Neural stem cells LewisX + CXCR4 + modify disease progression in an amyotrophic lateral sclerosis model

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by the degeneration of the motor neurons. We tested whether treatment of superoxide dismutase (SOD1)-G93A transgenic mouse, a model of ALS, with a neural stem cell subpopulation double positive for Lewis X and the chemokine receptor CXCR4 (LeX+CXCR4+) can modify the disease's progression. In vitro, after exposure to morphogenetic stimuli, LeX+CXCR4+ cells generate cholinergic motor neuron-like cells upon differentiation. LeX+CXCR4+ cells deriving from mice expressing Green Fluorescent Protein in all tissues or only in motor neurons, after a period of priming in vitro, were grafted into spinal cord of SOD1-G93A mice. Transplanted transgenic mice exhibited a delayed disease onset and progression, and survived significantly longer than non-treated animals by 23 days. Examination of the spinal cord revealed integration of donor-derived cells that differentiated mostly in neurons and in a lower proportion in motor neuron-like cells. Quantification of motor neurons of the spinal cord suggests a significant neuroprotection by LeX+CXCR4+ cells. Both VEGF- and IGF1-dependent pathways were significantly modulated in transplanted animals compared to controls, suggesting a role of these neurotrophins in MN protection. Our results support the therapeutic potential of neural stem cell fractions through both neurogenesis and growth factors release in motor neuron disorders.

Intrathecal transplantation of human neural stem cells overexpressing VEGF provide behavioral improvement, disease onset delay and survival extension in transgenic ALS mice

“…12 Transplantation of NSCs isolated from the adult mouse brain in ALS mouse spinal cord was also effective in delaying disease progression. 13 These cell transplantation studies have shown functional improvement in animal models of ALS; however, it is unlikely that the observed effects are results of replacement of lost neurons and establishment of neural circuitry by the grafted cells. Although it is unrealistic to expect the transplantation of stem cells or stem cellderived motoneurons in ALS patients to replace lost neurons, to integrate into existing neural circuitry and restore motor function, provision of neurotrophic factors by transplanted stem cells to prevent cell death in host motoneurons is a realistic and achievable approach.…”

“…31 In fact, the VEGF levels in cerebrospinal fluid tended to be lower in ALS patients than in the normal population. [32][33][34] Considering the evidence of clinical improvement in ALS animal models after transplantation of stem cells [10][11][12][13] and VEGF treatment, [16][17][18][19]29,30 we wished to investigate whether the human NSCs overexpressing VEGF, by pairing clonal human NSCs with VEGF gene, can lead to the clinical improvement in SOD1G93A mouse model of ALS.…”

Stem Cell Therapy for Amyotrophic Lateral Sclerosis

“…Stem cell therapies may modify disease pathophysiology [11], slow down or halt the progression of disease, and even improve neuromuscular function and motor unit pathology, possibly by providing protective factors to surrounding cells, modulating the host immune environment, inhibiting inflammation, or even replacing injured cells [12][13][14][15][16][17]. For patients carrying genetic mutations related to ALS, genetic corrected stem cells could be generated to correct the mutation, and for those carrying no genetic mutation, the protective and replacing effect of allogeneic stem cells are available.…”

“…When locally or systemically transplanted, stem cells are capable of migrating to disease-associated loci to exert the desired therapeutic effect [10]. Currently available cell therapies may take advantage of a variety of stem cells to modify disease pathophysiology [11], slow down or even halt the progression of disease, possibly by providing protective factors to surrounding cells, modulating the host immune environment, inhibiting inflammation, or even replacing injured cells [12][13][14][15][16][17]. Several types of stem cells have been studied as possibilities for treating ALS, including neural stem cells (NSCs), mesenchymal stem cells (MSCs), glial-restricted progenitor cells (GRPs), embryonic stem cells (ESCs), and induced pluripotent stem cells (IPSCs) [18].…”

Recent Advances and the Future of Stem Cell Therapies in Amyotrophic Lateral Sclerosis

“…In one study, mouse-derived NPCs selected for those expressing the Lewis X surface marker and the chemokine receptor CXCR4 supported native MNs via VEGF and insulin-like growth factor-I (IGF-I)-mediated neuroprotective pathways [46]. Subsequent use of human NPCs modified to overexpress VEGF also favored antiapoptotic pathways over proapoptotic pathways in native ALDH aldehyde dehydrogenase, BBB Basso-Beatti-Bresnahan scale, BDNF brain derived neurotrophic factor, BM bone marrow, CMAP compound muscle action potential, ES embryonic stem cell, FGF fibroblast growth factor, GDNF glial cell-line derived neurotrophic factor, GFP green fluorescent protein, GLT1 glutamate transporter 1, IGF-1 insulin-like growth factor 1, iPSC induced pluripotent stem cell, L1CAM L1 cell adhesion molecule, MN motor neuron, MSC mesenchymal stem cells, NPC neural progenitor cell, NT-3 neurotrophin 3, OEC olfactory ensheathing cell, SSC side scatter, TGF transforming growth factor, UCB umbilical cord blood cells, VEGF vascular endothelial growth factor, VLA4 very late antigen 4 (integrin alpha 4 beta 1) SOD1 superoxide dismutase; n/a not applicable; CNS central nervous system; i.t intrathecal; i.v.…”