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Mesenchymal Stem Cell Treatment Perspectives in Peripheral Nerve Regeneration: Systematic Review

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Mesenchymal Stem Cell Treatment Perspectives in Peripheral Nerve Regeneration: Systematic Review International Journal of Molecular Sciences Review Mesenchymal Stem Cell Treatment Perspectives in Peripheral Nerve Regeneration: Systematic Review Andrea Lavorato 1,* , Stefania Raimondo 2, Marina Boido 3, Luisa Muratori 2 , Giorgia Durante 4, Fabio Cofano 1 , Francesca Vincitorio 1 , Salvatore Petrone 1 , Paolo Titolo 5, Fulvio Tartara 6, Alessandro Vercelli 3 and Diego Garbossa 1 1 Neurosurgery Unit, Department of Neuroscience “Rita Levi Montalcini”, University of Turin, 10126 Turin, TO, Italy; [email protected] (F.C.); [email protected] (F.V.); [email protected] (S.P.); [email protected] (D.G.) 2 Department of Clinical and Biological Sciences, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano, TO, Italy; [email protected] (S.R.); [email protected] (L.M.) 3 Department of Neuroscience “Rita Levi Montalcini”, Neuroscience Institute Cavalieri Ottolenghi, University of Turin, 10043 Orbassano, TO, Italy; [email protected] (M.B.); [email protected] (A.V.) 4 Faculty of Medicine and Surgery, University of Turin, 10126 Turin, TO, Italy; [email protected] 5 Traumatology–Reconstructive Microsurgery, Department of Orthopaedics and Traumatology, CTO Hospital, 10126 Turin, TO, Italy; [email protected] 6 Neurosurgery Unit, Istituto Clinico Città Studi (ICCS), 20131 Milan, MI, Italy; [email protected] * Correspondence: [email protected] Abstract: Traumatic peripheral nerve lesions affect hundreds of thousands of patients every year; their consequences are life-altering and often devastating and cause alterations in movement and sensitivity. Spontaneous peripheral nerve recovery is often inadequate. In this context, nowadays, cell Citation: Lavorato, A.; Raimondo, S.; therapy represents one of the most innovative approaches in the field of nerve repair therapies. The Boido, M.; Muratori, L.; Durante, G.; Cofano, F.; Vincitorio, F.; Petrone, S.; purpose of this systematic review is to discuss the features of different types of mesenchymal stem Titolo, P.; Tartara, F.; et al. cells (MSCs) relevant for peripheral nerve regeneration after nerve injury. The published literature Mesenchymal Stem Cell Treatment was reviewed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Perspectives in Peripheral Nerve (PRISMA) guidelines. A combination of the keywords “nerve regeneration”, “stem cells”, “peripheral Regeneration: Systematic Review. Int. nerve injury”, “rat”, and “human” were used. Additionally, a “MeSH” research was performed J. Mol. Sci. 2021, 22, 572. in PubMed using the terms “stem cells” and “nerve regeneration”. The characteristics of the most https://doi.org/10.3390/ widely used MSCs, their paracrine potential, targeted stimulation, and differentiation potentials into ijms22020572 Schwann-like and neuronal-like cells are described in this paper. Considering their ability to support and stimulate axonal growth, their remarkable paracrine activity, their presumed differentiation Received: 15 December 2020 potential, their extremely low immunogenicity, and their high survival rate after transplantation, Accepted: 6 January 2021 ADSCs appear to be the most suitable and promising MSCs for the recovery of peripheral nerve Published: 8 January 2021 lesion. Clinical considerations are finally reported. Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional clai- Keywords: mesenchymal stem cells; nerve lesions; peripheral nerve regeneration; regenerative medicine ms in published maps and institutio- nal affiliations. 1. Introduction Traumatic nerve lesions affect several hundred thousand patients every year in Europe Copyright: © 2021 by the authors. Li- and the USA [1]. Common causes of the most severe cases include motor vehicle, domestic, censee MDPI, Basel, Switzerland. work, and sport accidents [2]. The consequences of peripheral nerve injuries (PNIs) are This article is an open access article distributed under the terms and con- notoriously life-altering and often devastating, resulting in various degrees of sensorimotor ditions of the Creative Commons At- impairment of the affected limb [3,4]. Nonetheless, nerve repair may occur to a certain tribution (CC BY) license (https:// extent. In the attempt to predict the outcome of peripheral nerve repair, many factors must creativecommons.org/licenses/by/ be considered, including type, location, and extent of nerve injury; timing of surgery; type 4.0/). of repair; proper alignment of fascicles; surgical technique; and patient comorbidities [5]. Int. J. Mol. Sci. 2021, 22, 572. https://doi.org/10.3390/ijms22020572 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 