Caenorhabditis elegans, homologs in vertebrates were first found in Xenopus [19] and then in humans [20]. In humans, the gene located at the break point on chromosome 9 in the t(7;9)(q34;q34) translocation that is found in a subset of acute T lymphoblastic leukemias was identified as a Notch homolog and named translocation-associated Notch homolog 1 (TAN-1) [20]. This gene is now called Notch1, and its discovery revealed that the Notch genes are very well conserved from nematode to humans. Leukemia cells harboring the t(7;9) translocation express a Notch1 protein with a large part of the extracellular domain truncated. The TAN-1 protein is localized intracellularly and is constitutively activated. Because disproportionately enhanced Notch signals, such as the one transduced by TAN1, were considered tumorigenic, the mechanisms of signaling through the Notch receptors further attracted the attention of researchers [18, 21, 22]. It is now known that the Notch signaling pathway also influences cell fate decisions in mammals, such as cell differentiation, survival/apoptosis, and cell cycle in both physiologic and pathologic contexts, particularly in conjunction with stem cell behavior.
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NOTCH SIGNALING PATHWAY AND ITS COMPONENTS |
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TopAbstractIntroductionHistorical Background of NotchNotch Signaling Pathway and...Notch Signaling in Stem...Roles of Notch Signaling...ConclusionDisclosuresAcknowledgmentsReferences |
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). This turns the CSL complex from a transcriptional repressor to a transcriptional activator [28], for which the mastermind adaptor protein is an essential component [29, 30]. The most well-defined targets of the NICD-CSL complex are the HES family [31] and their homologs, the Hey (also called HERP) family [9] of basic helix-loop-helix transcription factors. The regulated intramembrane proteolysis (RIP) of transmembrane proteins was first recognized to have biologic significance in the amyloid precursor protein (APP). In APP, RIP occurs at more than one site, which is believed to be linked to the pathogenesis of Alzheimer disease. Interestingly, a second RIP (designated S4 cleavage) has also been detected in Notch1 [32, 33]; this RIP might be related to the Notch signaling pathway. A number of Notch signal-modifying proteins have been identified, and the presence of noncanonical, CSL-independent pathways has been advocated, which are not included in this review. |
NOTCH SIGNALING IN STEM CELLS DURING EMBRYONIC DEVELOPMENT |
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TopAbstractIntroductionHistorical Background of NotchNotch Signaling Pathway and...Notch Signaling in Stem...Roles of Notch Signaling...ConclusionDisclosuresAcknowledgmentsReferences |
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On the other hand, successful progression to midgestation stages implies that Notch signaling is unnecessary for the very early stage of embryogenesis, including the fertilized egg stage [45]. This would be consistent with the fact that activation of Notch signaling in ESCs, which are derived from the inner cell mass, does not block differentiation of ESCs [46].
Roles in the Central Nervous System During Embryogenesis
Among undifferentiated neuroectodermal cells with the same potential during Drosophila embryogenesis, some cells will eventually express Delta at higher levels, which sends a signal to surrounding cells that uniformly express the Notch receptor. Cells receiving the signal are blocked from differentiating to neuroglioblasts (NGBs) and eventually assume another differentiation fate. On the other hand, cells that express Delta differentiate to NGBs and subsequently to neurons and glial cells [47]. Accordingly, insufficient levels of Notch signals result in the "neurogenic phenotype," in which all cells with neuronal potential differentiate into neurons.
Precocious neuronal differentiation observed in Notch pathway-deficient neurocompetent cells is also detected in mammals, such as in mice with inactivated Notch1 [48]. A conditional Notch1 knockout study [49] provides further support that Notch signaling inhibits the premature onset of neurogenesis. These studies, as well as those of rbpsuh (gene for CSL) knockout mice [50], suggest that, in addition to the differentiation blockade, this pathway is required for the maintenance and expansion of the neural stem/progenitor cell pool. Inactivation of HES1 [51]; HES1 and HES5 [52]; and HES1, HES5, and HES3 [53] in mice variably induces precocious neuronal differentiation accompanied by a decrease in neural progenitors. Together, these studies and HES protein overexpression studies [54] indicate that HES genes are the conserved targets of Notch-CSL signaling for regulating the expansion and differentiation of neural progenitors [6, 31, 54].
