Neural Stem Cells in the Mammalian Brain

A.V. Revishchin*,†; L.I. Korochkin*; V.E. Okhotin*; G.V. Pavlova*    * Institute of Gene Biology, Russian Academy of Sciences, Moscow, 119334 Russia
† Severtsov Institute of Ecology and Evolution, Russian Academy of Sciences, Moscow, 119071 Russia

Contents

1 INTRODUCTION

The stem cell is one of the most popular topics in current biology and medicine. The increasing number of publications indicates that stem cells are of great interest to a wide range of biological and medical scientists. The topic of stem cells is central in developmental biology. Studying molecular mechanisms of stem cell self-renewal and differentiation control promises to shed light on key problems in cell biology. A great number of publications form a base of new data; however, these data often do not solve the problem posed but rather raise new and more complex questions. One of these unclear issues is the definition of the stem cell or, to be more specific, what distinguishes a stem cell from other cells. The idea of stem cells was proposed by the Russian histologist Alexander Maximov (1907). It was accepted that the adult body lacks stem cells and their existence is limited to the earliest period of embryonic development. Another Russian histologist, Friedenstein (1976), found these cells in the mesenchyme (stroma) of the adult bone marrow. Based on their localization, these cells were later assigned to stromal or mesenchymal stem cell groups.

Stem cells are divided into embryonic stem cells (ESCs) isolated from blastocyst stage embryos and regional stem cells isolated from later embryonic or adult tissues. In ontogeny, all organs and tissues result from the proliferation and differentiation of blastocyst cells, which are ESCs in the strict sense (Brustle et al., 1999; Gage, 2000). ESCs are pluripotent (i.e., they give rise to derivatives of all germ layers including nervous system cells). The multistage development of ESCs results in pools of regional stem cells varying by their potential for differentiation in the developing and adult body.

Most adult stem cells have a limited differentiation potential and can largely give rise to derivatives of a single germ layer, ectoderm in the case of neural stem cells (NSCs). They also represent a substantial repair reserve and can correct various defects in different organs including the nervous system (Loseva, 2001).

The most common definition of stem cells involves their conformity to three main conditions: (1) multipotency (i.e., the capacity to give rise to different cell types); (2) high proliferative potential; and (3) self-renewal (i.e., the capacity to reproduce identical descendants by symmetrical divisions) (Hall and Watt, 1989; Potten and Loeffler, 1990). However, the diversity of cells assigned to stem cells can go beyond this definition. For instance, germline cells, often considered as stem cells, are unipotent. Other cells can self-renew only within a limited time period or under specific conditions. For instance, cells of the hippocampal dentate gyrus (DG) (described later) divide only asymmetrically in adult mammals to yield committed progenitors (Encinas et al., 2006); however, in culture these cells self-renew and generate neurospheres containing the whole range of neural progenitors including NSCs (Mignone et al., 2004). On the other hand, descendants of stem cells not recognized as stem cells in many cases meet all three conditions. For instance, type C cells in the subventricular zone (SVZ) of the lateral ventricles (see later), called amplifying progenitors rather than stem cells in culture medium supplemented with epidermal growth factor (EGF), satisfy all three conditions of stem cells (Doetsch et al., 2002). Hence, the above definition is vague and needs to be refined in the future. For instance, Mikkers and Frisen (2005) proposed defining stem cells as cells halted somewhere along the line of specialization and dividing to give rise to cells of their own type and to cells progressing along the line. In terms of formal logic, this definition seems more consistent; however, it also does not cover the whole range of stem cell properties. This chapter concerns some problems related to NSCs that we consider of primary importance for neurobiology and developmental biology.

2 NEURAL STEM CELLS AND THEIR NICHES IN THE ADULT MAMMALIAN BRAIN

2.1 General description of NCSs

NSCs are classified as regional stem cells. The finding of stem cells in the nervous system has shaken a number of established concepts, particularly concerning recovery processes in the central nervous system. NSC has the same properties as the stem cell in general. The molecular markers that allow the identification of NSCs as well as the subsequent stages of their differentiation are known (Gage et al., 1995). Note, however, that these markers are relative and their significance depends, in particular, on the cell environment and state. For instance, in the adult brain, the standard NSC marker nestin can be found in stem cells as well as in endothelial and reactive glial cells (e.g., in injury). Moreover, a single cell can express two or more of the above-mentioned markers under particular conditions. A virtually unlimited proliferative capacity allows stem cells to self-renew after symmetric divisions or to give rise to precursor cells after asymmetric divisions (Gage, 2000; van der Kooy and Weiss, 2000; Watt and Hogan, 2000).

Stem cells have been found in the central nervous system of adult animals and humans. First, they have been found in the brain parts known for active neurogenesis throughout the life span: the SVZ of the lateral ventricles and the dentate gyrus (DG) of the hippocampal formation. Proliferative activity of cells in these parts was reported long ago (Altman and Das, 1965; Altman, 1969). The ability of cells in these parts to give rise to both astrocytes and neurons was later demonstrated (Reynolds and Weiss, 1992; Luskin, 1993; Palmer et al., 1995).

Both proliferative zones of the adult mammalian brain, the subgranular layer of the DG and the subependymal layer of the SVZ, demonstrate that cells glial by morphology and protein markers, but essentially stem cells can divide to generate both glial cells and neurons (Seri et al., 2001). Notably, these DG and SVZ stem cells first give rise to glial fibrillary acidic protein (GFAP)-negative actively dividing progenitor cells (type C in the subependymal zone and type D in the subgranular zone of the DG) and only then to neuroblasts (Seri...