Stem cells and niches: mechanisms that promote stem cell maintenance throughout life

Abstract

Niches are local tissue microenvironments that maintain and regulate stem cells. Long-predicted from mammalian studies, these structures have recently been characterized within several invertebrate tissues using methods that reliably identify individual stem cells and their functional requirements. Although similar single-cell resolution has usually not been achieved in mammalian tissues, principles likely to govern the behavior of niches in diverse organisms are emerging. Considerable progress has been made in elucidating how the microenvironment promotes stem cell maintenance. Mechanisms of stem cell maintenance are key to the regulation of homeostasis and likely contribute to aging and tumorigenesis when altered during adulthood.

Figure 1. Two general classes of stem cell niche

A) The Drosophila male and female GSC niches are examples of the stromal niche. Non-dividing stromal cells (green) hold the GSCs (dark pink) in place via adherens junctions (black boxes). GSCs contain a spectrosome (S) and a localized centrosome (*) that in the male is known to be the maternal centrosome. The GSC is surrounded by escort stem cells (ESC) or cyst progenitor stem cells (CPC) whose daughters (light blue) encyst the GSC daughter cell (pink). B) The Drosophila follicle cell stem cell (FSC) is an example an epidermal niche. The FSC is surrounded by FSC daugher cells (light blue), and also contacts the thin escort cells (light blue) that surround developing germline cysts (pink). The FSC does not contact any permanent stromal cells, but remains associated with a region of the basement membrane (thick black line). Intercellular signals are shown in yellow. The movement of cells is indicated by black arrows.

Figure 2. HSC niches

A) Adult HSCs reside primarily within bone marrow. Bone marrow is a complex organ containing many different hematopoietic and non-hematopoietic cells. Bony trabeculae are found throughout the trabecular zone of bone, such that many cells in this region are close to bone surface. The interface of bone and bone marrow is known as the endosteum. Arteries carry oxygen, nutrients, and hematopoietic growth factors into the bone marrow, before feeding into venous circulation. Sinusoids are specialized venuoles that form a reticular network of fenestrated vessels that allow cells to pass in and out of circulation. B) A close up view of the bone marrow showing sinusoids (red), bone (grey), and hematopoietic areas (light red). Sinusoids are often associated with megakaryocytes (purple), CXCL12-expressing reticular cells (light green), and mesenchymal progenitors (white). The bone surface is covered by bone-resorbing osteoclasts (dark green) as well as bone lining cells that can differentiate into bone-forming osteoblasts. HSCs (highlighted blue cells) are found adjacent to sinusoidal blood vessels (arrows) as well as at or near the endosteum (arrowhead) (Adams and Scadden, 2006; Kiel et al., 2007b; Kiel et al., 2005; Nilsson et al., 2001). Osteoblasts and osteoclasts elaborate factors that regulate HSC maintenance and localization (Adams et al., 2006; Arai et al., 2004; Calvi et al., 2003; Kollet et al., 2006; Zhang et al., 2003). Perivascular reticular cells and mesenchymal progenitors have also been proposed to elaborate factors that regulate HSC maintenance (Sacchetti et al., 2007; Sugiyama et al., 2006). Low (C) and high (D) magnification views of a section through bone marrow showing a CD150⁺CD48⁻CD41⁻Lineage⁻ candidate HSC (approximately 50% of such cells give HSC activity upon transplantation into irradiated mice (Kiel et al., 2005); see arrow; this cell is red but not green) that is adjacent to a sinusoid (outlined by white (C) or light blue (D) Meca-32+ endothelial cells) and that is near but not at the endosteum (highly vascularized and outlined with a dotted line). Bone is marked with a ‘B’ and a large blood vessel lumen is marked with a ‘V’. Most differentiating hematopoietic cells stain green. Large yellow to orange cells are megakaryocytes. Fours possible niche models are consistent with available data. E) HSCs (round blue cells) may reside in perivascular niches in which HSCs adhere to perivascular cells but are influenced by soluble factors released by nearby endosteal cells. F) HSCs may reside in endosteal niches, but frequently migrate through perivascular environments where the cells may be regulated by perivascular cells. G) HSCs may reside in spatially distinct endosteal and perivascular niches that may or may not be functionally equivalent. H) HSCs may reside in a single type of niche that is created by both endosteal and perivascular cells.

Figure 3. Two general classes of stem cell asymmetry

A) The preprogrammed differentiation of the first class of stem cell, that includes Drosophila GSCs, is only repressed by a local signal (red arrow) generated by nearby stromal cells. Daughter cells become derepressed by becoming displaced from the repressive signal within the niche and differentiate. Mammalian GSCs may use a related mechanism as they are preferentially found near (but not attached to) hormone-producing interstitial cells (Yoshida et al., 2007a). B) A second class of stem cell requires signals to differentiate, such as the Drosophila intestinal stem cell (ISC) pictured. ISCs divide asymmetrically such that only one daughter receives a (Notch) signal that specifies its fate (Ohlstein and Spradling, 2007). Asymmetric partitioning of Notch activity also maintains Drosophila and mouse neural progenitors (Lee et al., 2006; Petersen et al., 2004).