Importantly, Notch signaling either promotes or, by default, facilitates glial cell fate, perhaps as a consequence of inhibiting neuronal cell fate [55–59]. It further induces astrocyte differentiation [60, 61]. Therefore, Notch signaling might act on neural stem cells in two steps: (a) initially inhibiting neuronal fate while allowing for glial cell fate; and (b) then promoting differentiation to astrocytes while inhibiting differentiation to both neurons and oligodendrocytes [61]. These concepts fit the conventional view of the fundamental function of Notch signaling to prevent cells from taking the first pathway while guiding them into a secondary pathway.
To add to the complexity, neural stem cells have been identified in glial cell populations, particularly in astrocytes [47]. It remains to be clarified how Notch signaling is involved specifically in the maintenance of stem cell characteristics and the promotion of glial differentiation.
Notch signaling is also involved in the regulation of apoptosis in mammals. It remains controversial, however, whether it is pro- or antiapoptotic in developing neural stem/progenitor cells. Conditional deletion of Notch1 [49] and both Notch1 and Notch3 [62] genes causes apoptosis and massive loss of developing neural progenitors as well as newly differentiating neurons. These studies suggest an antiapoptotic activity of Notch signaling. The results of other studies that analyzed conditional transgenic and knockout mice, however, led to the opposite conclusion. Conditional expression of a constitutively active form of Notch1 leads to p53-dependent apoptosis of early neural progenitors. Conversely, disruption of presenilin-1, the gene for a component of 
-secretase that is essential for Notch signaling, and conditional deletion of Notch1 result in reduced apoptosis of early neural progenitor cells [63]. Proapoptotic activity of Notch signaling occurs in keratinocytic [3, 64] and endothelial [65, 66] cells, partly through inactivation of the phosphatidylinositol 3-kinase (PI3K) pathway, whereas activation of the PI3K pathway and antiapoptotic effects have also been demonstrated in other cells, including tumor cells [67, 68]. Thus, the regulation of apoptosis and survival by Notch signaling must be highly context-dependent, and reciprocal directions should be considered on this axis for understanding the development of neural stem/progenitor cells.
Roles in Generating Hematopoietic Stem Cells
In mice, phenotypically defined endothelial cells that possess hematopoietic potential, called "hematogenic endothelial cells," are generated by E9.5 at the paraaorta-splanchnopleura (P-Sp) region. On E10.5, when the P-Sp develops to become the aorta-gonad-mesonephros (AGM), hematogenic endothelial cells develop into hematopoietic stem cells that have the potential to engraft in adult mouse bone marrow [69]. In the Notch1-null mutant mouse embryo, apparent hematogenic endothelial cells are recognizable, but they do not develop into hematopoietic stem cells [70]. Using different approaches, either Notch1-null ESC-chimeric mice [71] or rbpsuh-null mutant mice [72] produced similar results, indicating that Notch1 has an indispensable role at the point right before hematopoietic stem cells are generated.
On the other hand, Notch1 is dispensable for primitive hematopoiesis and secondary hematopoiesis that is derived from progenitors, not from HSCs, in the yolk sac. Thus the requirement of Notch signaling during hematogenesis is most prominent in adult-type HSC generation [70, 71].
Role in Melanoblast Survival
In embryonic skin, melanoblasts (Mbs) develop in the suprabasal and basal layers of the epidermis. The cleaved form of Notch1 is detected and the HES1 promoter is activated in the embryonic Mbs. A -secretase inhibitor induces apoptosis of embryonic Mbs, and tyrosinase promoter-dependent deletion of the rbpsuh gene results in severe coat color dilution in the initial hair [73]. These results indicate that the embryonic Mbs use the Notch1-CSL-Hes1 pathway to protect themselves from apoptosis.
Roles in Vasculature Formation
Mice with disrupted Notch-related molecules display various abnormalities in blood vessel formation, such as proliferation and migration of endothelial cells, smooth muscle differentiation, vascular remodeling processes [2], and arterial-venous identification [41, 42, 74, 75]. These studies describe the involvement of Notch1 [38], Notch3 [39], and Notch4 [38] receptors and Delta-like4 [41, 42, 74] and Jagged1 [43] ligands in vasculature formation.
