Notch signaling sculpts the stem cell niche

Abstract

Adult stem cells depend on their niches for regulatory signaling that controls their maintenance, division, and their progeny differentiation. While communication between various types of stem cells and their niches is becoming clearer, the process of stem cell niche establishment is still not very well understood. Model genetic organisms provide simplified systems to address various complex questions, for example, how is a stem cell niche formed? What signaling cascades induce the stem cell niche formation? Are the mechanisms of stem cell niche formation conserved? Notch signaling is an evolutionarily conserved pathway first identified in fruit flies, crucial in fate acquisition and spatiotemporal patterning. While the core logic behind its activity is fairly simple and requires direct cell–cell interaction, it reaches an astonishing complexity and versatility by combining its different modes of action. Subtleties such as equivalency between communicating cells, their physical distance, receptor and ligand processing, and endocytosis can have an effect on the way the events unfold, and this review explores some important general mechanisms of action, later on focusing on its involvement in stem cell niche formation. First, looking at invertebrates, we will examine how Notch signaling induces the formation of germline stem cell niche in male and female Drosophila. In the developing testis, a group of somatic gonadal precursor cells receive Delta signals from the gut, activating Notch signaling and sealing their fate as niche cells even before larval hatching. Meanwhile, the ovarian germline stem cell niche is built later during late larval stages and requires a two-step process that involves terminal filament formation and cap cell specification. Intriguingly, double security mechanisms of Notch signaling activation coordinated by the soma or the germline control both steps to ensure the robustness of niche assembly. Second, in the vast domains of mammalian cellular signaling, there is an emerging picture of Notch being an active player in a variety of tissues in health and disease. Notch involvement has been shown in stem cell niche establishment in multiple organs, including the brain, muscle, and intestine, where the stem cell niches are essential for the maintenance of adult stem cells. But adult stem cells are not the only cells looking for a home. Cancer stem cells use Notch signaling at specific stages to gain an advantage over endogenous tissue and overpower it, at the same time acquiring migratory and invasive abilities to claim new tissues (e.g., bone) as their territory. Moreover, in vitro models such as organoids reveal similar Notch employment when it comes to the developing stem cell niches. Therefore, a better understanding of the processes regulating stem cell niche assembly is key for the fields of stem cell biology and regenerative medicines.

Golgi-to-ER retrograde transport prevents premature differentiation of Drosophila type II neuroblasts via Notch-signal-sending daughter cells

“…The niche refers to the microenvironment, in which stem cells are located, and has a regulatory effect on stem cells. Generally, niche-forming cells are either cells independent of the stem cell lineage such as somatic cap cells or hub cells, which form the female or male Drosophila germline stem cell niche, respectively, 80 or highly differentiated daughter cells of stem cells, like Paneth cells acting as the niche of mammalian intestinal stem cells. 81 In the Drosophila CNS, previous studies have shown that highly differentiated glial cells form the NB niche, which regulates the quiescence, reactivation, survival, and proliferation of NBs.…”

Nanotechnology Meets Stem Cell Therapy for Treating Glioblastomas: A Review

“…87 Furthermore, the interaction between GSCs and endothelial cells (ECs) triggers activity in important stem cell signaling pathways, notably the Notch signaling pathway. 88 Nestinpositive GSCs exhibit elevated levels of Notch due to the expression of Notch receptors Notch-1 and Notch-2. 89 On the other hand, ECs express Notch ligands Delta-like 4 (DLL4) and Jagged-1.…”

Novel insights into Notch signaling in tumor immunity: potential targets for cancer immunotherapy

“…The N-terminal fragment of Notch receptors is O-glycosylated with the action of glycosyltransferase enzymes (e.g., members of the Fringe family) and transferred to the cell membrane ( 21 ). Notch receptors on the signal-receiving cell are activated by binding to Notch ligands on the cell surface of an adjacent signal-sending cell ( 26 ). Upon bound with ligands, Notch receptors are cleaved at Site 2 (S2) by a disintegrin and metalloprotease 10 (ADAM10) ( 27 ).…”