Glia: an emerging target for neurological disease therapy

Almad and Maragakis Stem Cell Research & Therapy 2012, 3:37 http://stemcellres.com/content/3/5/37 REVIEW Glia: an emerging target for neurological disease therapy Akshata A Almad and Nicholas J Maragakis* Abstract Therapeutic strategies using stem cells for treating neurological diseases are receiving more attention as the scientific community appreciates cell-autonomous contributions to several diseases of the central nervous system. The transplantation of stem cells from various sources is now being employed for both neuronal and glial replacement. This review provides an assessment of glial contributions to some of the central nervous system diseases and the advancements in cellular replacement approaches. The rationale for glial replacement in individual diseases and the potential hurdles for cell-replacement strategies are also emphasized. The significant progress in the field of stem cell biology with the advent of tools such as induced pluripotent stem cells and imaging techniques holds promise for the clinical application of cell therapeutics. Introduction Rudolf Virchow first introduced the term glia (glue) in 1895 as the connective tissue supporting neurons. Four major subtypes of glial cells have since been discovered: astrocytes, oligodendrocytes, microglia and nerve glial antigen 2 (NG2) cells [1]. While diverse subpopulations of each of these glial cell types have been investigated, for the purpose of this review we will discuss how astrocytes, oligodendrocytes and NG2 cells can be used as potential therapeutic targets for cell replacement strategies. Astrocytes Astrocytes are stellate cells abundant in both the gray matter and white matter of the central nervous system (CNS). The historical view of astrocytes as support cells for neurons is now evolving to include functions from homeostasis to gliotransmission as reviewed by Seifert and colleagues [2]. *Correspondence: Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA © 2010 BioMed Central Ltd © 2012 BioMed Central Ltd Astrocytes harbor a variety of different receptors and transporters that help mediate their primary function of homeostasis. Some of the key receptors on the astrocyte surface are the inward-rectifying K+ channel [3] and aquaporin-4 receptor [4], which regulate potassium levels and osmotic changes, respectively. Some of the key transporters on astrocytes are glucose transporters (glucose transporter 1) [5] and the glutamate transporters glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) [6]. Astrocytes are interconnected via gap junctions. Calcium waves propagate between astrocytes through these gap junctions, which can further regulate the vesicular release of neurotransmitters (such as glutamate, ATP and serine) from astrocytes. This process is referred to as gliotransmission and can be a critical regulator of synaptic inputs in neurons [7]. Considering the repertoire of channels and transporters present on astrocytes and their proximity to the neurovascular unit, it is easy to appreciate that the loss of any of these functions can lead to cellular dysfunction. Oligodendrocytes Oligodendrocytes are the myelinating cells of the CNS present in white matter (classic oligodendrocytes) and in gray matter (satellite oligodendrocytes). Myelination is the central role of oligodendrocytes and myelin serves to maintain efficient nerve conduction, regulate axon caliber, and promote axon survival (extensively discussed by Baumann and Pham-Dinh [8]). Satellite oligodendrocytes are perineuronal and are believed to regulate the local neuronal microenvironment. Current research efforts exploring neuron–glia interactions indicate a mutually beneficial relationship in which oligodendrocytes provide structural and neurotrophic support for neurons, and in turn neurons/axons induce maturation of oligodendrocytes. Novel roles of oligodendrocytes in neuroprotection, synaptic tuning, and higher cognitive functions in addition to their traditional roles in myelination are now being explored (as reviewed by Nave [9]). Nerve glial antigen 2 cells Recent fate-mapping studies confirm that NG2 cells are precursors of mature oligodendrocytes and co-localize Almad and Maragakis Stem Cell Research & Therapy 2012, 3:37 http://stemcellres.com/content/3/5/37 with the oligodendrocyte precursor cell (OPC) marker platelet-derived growth factor-α receptor [10-12]. However, the NG2 proteoglycan is also expressed on other cell types including macrophages and vascular mural pericytes [13]. NG2 cells constitute the highest proportion of dividing cells in the normal adult CNS [14] and in diseases including spinal cord injury [15] and amyotrophic lateral sclerosis (ALS) [10], among others. Besides its function as a progenitor cell, NG2 cells express ion channels and conduct electrical currents [1,16,17]. The ability of NG2 cells to self-propagate and then differentiate into oligodendrocytes makes them a potentially appealing cellular therapy for demyelinating diseases. New perspective: glial therapy Recent advances in the field of neuroscience are creating a holistic picture of CNS circuitry involving not just neurons, but also surrounding glial cells. The passive role of glial cells described in the past century is now overlaid with discoveries of crucial glial functions for normal CNS homeostasis [1]. This advance has shifted the focus in neuroscience from a neuron-centric to a glial-inclusive viewpoint [18]. This view allows for cell-replacement strategies to be designed around not just neuronal replacement but also glial cell replacement. For example, therapeutic strategies for spinal cord injury have evolved from attempts to conserve neurons and axons to now additionally safeguarding oligodendrocytes that could remyelinate and help preserve surviving axons. Notable work from Smith and colleagues shows that nerve conduction can be restored through remyelination [19]. Preventing demyelination has thus now become an acceptable therapeutic target. Clinical trials for spinal cord injury [20] involving the transplantation of oligodendrocyte precursor cells exemplifies the fast pace of glial replacement as a therapeutic approach [20,21]. Neuronal replacement may be a daunting task involving transplantation, neuronal survival, integration, and ultimately the formation of the right connections with target cells/ tissues. Glial replacement strategies promote the protection of existing host neuronal populations. This will be the central theme of the review discussing contributions of astrocytes, oligodendrocytes and NG2 cells to neurological diseases. Leukodystrophies Leukodystrophies are a group of diseases caused by genetic mutations resulting in abnormalities in myelin production or maintenance. Leukodystrophies can arise from a variety of gene mutations, including genes encoding myelin proteins, enzymes involved in fatty acid metabolism, lysosomal proteins, peroxisomal proteins an (...truncated)