In the vascular system, Hey1, Hey2, and HeyL are considered candidate Notch-CSL targets [2]. In fact, mice lacking both Hey1 and Hey2 are embryonic lethal due to abnormalities in the heart and vasculature [76]. The phenotypes of these mice, however, do not precisely recapitulate those of Notch1/Notch4 double mutant mice or Delta-like4 heterozygous mice. Thus, further studies are required before definitive conclusions can be drawn as to whether the Hey family alone comprises the transcription factors functioning downstream of the Notch signals in vasculature development. Endothelial cells of the artery and vein have distinct gene expression patterns at the early developmental stage. Many Notch-related molecules are preferentially expressed in the arterial endothelial cells [77, 78]. Strikingly, signals from Delta-like4 to the Notch receptors confers the identity of the arterial endothelium to the precursor cells, which is implicated by the analysis of Delta-like4 heterozygous mice [41, 42, 74]. rbpsuh-null mice have a similar arterio-venous misidentification [74]. In addition to the endothelium, Notch signaling is also involved in the differentiation and maturation of vascular smooth muscle cells, particularly their specification to arterial smooth muscle cells [39].
It has been proposed that the default pathway of the endothelial cells is "venous fate" and that Notch signaling instructively modulates endothelial cell fate to the "arterial fate" [79, 80]. It was recently reported, however, that the venous fate of endothelial cells is induced by a transcription factor, COUP-TFII, that inhibits Notch signaling [75]. In any case, it is clear that the Notch pathway is a critical determinant for arterial-venous endothelial cell fate.
Gain-of-function and loss-of-function experiments in vascular development sometimes yield similar results [81]. These findings often appear to contradict those observed in neural progenitors in which gain- and loss-of-function studies exhibit mirroring phenomena, that is, progenitor expansion with blocked differentiation by the gain-of-function studies and precocious differentiation with decreased progenitor pool by the loss-of-function studies. This might indicate that appropriate Notch signaling levels are most important for survival of the endothelial cells, given that Notch signals often affect endothelial cells in a proapoptotic manner [65, 66].
Roles in Organogenesis
Analyses of Notch gene knockout mice and identification of Jagged1 as a responsible gene for a hereditary disease that accompanies defects in organ morphogenesis provide evidence that Notch signaling has important roles in the development of kidney, liver, pancreas, heart, etc.
Notch2-null mouse embryos die before mesonephros generation [36] (described above). Notch2-hypomorphic mice, in which Notch2 lacks one or two epidermal growth factor-like domains in the extracellular region, survive until birth. In these mice, the glomeruli are severely hypoplastic, and the heart is also variably hypoplastic [82].
Alagille syndrome is an autosomal-dominant human disorder characterized by intrahepatic cholestasis; abnormalities of heart, eyes, and vertebrae; and a peculiar facial appearance. Haploinsufficiency of Jagged1 is responsible for this disorder [83, 84], suggesting that reduced Jagged1-Notch signaling results in organogenesis failure. Both hepatocytes and biliary epithelial cells are derived from common liver progenitor cells or liver stem cells [85]. Whether adequate Jagged1 function is required for the biliary epithelial cell induction from liver stem cells is not known. The phenotypes of Jagged1-disrupted mice [43] and Notch2-hypomorphic mice [82] are similar to that of Alagille syndrome.
In the pancreas of Delta-like1 or rbpsuh gene knockout mice, there is an excess of endocrine cells [86], suggesting that Notch signaling inhibits endocrine-lineage differentiation from the common exocrine and endocrine progenitors during pancreatic development. Analysis of HES1-null mice leads to a similar conclusion about the role of Notch signaling in pancreatic development [87]. Recently, somewhat different results were obtained from conditional deletion of the rbpsuh gene; the mice exhibited insulin-deficient diabetes with both endocrine and exocrine pancreatic hypoplasia [88]. HES1-null mice show agenesis of the gall bladder and hypoplastic bile ducts. Furthermore, bile epithelial cells differentiate to pancreatic cells in these mice [89], suggesting that Notch signaling physiologically inhibits pancreatic differentiation from bile epithelial cells, which have the potential to take the pancreatic cell fate in the absence of Notch signaling.
