International Journal of Molecular Sciences Review Role of Mesenchymal Stem Cells in Counteracting Oxidative Stress—Related Neurodegeneration Cristina Angeloni 1 , Martina Gatti 2, Cecilia Prata 3,* , Silvana Hrelia 4 and Tullia Maraldi 2 1 School of Pharmacy, University of Camerino, Via Gentile III da Varano, 62032 Camerino, Italy; [email protected] 2 Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy; [email protected] (M.G.); [email protected] (T.M.) 3 Department of Pharmacy and Biotechnology, Alma Mater Studiorum—University of Bologna, Via Irnerio 48, 40126 Bologna, Italy 4 Department for Life Quality Studies, Alma Mater Studiorum—University of Bologna, Corso d’Augusto 237, 47921 Rimini, Italy; [email protected] * Correspondence: [email protected] Received: 7 April 2020; Accepted: 4 May 2020; Published: 7 May 2020 Abstract: Neurodegenerative diseases include a variety of pathologies such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and so forth, which share many common characteristics such as oxidative stress, glycation, abnormal protein deposition, inflammation, and progressive neuronal loss. The last century has witnessed significant research to identify mechanisms and risk factors contributing to the complex etiopathogenesis of neurodegenerative diseases, such as genetic, vascular/metabolic, and lifestyle-related factors, which often co-occur and interact with each other. Apart from several environmental or genetic factors, in recent years, much evidence hints that impairment in redox homeostasis is a common mechanism in different neurological diseases. However, from a pharmacological perspective, oxidative stress is a difficult target, and antioxidants, the only strategy used so far, have been ineffective or even provoked side effects. In this review, we report an analysis of the recent literature on the role of oxidative stress in Alzheimer’s and Parkinson’s diseases as well as in amyotrophic lateral sclerosis, retinal ganglion cells, and ataxia. Moreover, the contribution of stem cells has been widely explored, looking at their potential in neuronal differentiation and reporting findings on their application in fighting oxidative stress in different neurodegenerative diseases. In particular, the exposure to mesenchymal stem cells or their secretome can be considered as a promising therapeutic strategy to enhance antioxidant capacity and neurotrophin expression while inhibiting pro-inflammatory cytokine secretion, which are common aspects of neurodegenerative pathologies. Further studies are needed to identify a tailored approach for each neurodegenerative disease in order to design more effective stem cell therapeutic strategies to prevent a broad range of neurodegenerative disorders. Keywords: mesenchymal stem cells; oxidative stress; neurodegeneration; secretome 1. Oxidative Stress and Neurodegenerative Diseases Neurodegenerative diseases are a heterogeneous class of disorders characterized by a slow and chronic loss of different neuronal populations in the central nervous system (CNS). Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and spinocerebellar ataxia (SCA) are the most common neurodegenerative diseases [1]. They are a primary public health problem, affecting tens of millions of people worldwide [2]. Although their complex and Int. J. Mol. Sci. 2020, 21, 3299; doi:10.3390/ijms21093299 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 29 their complex and multifactorial etiology has not been fully elucidated, increasing evidence suggests a causative role of oxidative stress in the onset and development of these disorders [3–6]. Oxidative stress, produced by an imbalance between reactive oxygen species (ROS) and the endogenous antioxidant defense system [7], plays a key role in neurodegeneration as the brain is characterized by an elevated oxygen consumption, high levels of iron and copper, involved in ROS production, elevated content of polyunsaturated fatty acids, and low antioxidant defenses [1,8]. A schematic representation of causes and consequences of oxidative stress is shown in Figure 1. ROS Int.can J. be Mol. produced Sci. 2020, 21 by, 3299 the Fenton and Haber–Weiss reactions, in which redox-active metals interact2 of 28 with oxygen species, or by the reactions catalyzed by NADPH oxidases or nitric oxide synthase (NOS). The most investigated ROS are hydrogen peroxide (H2O2), superoxide (O2•−), and hydroxyl multifactorialradical (•OH). etiology ROS are has principally not been generated fully elucidated, in the mitochondria, increasing evidence as they suggests are the largest a causative intracellular role of oxidativeoxygen consumer stress in