Notch Signaling in the Bone Marrow Lymphopoietic Niche

Abstract

Lifelong mammalian hematopoiesis requires continuous generation of mature blood cells that originate from Hematopoietic Stem and Progenitor Cells (HSPCs) situated in the post-natal Bone Marrow (BM). The BM microenvironment is inherently complex and extensive studies have been devoted to identifying the niche that maintains HSPC homeostasis and supports hematopoietic potential. The Notch signaling pathway is required for the emergence of the definitive Hematopoietic Stem Cell (HSC) during embryonic development, but its role in BM HSC homeostasis is convoluted. Recent work has begun to explore novel roles for the Notch signaling pathway in downstream progenitor populations. In this review, we will focus an important role for Notch signaling in the establishment of a T cell primed sub-population of Common Lymphoid Progenitors (CLPs). Given that its activation mechanism relies primarily on cell-to-cell contact, Notch signaling is an ideal means to investigate and define a novel BM lymphopoietic niche. We will discuss how new genetic model systems indicate a pre-thymic, BM-specific role for Notch activation in early T cell development and what this means to the paradigm of lymphoid lineage commitment. Lastly, we will examine how leukemic T-cell acute lymphoblastic leukemia (T-ALL) blasts take advantage of Notch and downstream lymphoid signals in the pathological BM niche.

Notch Signaling in Acute Inflammation and Sepsis

“…Thus, it is essential for definitive hematopoiesis in the developing embryo. Whether Notch signaling plays a similar role during the generation or maintenance of HSC in the adult BM compartment is still convoluted [ 48 ]. Jagged-1-induced Notch signaling was shown to regulate HSC homeostasis [ 49 ].…”

Differential regulation of skeletal stem/progenitor cells in distinct skeletal compartments

“…Eventually, hypoxic condition in limb forming cells promotes vascular invasion to the perichondrium leading to osteoblast differentiation, and development of perichondrium to periosteum and articular soft tissues (Percival and Richtsmeier, 2013). The periosteum becomes a layer of connective tissue housing the proliferating progenitor cells with chondrogenic and osteogenic differentiation properties, while the osteoblasts differentiating mostly from Dlx5 + cells of the periosteum form a bony collar around the shaft of limb bones (Vanderbeck and Maillard, 2019;Sottoriva and Pajcini, 2021;Matsushita et al, 2022). Subsequently, the marrow cavity forms as long bones develop, and blood vessels invade the cartilage template from the osteogenic perichondrium, which are maintained through Notch signaling (Vanderbeck and Maillard, 2019;Sottoriva and Pajcini, 2021).…”

“…The periosteum becomes a layer of connective tissue housing the proliferating progenitor cells with chondrogenic and osteogenic differentiation properties, while the osteoblasts differentiating mostly from Dlx5 + cells of the periosteum form a bony collar around the shaft of limb bones (Vanderbeck and Maillard, 2019;Sottoriva and Pajcini, 2021;Matsushita et al, 2022). Subsequently, the marrow cavity forms as long bones develop, and blood vessels invade the cartilage template from the osteogenic perichondrium, which are maintained through Notch signaling (Vanderbeck and Maillard, 2019;Sottoriva and Pajcini, 2021). Blood-borne hematopoietic progenitors and BM stromal cells then seed this environment.…”

“…In summary, calvarial and long bone development and remodeling leads to different bone morphologies and histologic characteristics. Although not all the regulatory pathways involved are the same (Table 1), Notch, BMP, TGFβ, Hedgehog (Hh) and Wnt/β-catenin signaling pathways play a key role in embryogenesis and regulation within the different bone compartments (Sottoriva and Pajcini, 2021). In addition, the balance between proliferation and differentiation is important in the development and remodeling of these compartments.…”

Multiple Mechanisms of NOTCH1 Activation in Chronic Lymphocytic Leukemia: NOTCH1 Mutations and Beyond

“…The Notch pathway is a ubiquitous signaling system, highly conserved among metazoans [ 19 ], with a fundamental role in cell-fate determination in almost all developing tissues and organs [ 20 , 21 , 22 ] from embryonic development throughout adulthood [ 23 ]. In addition, it also functions to regulate tissue homeostasis and maintenance of stem cells in adults [ 22 , 24 , 25 , 26 ].…”