Autism and autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders. They are enigmatic conditions that have their origins in the interaction of genes and environmental factors. ASDs are characterized by dysfunctions in social interaction and communication skills, in addition to repetitive and stereotypic verbal and nonverbal behaviours. Immune dysfunction has been confirmed with autistic children. There are no defined mechanisms of pathogenesis or curative therapy presently available. Indeed, ASDs are still untreatable. Available treatments for autism can be divided into behavioural, nutritional, and medical approaches, although no defined standard approach exists. Nowadays, stem cell therapy represents the great promise for the future of molecular medicine. Among the stem cell population, mesenchymal stem cells (MSCs) show probably best potential good results in medical research. Due to the particular immune and neural dysregulation observed in ASDs, mesenchymal stem cell transplantation could offer a unique tool to provide better resolution for this disease.
1. Autism Spectrum Disorders
Autism and autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders [1]. They are enigmatic conditions that have their origins in the interaction of genes and environmental factors. ASDs are characterized by dysfunctions in social interaction and communication skills, in addition to repetitive and stereotypic verbal and nonverbal behaviours [2, 3]. Several biochemical events are associated with ASDs: oxidative stress; endoplasmic reticulum stress; decreased methylation capacity; limited production of glutathione; mitochondrial dysfunction; intestinal dysbiosis; increased toxic metal burden; immune dysregulation; immune activation of neuroglial cells [4]. The exact aetiology of ASDs is unknown, likely it results from a complex combination of genetic, environmental, and immunological factors [5, 6]. This heritable disorder derives from genetic variations in multiple genes [7], making its treatment particularly difficult. Environment (i.e., air pollution, organophosphates, and heavy metals) also contributes to the incidence of ASDs [8].
Frequency of these disorders is increasing: 56% reported increase in paediatric prevalence between 1991 and 1997 [9] until present rates of about 60 cases per 10,000 children, according to Center for Disease Control [10, 11]. ASDs are increasingly being recognized as a public health problem [12]. Pathophysiology and defined mechanisms of pathogenesis of autism remain still unclear. There are no drugs effective for treatment of core symptoms of ASDs [10]. Indeed, ASDs are still untreatable. Current available treatments for autism can be divided into behavioural, nutritional, and pharmacological options, in addition to individual and family psychotherapy and other nonpharmacologic interventions [13]. However, no defined standard approach exists [14]. Pharmacological approaches are direct towards neuropsychiatric disorders coassociated with ASDs. Psycho-stimulants, alpha-2 agonists, beta blockers, lithium, anticonvulsant mood stabilizers, atypical antipsychotics, traditional antipsychotics, selective serotonin reuptake inhibitors, antidepressants, and antipsychotics, are drugs commonly prescribed [14–16]. Catatonia is treated with lorazepam and bilateral electroconvulsive therapy [17]. Selective serotonin reuptake inhibitors are prescribed for the treatment of depression, anxiety, and obsessive-compulsive ASD-associated behaviours [2].
Other nonpsychotropic drugs which are supported by at least 1 or 2 prospective randomized controlled trials or 1 systematic review include melatonin, acetylcholinesterase inhibitors, naltrexone, carnitine, tetrahydrobiopterin, vitamin C, hyperbaric oxygen treatment, immunomodulation and anti-inflammatory treatments, oxytocin, and even music therapy and vision therapy [18].
Alternative and complementary treatments, not sufficiently supported by medical literature, include herbal remedies, vitamin and mineral therapies, piracetam, elimination diets, chelation, cyproheptadine, famotidine, glutamate antagonists, special dietary supplements, acupuncture, neurofeedback, and sensory integration training [14, 19, 20]. On the other hand, behavioural treatment could represent the effective intervention strategy for autism [21–23]. A plethora of behavioural strategies and social skill trainings have been used [24–26]. However, it has been demonstrated that no definitive behavioural intervention completely improves all symptoms for all ASD patients [27, 28].
Summarizing, all these therapies indicate that further research is needed to better address treatment of several medical conditions experienced by ASD patients [29].
2. Mesenchymal Stem Cells
Nowadays, stem cell therapy represents the great promise for the future of molecular medicine. The progression of several diseases can be slowed or even blocked by stem cell transplantation [30].
