Regulating the Notch pathway in embryonic, adult and old stem cells

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The Notch pathway represents a highly conserved signaling network, which is critical to both embryonic skeletal muscle formation and regeneration in the adult. In addition to skeletal muscle, Notch also regulates the formation and maintenance of various organ systems, such as brain, blood and intestine, in evolutionary distinct vertebrate and invertebrate species. The Notch network ‘cross talks’ with all other key cell-fate determinants, such as the Wnt (Wingless), TGF-β/BMP, Hh and RTK/Ras pathways. Hence, modulating the intensity of Notch resonates through multiple regulatory circuitries, and exerts profound effects on cell behaviour. Therefore, various approaches to the targeted manipulation of Notch have been developed (e.g. genetic constructs, antibodies, RNA interference, receptor decoys and γ-secretase inhibitors). These tools might be used to broaden our understanding of this pathway in regulating responses of embryonic and adult stem cell subsets, and to develop therapeutic approaches against Notch-based diseases (e.g. Alzheimer's, Alagille Syndrome, various cancers and other disease states).

Introduction

Since its discovery approximately 90 years ago, the Notch pathway (from ‘notched’ wingblade phenotype in fruit flies defective for this locus) has been extensively studied and exploited within arenas of developmental biology, regenerative medicine and oncology. Notch is considered to be almost universally conserved in its role of controlling embryonic organogenesis and postnatal tissue repair [1, 2, 3•]. The variable strength of Notch signaling represents a highly reliable molecular mechanism that regulates cell-fate determination, and enables formation of tissues and organs from initially equivalent groups of stem cells. Likewise, we know that Notch signaling is involved with embryonic, postnatal, aged and oncogenic properties of stem and progenitor cells.

The interactions between Notch signaling and other key molecular networks (e.g. transforming growth factor/bone morphogenetic protein-4 and Wingless [Wnt]) have also been conserved in postnatal regeneration of multiple tissues, and are implicated in Notch-imposed control of stem cell responses [4, 5, 6]. Consequentially, our ability to regulate Notch signalling, both positively and negatively, has wide implications for many areas of experimental biology, ranging from the bourgeoning field of embryonic stem cell research to the studies of aging. Here, we review the role of Notch signaling, from embryonic to specific adult stem cell subsets. We also outline recent advances in our ability to manipulate the Notch pathway, and discuss both their clinical and research implications.

Section snippets

Notch signaling

To date, four isoforms of the Notch receptor have been identified in mammals (Notch1–4), whereas two isoforms are reported in Caenorhabditis elegans (LIN-12 and GLP-1) and one in Drosophila melanogaster (Notch) [7, 8•]. As a precursor protein, immature Notch undergoes furin-like proteolytic processing (S1 cleavage) in the trans-golgi, before being presented as a single-pass transmembrane receptor on the cell surface [9]. The mature Notch receptor is a heterodimer, consisting of a large

Stem cells and their niche in young and old organisms: role of the Notch pathway

A diversity of stem cell subsets require Notch signaling for the productive maintenance of tissues [11]. However, with advancing age, stem-cell-regulating extrinsic cues become adversely altered, both systemically and in the local organ environment. This phenomenon precludes productive tissue repair, and has been demonstrated in heterochronic tissue transplantation and parabiosis studies, as well as with embryonic stem cells [33, 34, 35]. The age-associated decline in stem cell regeneration

Therapeutic potential of embryonic stem cells

ESCs possess the distinct and defining features of both unlimited self-renewal and pluripotency [45, 46]. These characteristics endow ESCs with tremendous neo-organogenesis potential and have consequently generated great interest in ESC-based cell-replacement therapies. Understanding the molecular events that govern self-renewal and tissue-specific differentiation of ESCs is critical to controlling their productive regenerative properties. In vitro multilineage differentiation of ESCs is

The Notch pathway and the directed differentiation of embryonic stem cells

The function of endogenous Notch signaling in mammalian ESCs is just beginning to be understood in detail. mRNAs encoding Notch1–3 and DLL1 are present at high levels in hESCs [54, 55]; additionally, both Notch3 and active-form γ-secretase components are reported to be highly expressed in mESCs and hESCs [56, 57]. Conversely, Notch2 is expressed at much lower levels [54]. Notch signaling is thought to be relatively inactive in undifferentiated hESCs, and not necessary for their propagation.

Pharmacological manipulation of the Notch pathway

Notch signaling can be inhibited through various means, including monoclonal antibodies, RNA interference, antisense Notch, receptor and mastermind-like 1 (MAML1) decoys, and the use of γ-secretase inhibitors (GSIs) [69]. Experimental manipulation of the strength of Notch signaling has provided important data on somitogenesis, myogenesis, neurogenesis and the transdifferentiation of bone marrow mesenchymal stem cells into muscle cells [4, 11, 70••, 71, 72]. In particular, GSIs have become an

Conclusions

After many decades of productive research, the Notch pathway remains at the forefront of modern biomedical science and continues to inform us of the mechanisms controlling cell behavior. The conservation of this signaling network between evolutionarily distinct species and different cell types is truly remarkable, and productive Notch activity is critically important not only for the formation, but also for the maintenance and repair, of numerous organs and tissues. Alterations in Notch

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors would like to acknowledge, and apologise to, the numerous authors who have made important contributions to the fields addressed in this review, but whose work was not included due to the limited scope and space restrictions of this article.

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