The same mice exhibit excess differentiation to secretory cells, such as Goblet cells, in the intestinal mucosa at the expense of enterocytes [87]. A mirroring phenotype has been reported in Villin promoter-controlled Cre and Rosa-Notch transgenic mice. These mice, in which constitutively active Notch1 is expressed in the intestinal epithelium, survive until birth at Mendelian ratios but die of malnutrition within 3 days after birth. The architecture of the intestinal epithelium in neonatal mice is markedly altered by amplification of the intestinal progenitor pool and inhibition of cell differentiation [90]. These findings together suggest a role of Notch signaling in the developing intestinal epithelium to regulate specification of the intestinal progenitor cells.
Cell Fate Determination by Notch Signaling During Embryogenesis
The above observations indicate that from the viewpoint of cell differentiation, Notch signaling has three major roles during embryonic development. First, it affects differentiation from primordial cells to tissue-specific stem cells in the early- to midstage embryo. In the traditional view of Drosophila nervous system development, differentiation from undifferentiated neuroectodermal cells to NGBs is inhibited. In mammals, however, induction rather than inhibition is postulated for HSC generation from upstream progenitors. The effect of Notch signaling on differentiation fate from primordial cells to tissue-specific stem cells might be context-dependent. Second, it inhibits tissue- or organ-specific stem cells or immature progenitors from further differentiation and presumably helps them expand while maintaining the immature state. Third, it blocks the default pathway and promotes the alternative pathway, which is typically observed during mid- to late-stage embryo development, such as during organ formation (Fig. 2).
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ROLES OF NOTCH SIGNALING IN STEM CELLS POSTDEVELOPMENT |
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TopAbstractIntroductionHistorical Background of NotchNotch Signaling Pathway and...Notch Signaling in Stem...Roles of Notch Signaling...ConclusionDisclosuresAcknowledgmentsReferences |
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Roles in the Skin
Involvement of Notch signaling in postdevelopmental stem cell systems is best understood in the skin, particularly in the hair follicles. Notch1, Notch2, and Notch3 are expressed and differentially localized to various layers of the hair follicle [91, 92]. Notch signals do not affect the pattern of skin formation during embryogenesis. Thin, short, and wavy hair grows when Notch1 is inactivated specifically in the hair follicles during embryogenesis, where Notch1 activity in the cortical progenitors affects the neighboring inner root sheath and medulla cells from their progenitors in a nonautonomous manner [92].
After birth, the first hair cycle of Notch1-null mice shows a shortened anagen phase and premature entry into the catagen phase, and inactivation of Notch1 in adult mice results in almost complete hair loss followed by cyst formation. These observations indicate that Notch1 is essential for postnatal hair follicle development and homeostasis [92, 93]. Compared with the phenotypes of Notch1-null mice, Notch1 and Notch2 double-null mice display stronger hair follicle phenotypes. The phenotypes of triple-null (i.e., Notch1-, Notch2-, and Notch3-null) mice appear to be even stronger than those of double-null mice. Presenilins are necessary for hair follicle maintenance in mice, and the hair and skin phenotypes of the Notch1-, Notch2-, and Notch3-null mice are very similar to those of presenilin-1 and presenilin-2 double-null mice [92].
Notch overactivity in hair follicle cells also leads to abnormal hair formation [94, 95]. Notch1 overactivity in the cortex affects neighboring cells, indicating a nonautonomous role for Notch-regulated transcripts [94]. Transgenic mice expressing constitutively active Notch1 in the suprabasal epidermal keratinocytes and inner root sheath of the hair follicle have epidermal hyperplasia and delayed inner root sheath differentiation, which leads to hair shaft abnormalities and alopecia associated with defects in the anagen phase of the hair cycle [95]. Thus, it is noteworthy that both loss and gain of Notch signaling similarly result in hyperkeratosis and hair loss due to hair cycle disturbances.
Analysis of mice with a specific deletion of rbpsuh in the skin using a nestin promoter-controlled Cre-lox system reveals that Notch signaling inhibits stem cells in the bulge, the stem cell niche in the hair follicle, from differentiating into epidermal cells and promotes hair formation [96]. This conclusion is consistent with observations that defects in Notch signaling result in markedly impaired hair formation and excess differentiation to the epidermal cells during the catagen phase, which eventually causes epidermal hyperplasia and epidermal cyst formation [92, 93]. Moreover, a lack of Notch1 caused by a tamoxifen-inducible K5 promoter-controlled Cre-lox system leads to skin tumor generation [97], indicating that Notch signaling is sometimes tumor-suppressive [98].
