Autophagy for the quality control of adult hippocampal neural stem cells

Highlights

• Programmed cell death is important in regulating the pool of neural stem cells.

• Insulin withdrawal induces cell death in adult hippocampal neural stem (HCN) cells.

• Autophagic cell death (ACD) is the primary cell death mode by insulin withdrawal.

• GSK-3β and calpain are the key regulators of ACD in HCN cells.

Abstract

Autophagy plays an important role in neurodegeneration, as well as in normal brain development and function. Recent studies have also implicated autophagy in the regulation of stemness and neurogenesis in neural stem cells (NSCs). However, little is known regarding the roles of autophagy in NSC biology. It has been shown that in addition to cytoprotective roles of autophagy, pro-death autophagy, or ׳autophagic cell death (ACD),’ regulates the quantity of adult NSCs. A tight regulation of survival and death of NSCs residing in the neurogenic niches through programmed cell death (PCD) is critical for maintenance of adult neurogenesis. ACD plays a primary role in the death of adult hippocampal neural stem (HCN) cells following insulin withdrawal. Despite the normal apoptotic capability of HCN cells, they are committed to death by autophagy following insulin withdrawal, suggesting the existence of a unique regulatory program that controls the mode of cell death. We propose that dual roles of autophagy for maintenance of NSC pluripotency, as well as for elimination of defective NSCs, may serve as a combined NSC quality control mechanism.

This article is part of a Special Issue entitled SI:Autophagy.

Introduction

Neurodegenerative diseases are characterized by progressive loss of neurons through programmed cell death (PCD) at specific anatomical and functional units (Vila and Przedborski, 2003). Lockshin and Williams defined PCD as strictly controlled cell death mechanisms regulated by various intracellular and extracellular signals (Ellis et al., 1991, Lockshin and Williams, 1965). PCD can be classified into three types according to morphological and biological characteristics; apoptosis, autophagic cell death (ACD), and necrosis (Chung and Yu, 2013, Clarke, 1990). For several decades, research regarding the molecular mechanisms of PCD in neuronal cell death has focused on identifying the pivotal signaling targets for therapeutic purposes. However, the PCD of NSCs remains under-studied.

Neural stem cells (NSCs), multipotent stem cells present in neurogenic niches in the brain, maintain the capacity for self-renewal, as well as for the proliferation and differentiation into neural lineage cell types (Doetsch, 2003, Temple, 2001). The discovery of the presence of multipotent NSCs in the adult mammalian brain has generated a high level of interest in both the scientific community and the public as well, based on their immediate appeal as potential therapeutic sources for the treatment of many inexorable neurodegenerative diseases. However, the results have been disappointing and dissatisfactory to date. Clearly, the neurodegeneration process affects exogenously added or endogenous NSCs residing in the neurogenic niches (Cicchetti et al., 2009). Various cellular events including neuroinflammation, deprivation of neurotrophic factors, alteration of cellular metabolism, and loss of cell–cell interaction in the stem cell niches occur in the degenerating brain areas, leading to perturbation of cellular homeostasis and the ultimate death of NSCs (Kwon, 2002, Sleeper et al., 2002).

Cellular homeostasis of NSCs will be critical in all aspects of stem cell functions. Examples of such functions include proliferation, self-renewal, multipotency, neurogenesis, and migration and incorporation into the neural circuits for regeneration. Autophagy is a vital lysosomal catabolic process for the degradation of a variety of cellular constituents including damaged or old proteins and organelles, and intracellular or extracellular pathogens (Gutierrez et al., 2004, Nakagawa et al., 2004, Shintani and Klionsky, 2004). As a basic cellular response to stress, we can infer the critical role of autophagy in the cellular homeostasis of NSCs. However, while our understanding of autophagy and related signaling mechanisms in the regulation of cellular functions and disease processes is fast improving, the role of autophagy in NSC biology remains to be elucidated. In this review, we will provide an overview of the key aspects of PCD and more closely examine the interplay between PCD and autophagy in the regulation of both homeostasis and function in NSCs. It is important to note that in stark contrast to the generally conceived cytoprotective role of autophagy, the pro-death role of autophagy in adult hippocampal neural stem (HCN) cells will be presented as well.