Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

Abstract

in experimental ALS and SCI models and we discuss avenues for future directions based on latest molecular findings regarding astrocyte biology. Core tip: Amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI) result in incurable neurological dysfunction due to loss of spinal motor neurons and axonal degeneration, amongst other mechanisms. Astrocytes are increasingly recognized as being necessary for neuroprotection and regeneration in the central nervous system as they promote axonal growth and deliver essential neurotrophic factors under both physiological and pathophysiological conditions. Given the central role played by astrocytes, we gathered convincing results from ALS and SCI literature that argue in favor of stem cell-based astrocyte replacement therapies and stress the scientific community to investigate more deeply the molecular understanding of astrocyte biology. MULTIPLE FACETS OF ASTROCYTES IN THE CENTRAL NERVOUS SYSTEM Astrocyte functionsAstrocytes are the most abundant cells in the central nervous system (CNS), outnumbering neuronal cells by several fold in some CNS regions. They have long been relegated to a secondary position, behind neurons or oligodendrocytes, as many thought that astrocytes were barely by-standers of the CNS. Accounting for a large fraction of the brain volume, their particular shape and tissue distribution are known to elaborate an extensive network of fine interconnected processes. Their star-shaped morphology projecting long branched processes provides a large coverage of CNS structures and the ensheathment of the brain or spinal cord in the pia matter. They draw the whole brain microanatomy by secreting astrocyte-derived extracellular matrix proteins (e.g., chondroitin sulfate proteoglycans, hyaluronan, tenascin proteins family, thrombospondin), thereby providing structural support for nervous system cells. Beside their structural role, astrocytes are recognized to fulfill and support many, if not all, functions of the healthy CNS [1] . Astrocyte endfeet cover more than 90% of the CNS vasculature and come in contact with endothelial cells. Expressing key glucose transporter-1, astrocytes convoy glucose from blood vessels to nervous system cells, most of them being devoid of direct access to this high-end source of energy. Hence, astrocytes synthetize via specific metabolic pathways glycogen and lactate, main energy fuels for neurons or distant synapses. Through humoral factors released at the perivascular space, astrocytes control local cerebral blood flow and bloodbrain barrier (BBB) integrity. Transforming growth factor-beta, glial-derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF2) and angiopoietin 1 (binding the endothelium-specific receptor TIE2), all secreted at the vascular end-feet, act on endothelial cells in order to induce or maintain an operational BBB [2,3] . Astrocytes-released growth factors [e.g., brainderived neurotrophic factor, BDNF; ciliary neurotrophic factor (CNTF)] exert beneficial effects far beyond the perivascular spa...

Heterogeneous astrocytes: Active players in CNS

“…Given the astrocyte-mediated essential functions in the CNS, astroglial transplantation maybe represent a promising approach to enhance CNS repair through alleviating astroglial dysfunction, delivering neurotrophic factors and inducing endogenous repair abilities (Nicaise et al 2015). The cells used for astroglial transplantation include primary astrocytes and neural stem cells (NSCs), bone marrow stromal cells (BMSCs) or ependymal cells-derived astrocytes (Cao et al 2005;Kitada et al 2001;Talaveron et al 2014;Wunderlich et al 1994;Zhang et al 2014).…”

Affected astrocytes in the spinal cord of the leukodystrophy vanishing white matter

“…Remarkably, most transplantation studies have so far focused on the brain, while many leukodystrophies also show spinal cord involvement, such as Alexander disease (Liu et al, 2016; van der Knaap et al, 2006), PMD (Koeppen & Robitaille, 2002), MLD (Toldo, Carollo, Battistella, & Laverda, 2005) and Krabbe disease (Wang, Melberg, Weis, Mansson, & Raininko, 2007). In rodent models of spinal cord injury, glial transplantations in the spinal cord resulted in decreased pathology and functional recovery (Haidet‐Phillips et al, 2014; Li et al, 2015; Nicaise, Mitrecic, Falnikar, & Lepore, 2015). Also a clinical trial, where patients with spinal cord injury were transplanted with human neural stem cells, showed moderate clinical improvements (Shin et al, 2015).…”

The effect of fetal rat brain extract on morphology of bone marrow-derived mesenchymal stem cells

“…Amelioration of nervous system diseases like Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis had been shown by the formation of neuron-like cells from BM-MSCs (Tanna and Sachan 2014). Transplantation of BMMSCs into the mouse brain ventricles resulted in the migration of these cells to the forebrain and cerebellum and also differentiation into the astrocytes and neurons (Nicaise et al 2015). After MSC injection into a blood vessel, neurons with MSC origin formed in the central nervous system (Donaghue et al 2014).…”