In summary, Notch signals are likely to promote the selection of hair formation in bulge stem cells. Thus, ex vivo expansion of hair stem cells with the use of an artificial stem cell niche could revolutionize the dermatology/cosmetology field. Notch signaling should be an important component of such an artificial niche for hair stem cells. Moreover, the regulation of Notch signaling might be considered as a means for skin surface management.
Roles in Hematopoietic and Immune Systems
In the hematopoietic and immune systems, Notch1, Notch2, and Notch3 are expressed in immature, as well as mature, blood cells and lymphocytes. Notch ligands are mainly expressed in the stromal cells and antigen-presenting cells, yet subsets of hematolymphopoietic cells also express some Notch ligands [4]. A number of studies demonstrate that Notch signaling inhibits myeloid differentiation from progenitor cells [5]. Whether this signaling pathway is involved in HSC maintenance in the bone marrow niche and whether ex vivo HSC expansion is feasible using Notch signaling activators are issues that remain to be examined.
HSC Maintenance in Adult Bone Marrow.
Osteoblasts on the surfaces of trabecular bone have been identified as one of the bone marrow HSC niches [99–101]. Sinusoidal endothelial cells in the bone marrow and spleen also provide a niche for HSCs [102]. Two groups have proposed that Notch signaling is actively involved in HSC maintenance/growth in the osteoblastic niche using different experimental animals. One group, using transgenic mice that express constitutive active parathyroid hormone receptor under the control of the collagen type-IV promoter, reported that the trabecular bone mass is increased and the Notch ligand, Jagged1, is overexpressed in the osteoblasts. The authors of this report argue that the increase in bone marrow HSCs is a direct consequence of the increased osteoblastic niche area and overexpression of Jagged1 in the niche cells [100]. This finding does not necessarily imply that physiologic levels of Notch signaling contribute to HSC maintenance, particularly as the long-term culture-initiating cells decreased only to basal levels, but not below basal levels, by a -secretase inhibitor in the coculture with bone marrow stromal cells derived from the transgenic mice. The other group used mice harboring green fluorescence protein as a reporter under the CSL binding sequence and explored Notch activation at the cellular level in situ. In these mice, green fluorescence protein is expressed in the c-Kit-positive cells near the trabecular bone area, indicating Notch activation in the HSCs, which contributes to inhibiting HSC differentiation [103].
Taken together, interactions between osteoblast-expressed Notch ligands such as Jagged1 and signal transmission to the Notch receptor-expressing HSCs might be one of the molecular mechanisms underlying the regulation of HSC in the osteoblastic niche in the bone marrow. The conditional deletion of both Notch1 and Jagged1, however, fails to show a clear-cut role for the Jagged1-Notch1 pathway in HSC maintenance [104]. Therefore, truly convincing evidence must be demonstrated before we can draw conclusions about the physiologic role of Notch signaling for HSC maintenance in the bone marrow niche, including the osteoblastic and sinusoidal endothelial niches.
Ex Vivo Expansion of HSCs Using Notch Signaling. Ex vivo expansion of HSCs maintained in the immature state has long attracted interest because of the potential utilization of expanded HSCs for transplantation, gene therapy, etc. [105]. Forced expression of a constitutively active form of Notch1 [106, 107] or wild-type HES1 [108] inhibits murine HSC differentiation and potentially expands the HSCs. There are no clear-cut data, however, showing ex vivo expansion of transplantable murine HSCs that retain full hematopoietic activity by stimulating with Notch ligands, although a number of studies have demonstrated the influence of Notch signaling on murine hematopoietic progenitor cells (Table 2) [109–121]. In contrast, investigations using human cord blood-derived cells demonstrated ex vivo expansion of severe combine immunodeficiency (SCID) mouse-repopulating cells (SRCs), which are established surrogates for HSCs (Table 2). For the latter, soluble forms of Delta-like1, such as fusion with the Fc portion of human immunoglobulin G (Dll1-Fc), have been used to show the increase in the potential or the numbers of human SRCs when HSC-enriched cells are cultured in the presence of hematopoietic cytokines, such as stem cell factor and thrombopoietin [116, 118, 121, 122]. These findings raise the possibility of the clinical use of these proteins. To date, however, the degrees of SRC expansion have not been robust enough to establish clinically applicable ex vivo HSC expansion methods, although expansion of progenitors has been demonstrated to be more massive.
