Metabolic circuits in neural stem cells

Metabolic activity indicative of cellular demand is emerging as a key player in cell fate decision. Numerous studies have demonstrated that diverse metabolic pathways have a critical role in the control of the proliferation, differentiation and quiescence of stem cells. The identification of neural stem/progenitor cells (NSPCs) and the characterization of their development and fate decision process have provided insight into the regenerative potential of the adult brain. As a result, the potential of NSPCs in cell replacement therapies for neurological diseases is rapidly growing. The aim of this review is to discuss the recent findings on the crosstalk among key regulators of NSPC development and the metabolic regulation crucial for the function and cell fate decisions of NSPCs. Fundamental understanding of the metabolic circuits in NSPCs may help to provide novel approaches for reactivating neurogenesis to treat degenerative brain conditions and cognitive decline.     

Hypoxia in the regulation of neural stem cells

In aerobic organisms, oxygen is a critical factor in tissue and organ morphogenesis from embryonic development throughout post-natal life, as it regulates various intracellular pathways involved in cellular metabolism, proliferation, survival and fate. In the mammalian central nervous system, oxygen plays a critical role in regulating the growth and differentiation state of neural stem cells (NSCs), multipotent neuronal precursor cells that reside in a particular microenvironment called the neural stem cell niche and that, under certain physiological and pathological conditions, differentiate into fully functional mature neurons, even in adults. In both experimental and clinical settings, oxygen is one of the main factors influencing NSCs. In particular, the physiological condition of mild hypoxia (2.5–5.0% O₂) typical of neural tissues promotes NSC self-renewal; it also favors the success of engraftment when in vitro-expanded NSCs are transplanted into brain of experimental animals. In this review, we analyze how O₂ and specifically hypoxia impact on NSC self-renewal, differentiation, maturation, and homing in various in vitro and in vivo settings, including cerebral ischemia, so as to define the O₂ conditions for successful cell replacement therapy in the treatment of brain injury and neurodegenerative diseases.     

Vascular stem/progenitor cells: functions and signaling pathways

Vascular stem/progenitor cells (VSCs) are an important source of all types of vascular cells needed to build, maintain, repair, and remodel blood vessels. VSCs, therefore, play critical roles in the development, normal physiology, and pathophysiology of numerous diseases. There are four major types of VSCs, including endothelial progenitor cells (EPCs), smooth muscle progenitor cells (SMPCs), pericytes, and mesenchymal stem cells (MSCs). VSCs can be found in bone marrow, circulating blood, vessel walls, and other extravascular tissues. During the past two decades, considerable progress has been achieved in the understanding of the derivation, surface markers, and differentiation of VSCs. Yet, the mechanisms regulating their functions and maintenance under normal and pathological conditions, such as in eye diseases, remain to be further elucidated. Owing to the essential roles of blood vessels in human tissues and organs, understanding the functional properties and the underlying molecular basis of VSCs is of critical importance for both basic and translational research.     

Neuroreplacement therapy and stem cell biology under disease conditions

Recent advances in stem cell technology are expanding our ability to replace a variety of cells throughout the body. In the past, neurological diseases caused by the degeneration of neuronal cells were considered incurable because of a long-held 'truism'; neurons do not regenerate during adulthood. However, this statement has been challenged, and we have now found much evidence that the brain is indeed capable of regenerating neurons after maturing. Based on this new concept, researchers have shown neural differentiation of stem cells and recovery of function following transplantation of these cells into the brain. These results may promise a bright future for clinical applications of stem cell strategies in neurological diseases; however, we must consider the pathophysiological environments of individual diseases that may affect stem cell biology. Before we begin to develop clinical applications, we must consider environmental factors that have not been discussed in the current preclinical studies. Here, we study cases of Alzheimer's disease and schizophrenia and discuss the effects of environmental factors under disease conditions.Received 15 January 2003; received after revision 7 April 2003; accepted 8 April 2003     

Using human pluripotent stem cells to untangle neurodegenerative disease mechanisms

Human pluripotent stem cells, including embryonic (hES) and induced pluripotent stem cells (hiPS), retain the ability to self-renew indefinitely, while maintaining the capacity to differentiate into all cell types of the nervous system. While human pluripotent cell-based therapies are unlikely to arise soon, these cells can currently be used as an inexhaustible source of committed neurons to perform high-throughput screening and safety testing of new candidate drugs. Here, we describe critically the available methods and molecular factors that are used to direct the differentiation of hES or hiPS into specific neurons. In addition, we discuss how the availability of patient-specific hiPS offers a unique opportunity to model inheritable neurodegenerative diseases and untangle their pathological mechanisms, or to validate drugs that would prevent the onset or the progression of these neurological disorders.     

