ReviewNotch signaling and the bone marrow hematopoietic stem cell niche
Introduction
In the late 1970s Schofield used the term niche to define custom microenvironments composed of subset of cells and extracellular substrates required to support localization, survival, and self-renewal of stem cells in vivo [1]. Conceptually the niche can be thought of as a region that can harbor stem cells and maintain balance between self renewal and differentiation. Over the years, a body of evidence has accumulated in a number of animal models that supports the concept of microenvironmental regulation of stem cells [2]. Notch signaling is in many ways ideal for instructive communication between the niche and stem cells as it is highly conserved, requires direct contact of adjacent cells, and Notch signaling can influence cell fate decisions [3]. While HSCs are fairly well understood, only recently data have indicated cellular and molecular components of the bone marrow HSC niche [4], with some of the first evidence suggesting that osteoblastic cells are supportive of HSCs coming from in vitro work [5]. The important role of Notch signaling in hematopoiesis was highlighted by its association with hematological malignancies [6], [7], which initiated a great deal of interest in the role of Notch signaling in HSC regulation and in hematopoietic lineage allocation and differentiation, as we will review. Most recently, in vivo evidence has strongly implicated Notch signaling in regulation of osteoblastic differentiation [8], [9]. Together, these lines of investigation would suggest that Notch signaling in the bone marrow microenvironment could be essential in HSC-osteoblastic regulatory interactions, and in fact, data defining the role of osteoblastic cells in HSC regulation point to Notch signaling as a potential intermediary [10]. In this review we will discuss the Notch signaling pathway and how it functions in the hematopoietic system, osteoblastic cells, and the interaction between HSC and their microenvironment which have emerged so far.
Section snippets
Notch signaling
The canonical Notch Signaling pathway is highly conserved and plays roles in many cellular functions including cellular growth, differentiation, and fate choices [3]. In mammals four Notch receptors (Notch 1–4) and five ligands (Jagged1–2 and Delta-like 1, 3, and 4) have been identified, all of which are single span transmembrane proteins that require cell–cell contact for activation [11]. When a Notch ligand comes in contact with Notch, the external portion of Notch is cleaved by tumor
Notch, leukemias and hematopoietic lineage allocation
Strong evidence for the role of Notch signaling in hematopoiesis is provided by the finding that aberrations in Notch can lead to leukemias. Notch was first linked to T-cell neoplasias in the late 1980s and early 1990s with the identification of the t(7;9) chromosomal translocation which was cloned from a subset of T-cell acute lymphoblastic leukemias (T-ALL) [6], [7]. This translocation resulted in a truncated form of Notch1 termed translocation associated Notch homolog (TAN1), which
In vitro studies
Many independent studies have established that Notch1 and the Notch ligands Jagged1 and Delta-like1 are expressed in osteoblasts [10], [31], [32], [33], [34], [35], [36]. In vitro studies attempting to elucidate the role of Notch signaling in bone have led to contradictory conclusions that Notch activation either impairs [32], [33], [37], [38], [39] or facilitates [34], [40], [41] osteoblastic differentiation. The disparity in these studies could be due to different cellular models, different
Notch and stem cell niches
As a system providing rapid environmental cell-initiated signals to stem cells, the Notch signaling pathway would be predicted to play an important role in stem cell niches. In fact, much data support the role of Notch signaling as a key mediator of niche-stem cell interactions in a number of organisms and in numerous organ systems. For example, Notch is reported to be important in gonadal niches in both worms [46] and flies [47], [48], where Notch signaling may also determine niche size. In
Notch and the microenvironmental control of hematopoiesis
Examples exist of the importance of Notch signaling in relaying instruction from the microenvironment to stem cells in numerous systems, but what about mammalian HSCs? Mammalian HSCs are some of the best characterized stem cells. One of the difficulties in determining the signals involved in HSC regulation by the microenvironment has been that the cellular regulatory components of the bone marrow microenvironment have only recently come to light. Currently the HSC niche is thought to be
Concluding thoughts
Although the verdict is still out on the role of Notch in HSC maintenance, it is evident from in vitro studies that Notch ligands can increase HSC and maintain progenitor populations. It also appears that normal Notch signaling in the bone marrow microenvironment is necessary to maintain normal hematopoiesis. Based on the data available so far, it is unlikely that Notch signaling is the only pathway to regulate HSC within the niche. Many other pathways, such as N-cadherin [50],
Acknowledgments
This work was supported by the National Institutes of Health, National Institute of Diabetes, Digestive and Kidney Diseases (K08 DK064381, R21 DK069563, R01 DK 076876 to L.M.C.), the Wilmot Cancer Scholar Foundation (L.M.C.) and the Pew Foundation (L.M.C.). J.M.W. is supported by T32 AR05345903. The authors thank Matthew J. Hilton, Benjamin J. Frisch and Rebecca L. Porter for their helpful discussions.
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