Therapeutic applications of mesenchymal stem cells for amyotrophic lateral sclerosis

Lewis and Suzuki Stem Cell Research & Therapy 2014, 5:32 http://stemcellres.com/content/5/2/32 REVIEW Therapeutic applications of mesenchymal stem cells for amyotrophic lateral sclerosis Christina M Lewis1 and Masatoshi Suzuki2* Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the neuromuscular system and does not have a known singular cause. Genetic mutations, extracellular factors, non-neuronal support cells, and the immune system have all been shown to play varied roles in clinical and pathological disease progression. The therapeutic plasticity of mesenchymal stem cells (MSCs) may be well matched to this complex disease pathology, making MSCs strong candidates for cellular therapy in ALS. In this review, we summarize a variety of explored mechanisms by which MSCs play a role in ALS progression, including neuronal and non-neuronal cell replacement, trophic factor delivery, and modulation of the immune system. Currently relevant techniques for applying MSC therapy in ALS are discussed, focusing in particular on delivery route and cell source. We include examples from in vitro, preclinical, and clinical investigations to elucidate the remaining progress that must be made to understand and apply MSCs as a treatment for ALS. Introduction Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs). The mechanisms of cell death and functional deficits, and consequently the potential treatment approaches, are complex and varied. Cell therapy approaches complement this complexity well in their ability to respond to the host environment with multiple mechanisms of repair. Recently, new potentials of stem cells have been highlighted for the treatment of many human diseases. While various types of stem cells are available from different tissues, mesenchymal stem cells (MSCs) * Correspondence: 2 Department of Comparative Biosciences, The Stem Cell and Regenerative Medicine Center, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706, USA Full list of author information is available at the end of the article have been broadly applied as treatment to many disease types, including neurodegenerative diseases. In this review, we discuss the investigation of stem cell therapy using MSCs as a potential treatment for ALS. We describe the strengths of MSCs for cell therapy, the potential mechanisms of MSC actions in treating ALS, the design of MSC treatment and delivery, and the recent translation of this therapy from preclinical models into early-phase clinical trials. Amyotrophic lateral sclerosis Neurodegenerative diseases are characterized by the progressive degeneration of selective neural populations with subsequent functional loss. ALS, also known as Lou Gehrig’s disease, is a fatal neurodegenerative disease caused by the selective loss of MNs in the spinal cord and brain stem. MN degeneration and neuromuscular junction (NMJ) denervation rapidly result in decreased motor function. In humans, death typically results 3 to 5 years after diagnosis because of respiratory failure after loss of diaphragm control. About 90% of ALS cases occur sporadically; the remaining 10% are familial (fALS). Approximately 70% to 80% of fALS cases have mutations of the Cn2+/Zn2+ superoxide dismutase 1 (SOD1), TDP43, FUS, or C90ORF72 genes [1]. Rat and mouse models overexpressing mutated human SOD1 gene have been developed and follow patterns of pathology and disease progression similar to those observed in humans. These models are the basis for most in vivo preclinical research probing the causes of and potential treatments for ALS. Although a disease cause of sporadic ALS has not been specified, this disease is generally regarded as resulting from factors involving environment, lifestyle, aging, and genetic predisposition [2]. Several proposed pathological mechanisms of disease include protein misfolding and aggregation, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, glial cell activation and related inflammatory processes, and axonal transport defects [3]. Currently, the only available treatment approved by US Food and Drug Administration is riluzole, which has been © 2014 Lewis and Suzuki; licensee BioMed Central Ltd. The licensee has exclusive rights to distribute this article, in any medium, for 12 months following its publication. After this time, the article is available under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lewis and Suzuki Stem Cell Research & Therapy 2014, 5:32 http://stemcellres.com/content/5/2/32 shown to increase median survival in patients by about 3 months [4]. A treatment for ALS that more significantly slows disease progression and improves quality of life would drastically alter the prognosis for patients with this disease. Owing largely to the modest effects and partly to minor concerns regarding side effects on the neuromuscular system [5], development of new and effective therapies has high priority and a variety of alternates are in various stages of development and clinical trial. These therapies include anti-glutamatergic, anti-oxidant, mitochondrial, and anti-inflammatory agents [2]. Gene therapy has been also explored for the delivery of supportive trophic factors. Recently, stem cell therapy has been of great interest for ALS treatment, particularly because of the potential for multiple mechanisms of action. Stem cell therapy Cell therapy is a promising candidate for ALS treatment, largely because of the selective MN death and the variety of proposed mechanisms of degeneration that characterize the disease. The primary aim of stem cell therapy in neurodegenerative diseases is cell replacement, neuroprotection, or a combination of the two. Direct cell replacement may be challenging because of the anatomical and functional complexity of the central nervous system (CNS), whereas neuroprotection may be a more feasible short-term goal [6]. Multiple stem and progenitor cell types could have the potential to either directly replace MNs and diseased glia or provide support to slow degeneration. These cells include pluripotent cells such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. ES and iPS cells are attractive in their potential for replacement of multiple cell types. Also, the establishment of a method for inducing pluripotency from adult cells reduces ethical issues surrounding the use of ES cells [7]. However, doubts remain about the functional potency of iPS cells, and these cells carry the risk of teratoma formation [8]. Tissue-specific progenitors, which are categorized as adult stem cells, are also candidates for cell therapy in neurodegenerative disease. These progenitor cells inc (...truncated)