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
Morphogens are required for morphogenesis, as the term itself indicates. Therefore, it is expected that adult tissue regeneration may also be controlled by morphogens. Classical morphogens are expressed in the adult organism and play a central role in the regeneration of tissues. BMP2 associated with ECM is effective for differentiation of stem cells to osteoblasts. This controls osteoblast-specific gene-encoding proteins, such as osteocalcin, that are selectively expressed in bone (Seib et al., 2010), a central issue in the repair of bone fractures. Wnt and Shh signalling are involved in liver regeneration after partial hepatectomy (Omenetti and Diehl, 2008). Extracellular ligands are a critical component of the regulatory niche necessary for neural stem cell (NSC) maintenance of self-renewal, differentiation, cell adhesion and migration. Some of the many extracellular factors implicated in cell specification and signalling include FGF, epidermal growth factor (EGF), CXCL12 (stromal cell-derived factor-1, SDF-1), Shh, BMP, and Notch (Wade et al., 2014).
Neurogenesis, the process of generating functionally integrated neurons from stem cells, was once believed to occur only during embryonic stages in the mammalian central nervous system (CNS). However, new neurons are now known to be added in distinct regions of the mammalian CNS system in the adult brain, suggesting a degree of inherent plasticity (Lie et al., 2004). In most mammals, active neurogenesis occurs throughout life in the subventricular zone (SVZ) of the lateral ventricle and in the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. Neurogenesis outside these two regions appears to be extremely limited or nonexistent in the intact adult mammalian CNS. Following pathological stimulation, such as by brain insults, adult neurogenesis appears to occur in regions otherwise considered to be nonneurogenic (Gage, 2000; Lie et al., 2004). The niche plays an extremely crucial role in orchestrating the complex cascade of events involving proliferation and fate specification of NSCs to migration, nerve guidance, neuronal maturation and synaptic integration of newborn neurons in the adult CNS environment. The highly specialized architecture within this niche implicates both cell – cell interactions and soluble factors as important regulators of NSC behaviour. Shh has been shown to regulate both SVZ and SGZ NSCs. Overexpression of Shh near the dentate gyrus increases proliferation and neurogenesis of SGZ cells and maintains proliferation of adult hippocampal neuronal progenitors (Lai et al., 2003). Interestingly, in the adult SVZ, both BMP and Shh signalling are intermixed within the same region. BMP signalling during development promotes astrocyte differentiation of SVZ precursors at the expense of oligodendrogliogenesis and neurogenesis. Adult SVZ cells themselves produce BMPs and their receptors (Alvarez-Buylla and Lim, 2004). EGF, FGF and PDGF are important mitogenic regulators for multipotent stem cells in the SVZ (Gonzalez-Perez and Alvarez-Buylla, 2011). ECM structures termed fractones, which resemble basement membranes with components including laminin, collagen IV, nidogen and HSPG, have been identified in neurogenic niches located in the SVZ of the human brain. Binding of FGF-2 next to these fractones stimulates the proliferation of stem cells (Kerever et al., 2007).
Within the bone marrow, HSCs reside at, or near, the endosteum. The endosteal surface is covered by a protective layer of bone-lining cells that can differentiate into bone-forming osteoblasts. Endosteal cells secrete regulatory factors that promote HSC maintenance (Li and Xie, 2005; Adams and Scadden, 2006). This generates a complex three-dimensional stem cell niche comprising many cell types, growth factors and ECM proteins, including hyaluronic acid, fibronectin, collagen types I, III and IV, laminin, thrompospondin, hemonectin and PGs (Keating and Gordon, 1988; Nilsson et al., 2003; Sagar et al., 2006; Can, 2008). The homing, proliferation and differentiation of HSCs after grafting is strictly dependent on adequate endosteal niche composition, with the expression of ECM elements and growth factors, such as SDF-1, steel factor (SLF), interleukin 11 (IL-11), interleukin 6 (IL-6), thrombopoietin (TPO), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) (Marquez-Curtis et al., 2011; Sharma et al., 2011; Suбrez-Бlvarez et al., 2012; Khurana et al., 2013). The elements of the niche are essential for reconstitution of haematopoiesis in clinical haematopoietic regeneration in transplantation by HSC adhesion and differentiation.