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Effects of Notch Signaling on Early Lymphopoietic Cells. Several important conclusions have been drawn from hematolymphopoietic cells differentiated from HSCs, such as that Notch signaling guides further differentiation of HSC-derived hematolymphopoietic cells, for example: (a) T and B lineage determination (in the progenitor stage between the HSCs and the most early thymocytes, Notch signaling blocks B lineage differentiation and promotes T-lineage differentiation) [123–126], (b) further acceleration of thymocyte differentiation and proliferation [127–130], and (c) splenic marginal zone B cell formation [131–134]. Sambandam et al. identified "early T lineage progenitors" in the thymus, which express Flt3 and preserve B lineage potential, as the cell subset that first receives Notch signals rather than multipotent hematopoietic progenitors circulated in the blood [135]. Notch signals are also necessary for the differentiation, proliferation, and rescue from apoptosis at multiple checkpoints during thymocyte development. Interestingly, the glucose metabolism induced by activation of phosphatidylinositol-3-OH kinase is proposed to be the major contributor to apoptosis prevention by Notch signaling at the ß-selection checkpoint [13]. It is now known that either Delta-like1 or Delta-like4 is sufficient to induce T-lineage cells down to the CD4+CD8+ stage from upstream progenitors in in vitro culture [134–136].
Information regarding the involvement of Notch signaling in the immune system is accumulating rapidly, and a comprehensive discussion of this topic is beyond the scope of this review. A number of review papers summarize the influence of Notch signals on lymphocyte development, particularly on T-cell development in the thymus [4, 7, 137, 138].
Roles in Intestinal Mucosal Cells
Intestinal epithelial stem/progenitor cells are localized in the basal area of the crypts and continuously supply multiple types of mature cells [139, 140]. These cells express Notch receptors and molecules necessary for Notch signaling [141, 142].
The administration of -secretase inhibitors induces gross histologic changes in the intestinal epithelial layer of mice, such as an increased number of Goblet cells, endocrine cells, and abnormal crypts [143–146]. Conditional inactivation of rbpsuh in the epithelium of the small intestine and colon by an inducible Cyp1A promoter-expressed Cre enzyme induces rapid and massive conversion of proliferative crypt cells to postmitotic Goblet cells [146]. These findings are consistent with observations of HES1-null mice [87] and Villin-Cre Rosa-Notch transgenic mice [90] and suggest that Notch signaling in adults functions to maintain intestinal epithelial stem/progenitor cells.
Roles in Skeletal Muscle Regeneration
Satellite cells are stem cells of skeletal muscle fibers [147]. In aged mice, satellite cells have a markedly impaired propensity to proliferate and produce the myoblasts necessary for muscle regeneration. This is attributed to insufficient upregulation of Delta1, in contrast to the injured muscle in young mice in which Delta1 is sufficiently upregulated. Ultimately, Notch signaling is insufficient for the regeneration of injured muscle in aged mice. Notch inhibition impairs regeneration in young mouse muscle, and forced Notch activation restores the regenerative potential to aged mouse muscle [148, 149]. Thus, Notch signaling is a key determinant of the muscle regenerative potential that declines with age.
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CONCLUSION |
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TopAbstractIntroductionHistorical Background of NotchNotch Signaling Pathway and...Notch Signaling in Stem...Roles of Notch Signaling...ConclusionDisclosuresAcknowledgmentsReferences |
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DISCLOSURES |
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TopAbstractIntroductionHistorical Background of NotchNotch Signaling Pathway and...Notch Signaling in Stem...Roles of Notch Signaling...ConclusionDisclosuresAcknowledgmentsReferences |
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ACKNOWLEDGMENTS |
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TopAbstractIntroductionHistorical Background of NotchNotch Signaling Pathway and...Notch Signaling in Stem...Roles of Notch Signaling...ConclusionDisclosuresAcknowledgmentsReferences |
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REFERENCES |
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TopAbstractIntroductionHistorical Background of NotchNotch Signaling Pathway and...Notch Signaling in Stem...Roles of Notch Signaling...ConclusionDisclosuresAcknowledgmentsReferences |
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