22 sensorimotor impairment of the affected limb [3,4]. Nonetheless, nerve repair may occur to a certain extent. In the attempt to predict the outcome of peripheral nerve repair, many Int. J. Mol. Sci. 2021, 22, 572 factors must be considered, including type, location, and extent of nerve injury; timing2 of of 21 surgery; type of repair; proper alignment of fascicles; surgical technique; and patient comorbidities [5]. Spontaneous peripheral nerve recovery is often inadequate and strictly depends on the injurySpontaneous type and peripheralextension [2]: nerve for high-ene recoveryrgy is often traumatic inadequate injuries, and recovery strictly is depends negatively on affectedthe injury by typethe severity and extension and nerve [2]: fordiscontinuit high-energyy [6]. traumatic The functional injuries, outcome recovery can is be negatively limited affected by the severity and nerve discontinuity [6]. The functional outcome can be limited by inflammation, scar formation, and misdirection of regenerating sensory and motor ax- by inflammation, scar formation, and misdirection of regenerating sensory and motor ons [7]. For nerve injuries with a gap, nerve autograft treatment could present many dis- axons [7]. For nerve injuries with a gap, nerve autograft treatment could present many advantages such as biological complexity, donor site morbidity, limited length of graft disadvantages such as biological complexity, donor site morbidity, limited length of graft tissue availability, and the requirement of multiple surgeries [8]. For these reasons, the tissue availability, and the requirement of multiple surgeries [8]. For these reasons, the currently approved therapies are not fully satisfactory [3]. currently approved therapies are not fully satisfactory [3]. The morbidity and devastating physical and psychological effects on patients encour- The morbidity and devastating physical and psychological effects on patients en- age researchers to provide alternative and potentially more efficacious treatment/inter- courage researchers to provide alternative and potentially more efficacious treatment/ vention modalities. intervention modalities. In this context, cell therapy represents one of the most innovative therapeutic ap- In this context, cell therapy represents one of the most innovative therapeutic ap- proaches in the field of nerve repair [7,9]. In particular, the use of mesenchymal stem cells proaches in the field of nerve repair [7,9]. In particular, the use of mesenchymal stem cells (MSCs)(MSCs) is is of great interestinterest inin regenerative regenerative medicine medicine since since they they can can support support damaged damaged tissues tis- suesby targeting by targeting differentiating differentiating processes processes that th influenceat influence several several changes changes in cellin cell morphology, morphol- ogy,metabolic metabolic activity, activity, secretion secretion of growth of growth factors, factors, and signaland signal responsiveness responsiveness [7]. [7] TheThe cellular cellular mechanisms mechanisms by by which which MSCs MSCs exer exertt their their biological biological effects effects (Figure (Figure 11)) areare notnot completely completely understood, understood, and and their their clinical clinical applications applications in in peripheral peripheral nerve nerve repair repair are are stillstill in in development. development. For For this this reason, reason, MSCs MSCs have have been been widely widely considered considered for for inin vitro vitro andand inin vivo vivo studies studies to to test test their their efficacy efficacy in in supporting supporting nerve nerve regrowth regrowth [10]. [10]. FigureFigure 1. 1. (A(A) Peripheral) Peripheral nerve nerve injury injury triggers triggers a casca a cascadede of cellular/molecular of cellular/molecular events, events, including including axonalaxonal damage, damage, myelin myelin disruption, disruption, early early inflamma inflammatorytory reactions, reactions, immune immune system system activation, activation, and and microcirculationmicrocirculation modifications. modifications. (B) ( BMesenchymal) Mesenchymal stem stem cells cells (MSC (MSCs),s), exerting exerting their prominent their prominent paracrineparacrine role role by by exosome/microvesicle exosome/microvesicle secretion, secretion, can can effectively effectively counteract counteract these these events: events: indeed, indeed, MSCsMSCs are are able able to to modulate modulate neuroinflammation neuroinflammation and and immune immune cell cell reaction, reaction, to topromote promote new new blood blood vessel formation (angiogenesis), to form ECM components, and to sustain axonal regrowth and vessel formation (angiogenesis), to form ECM components, and to sustain axonal regrowth and remyelination.
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