theduring onset electron and development transfer in of mi thesetochondrial disorders respiratory [3–6]. chain by the interaction betweenOxidative the leaking stress, electrons produced and by molecular an imbalance oxygen between [9]. Oxidative reactiveoxygen stress can species also (ROS)be induced andthe by endogenousreactive nitrogen antioxidant species defense(RNS) [10]. system RNS [are7], playsproduced a key by role the infast neurodegeneration reaction of O2•− with as thenitric brain oxide is characterized(NO), resulting by in an the elevated generation oxygen of peroxynitrite consumption, (ONOO high levels−) thatof can iron trigger and copper,DNA fragmentation involved in ROS and production,lipid peroxidation elevated [11,12]. content Three of polyunsaturateddifferent isoforms fatty of NOSs, acids, namely and low endothelial antioxidant (eNOS), defenses neuronal [1,8]. A(nNOS), schematic and representation inducible (iNOS), of causes generate and NO. consequences It has also ofbeen oxidative observed stress that is NO shown inhibits in Figure complexes1. ROS I canand beIV produced of the mitochondrial by the Fenton electron and Haber–Weiss transport chain, reactions, inducing in which ROS redox-activegeneration [4]. metals interact with oxygenCells species, respond or byto theoxidative reactions stress catalyzed by inducing by NADPH antioxidant oxidases enzymes or nitric that oxide can synthaseneutralize (NOS). ROS Thecounteracting most investigated cell damage ROS are[13,14]. hydrogen In particular, peroxide nuclear (H2O2), factor superoxide erythroid (O2•− 2-related), and hydroxyl factor 2 radical(Nrf2) ( OH). ROS are principally generated in the mitochondria, as they are the largest intracellular oxygen enhances• the expression of these antioxidant enzymes thanks to its binding to a specific sequence in consumerthe promoter during region electron of these transfer genes in called mitochondrial antioxidant respiratory response chainelement by ( theARE interaction) [15,16]. In between normal thephysiological leaking electrons condition, and Nrf2 molecular is sequestered oxygen in [9 the]. Oxidativecytoplasm stressby Kelch-Like can also ECH-Associated be induced by reactive Protein nitrogen1 (Keap1) species that promotes (RNS) [10 ubiquitination]. RNS are produced and degrad by theation fast of reaction Nrf2 in ofthe O 2proteasome.•− with nitric Nevertheless, oxide (NO), resultingwhen ROS in theor electrophiles generation of modify peroxynitrite the nucleophilic (ONOO−) cysteine that can triggersulfhydryl DNA groups fragmentation on Keap1, and Nrf2 lipid is peroxidationreleased and [it11 moves,12]. Three to the di ffnucleuserent isoforms [17]. Furtherm of NOSs,ore, namely Nrf2 also endothelial exerts anti-inflammatory (eNOS), neuronal (nNOS),activity andand induciblemodulates (iNOS), both generatebiogenesis NO. and It has mitochondrial also been observed function that [18–20]. NO inhibits On complexesthese bases, I and Nrf2 IV ofis theconsidered mitochondrial an interesting electron therapeutic transport chain, target inducing in counteracting ROS generation neurodegeneration [4]. [21,22]. FigureFigure 1.1. Schematic representation of oxidativeoxidative stressstress sourcessources andand eeffects.ffects. Image createdcreated withwith BioRender.com.BioRender.com. Cells respond to oxidative stress by inducing antioxidant enzymes that can neutralize ROS counteracting cell damage [13,14]. In particular, nuclear factor erythroid 2-related factor 2 (Nrf2) enhances the expression of these antioxidant enzymes thanks to its binding to a specific sequence in the promoter region of these genes called antioxidant response element (ARE)[15,16]. In normal physiological condition, Nrf2 is sequestered in the cytoplasm by Kelch-Like ECH-Associated Protein 1 (Keap1) that promotes ubiquitination and degradation of Nrf2 in the proteasome. Nevertheless, when ROS or electrophiles modify the nucleophilic cysteine sulfhydryl groups on Keap1, Nrf2 is released and it moves to the nucleus [17]. Furthermore, Nrf2 also exerts anti-inflammatory activity and modulates Int. J. Mol. Sci. 2020, 21, 3299 3 of 28 both biogenesis and mitochondrial function [18–20]. On these bases, Nrf2 is considered an interesting therapeutic target in counteracting neurodegeneration [21,22]. In the following paragraphs, we describe the impact of oxidative stress in different neurodegenerative diseases. 1.1. Alzheimer’s Disease Alzheimer’s disease (AD) is the main cause of dementia and affects about 5.7 million Americans and over 30 million people worldwide [23]. It is characterized by the degeneration and irreversible loss of neurons and