Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)
Part I. Stem Cells
In normal adult tissues, stem cells are responsible for renewal, repair, and remodelling through their self-renewal capacity and multipotency. They govern tissue homeostasis under diverse physiological (ageing) and pathological (injury or disease) conditions throughout the lifetime of the organism. Such homeostasis is dependent on the ability of the stem cells to maintain themselves over prolonged periods of time (self-renewal) and to differentiate into multiple, but limited, cell types (multipotency). By adjusting cell divisions to meet the needs of resident tissues, stem cells enable lifelong optimization of tissue and organ formation and function (O’Brien and Bilder, 2013). The balance between self-renewal and differentiation is the basis for tissue homeostasis, as well as for its regeneration. This can be achieved by combining different extracellular components that act as regulators of these two distinct processes. These extracellular components are mainly composed of the extracellular matrix (ECM) – which functions in cell adhesion, cell – cell communication and differentiation – and of cells and growth factors (Abedin and King, 2010; Brizzi et al., 2012). In 1977, it was demonstrated that many different cells, including endothelial cells and macrophages, could interact with haematopoietic stem cells (HSCs), to support their survival and differentiation (Dexter et al., 1977). Other studies have shown that many other cells are able to function as a supportive stroma (stromal cells) for HSCs, including adventitial reticular cells (Weiss, 1976), osteoblasts (Calvi et al., 2003), glial cells (Yamazaki et al., 2011), adipocytes (Naveiras et al., 2009), fibroblasts and mesenchymal stem cells (MSCs) (Bianco, 2011). These cells are able to produce a broad combination of ECM and growth factors and to express cell membrane molecules that can interact with and control the self-renewal and differentiation of HSCs (Kunisaki et al., 2013; Morrison and Scadden, 2014). The association of ECM, cells and growth factors organizes the bone microenvironment, which ultimately regulates HSCs. Although complex, the microenvironment influences haematopoiesis in a coordinated manner to maintain homeostasis of the organism. The ability of HSCs to sense and respond to organismal needs derives, in large part, from their intimate association with this microenvironment.
Schofield (1978) proposed the existence of a niche for HSCs that could dynamically regulate stem cell behaviour, maintaining equilibrium amongst quiescence, self-renewal and differentiation. The stem cell niche was understood as a physiological microenvironment consisting of specialized cells within fixed compartments that would act as stromal cells to HSCs and provide the growth factors and ECM required to maintain HSC properties. This niche can be viewed as specific areas of a tissue with local and specialized microenvironments consisting of soluble and surface-bound signalling factors, cell – cell contacts, stem-cell-niche support cells and the ECM, all able to maintain stem cell functions (Figure 3.1). In sum, the stem cell niche provides a protective environment that regulates proliferation, differentiation and apoptosis to control stem cell reserves. Thus, maintaining a balance between stem cell quiescence and activity is a hallmark of a functional niche (Moore and Lemischka, 2006).
Although the idea of a stem cell niche originates from studies on mammalian HSCs, a detailed description of a stem cell compartment at the cellular level was first achieved in the Drosophila melanogaster ovary (Xie and Spradling, 2000; Losick et al., 2011). Since then, the concept of the stem cell niche has been extended to include various stem cell types, including the progenitors of mammalian gut and hair cells.