Stress proteins in neural cells: functional roles in health and disease

Heat shock proteins (HSPs) or stress proteins participate in protein synthesis, protein folding, transport and translocalization processes. Stress situations trigger a heat shock response leading to their induction. Similarly, they can be upregulated by impairment of the proteasomal degradation pathway. The upregulation of stress proteins is an important step in prevention of protein aggregation and misfolding after stress, and also is essential during development and differentiation. A number of HSPs are constitutively or inducibly expressed in the nervous system and connected to protection of nerve cells and glia. The cytoskeleton is affected by stress, and HSPs have been shown to interact with the cytoskeleton in normal cells and to assist proper assembly, spatial organization and cross-linking properties. The integrity of the cytoskeleton is disturbed in many neurodegenerative disorders, and filamentous cytoplasmic inclusion bodies, containing a variety of HSPs, are observed. This review summarizes the recent literature on the presence and induction of HSPs in neural cells, and their possible functional roles in health and disease are discussed.     

Wnt signaling: multiple functions in neural development

Wnt signaling has proven to be essential for neural development at various stages and across species. Wnts are involved in morphogenesis and patterning, and their proliferation-promoting role is a key function in stem cell maintenance and the expansion of progenitor pools. Moreover, Wnt signaling is involved in differentiation processes and lineage decision events during both central and peripheral nervous system development. Additionally, several reports point to a role of Wnt signaling in axon guidance and neurite outgrowth. This article reviews and consolidates the existing evidence for the functions of Wnt signaling in neural development.Received 10 December 2004; received after revision 19 January 2005; accepted 21 January 2005     

Expression and function of galectin-1 in adult neural stem cells

Neural stem cells (NSCs) in the adult mammalian brain proliferate and continuously produce new neurons. To date, there has been little research into the functions of lectins in adult NSCs. Recently, we reported that a lectin, galectin-1, is expressed on adult NSCs and promotes their proliferation through its carbohydrate-binding ability. This evidence raises the possibility that glycans play roles in the proliferation of adult NSCs. Received 6 November 2006; received after revision 13 December 2006; accepted 15 February 2007     

Interactions between VEGFR and Notch signaling pathways in endothelial and neural cells

Notch cell interaction mechanism governs cell fate decisions in many different cell contexts throughout the lifetime of all Metazoan species. It links the fate of one cell to that of its neighbors through cell-to-cell contacts, and binding of Notch receptors expressed on one cell to their membrane bound ligands on an adjacent cell. Environmental cues, such as growth factors and extracellular matrix molecules, superimpose a dynamic regulation on this canonical Notch signaling pathway. In this review, we will focus on Notch signaling in the vertebrate vascular and nervous systems and examine its role in angiogenesis, neurogenesis, and neurovascular interactions. We will also highlight the molecular relationships of the Notch pathway with vascular endothelial growth factors (VEGFs) and their high-affinity tyrosine kinase VEGF receptors, key regulators of both angiogenesis and neurogenesis.     

Host-defense peptides: from biology to therapeutic strategies

Primitive innate defense mechanisms in the form of gene-encoded antimicrobial peptides are now considered as potential candidates for the development of new therapeutics. They are well known for their function as the first protective barrier of all organisms against microbial infections. In addition, emerging studies reveal that they assist in modulating the host immune system. The biological properties of these host-defense peptides, their role in human health, their cell selectivity and related molecular mechanisms are discussed in this multi-author review along with the strategies to transform them or their peptidomimetics into clinically usable drugs.