Among the stem cell population, mesenchymal stem cells (MSCs) show probably best potential good results in medical research [31–33]. These cells are nonhematopoietic stem cells having a multilineage potential, as they have the capacity of differentiating into both mesenchymal and nonmesenchymal lineages. MSCs are a population of progenitor cells of mesodermal origin found principally in the bone marrow of adults, giving rise to skeletal muscle cells, blood, fat, vascular, and urogenital systems, and to connective tissues throughout the body [34–36]. According to the International Society of Cellular Therapy, MSCs are defined by the following minimal set of criteria: (1) grown in adherence to plastic surface of dishes when maintained in standard culture conditions; (2) express cytospecific cell surface markers, that is, CD105, CD90, and CD73, to be negative for other cell surface markers, that is, CD45, CD34, CD14, and CD11b; (3) possess the capacity to differentiate into mesenchymal lineages, under appropriate in vitro conditions [37]. MSCs can be isolated from different tissues other than bone marrow: adipose tissue, liver, tendons, synovial membrane, amniotic fluid, placenta, umbilical cord, and teeth. MSCs show a high expansion potential, genetic stability, stable phenotype, high proliferation rate as adherent cells, and self-renew capacity and can be easily collected and shipped from the laboratory to the bedside and are compatible with different delivery methods and formulations [38, 39]. In addition, MSCs have two other extraordinary properties: they are able to migrate to sites of tissue injury, where they are able to inhibit the release of proinflammatory cytokines and have strong immunosuppressive activity that renders them a useful tool for successful autologous, as well as heterologous, transplantations without requiring pharmacological immunosuppression [40–43]. Besides, MSCs are easily isolated from a small aspirate of bone marrow and expanded with high efficiency [44]. Given that MSCs are multipotent cells with a number of potential therapeutic applications, and they represent a future powerful tool in regenerative medicine, including ASDs. Mesenchymal stem cells could be transplanted directly without genetic modification or pretreatments. They simply eventually differentiate according to cues from the surrounding tissues and do not give uncontrollable growth or tumours. In clinical application, there is no problem with immune rejection because of their in vivo immunosuppressive properties [45, 46]. In addition, MSCs can readily be isolated from the patients requiring transplant or from their parents. There is also no tumour formation on transplantation [47]. No moral objection or ethical controversies are involved [48].
In principle, mesenchymal stem cells can act through several possible mechanisms, that is, stimulating the plastic response in the host damaged tissue, secreting survival-promoting growth factors, restoring synaptic transmitter release by providing local reinnervations, integrating into existing neural and synaptic network, and reestablishing functional afferent and efferent connections [49]. Since MSCs have the capability to produce a large array of trophic and growth factors both in vivo and in vitro. (MSCs constitutively secrete interleukins (IL)-6, IL-7, IL-8, IL-11, IL-12, IL-14, IL-15, macrophage colony-stimulating factor, Flt-3 ligand, and stem-cell factor [50]). A more reasonable explanation for the functional benefit derived from MSC transplantation is their paracrine activity, by which these cells are able to produce factors that activate endogenous restorative mechanisms within injured tissues contributing to recovery of function lost as a result of lesions [49, 51].
3. Autism, Personalized Therapy through Mesenchymal Stem Cells
MSCs have a strong long-lasting immunosuppressive capacity [52]. This extraordinary property is mediated via soluble factors. MSCs are able to inhibit the proliferation of CD8+ and CD4+ T lymphocytes and natural killer (NK) cells, to suppress the immunoglobulin production by plasma cells, to inhibit the maturation of dendritic cells (DCs) and the proliferation of regulatory T cells [53]. It has been demonstrated that MSCs are also able to inhibit T lymphocyte pro-inflammatory cytokine production in vitro [54, 55], as well as in vivo [56]. Their ability to modulate the immune system opens a wide range of cell-mediated applications, not only for autoimmune diseases and graft-versus-host disease. Due to the particular immune system dysregulation observed in ASDs [57, 58], mesenchymal stem cell transplantation could offer a unique tool to provide better resolution for this disease. Indeed, in ASDs pathogenesis, innate and adaptive immunity changes have been reported [59]. ASD patients show an imbalance in CD3+, CD4+, and CD8+ T cells, as well as in NK cells. In addition, peripheral blood mononuclear cells (PBMCs) extracted from ASD patients are able to overproduce IL-1β resulting in long-term immune alterations [60]. MSC-mediated immune suppressive activity could restore this immune imbalance (Figure 1). Indeed, MSC immunoregulatory effects strongly inhibit T-cell recognition and expansion by inhibiting TNF-α and INF-γ production and increasing IL-10 levels [51].
Paracrine and immunomodulatory effects as possible mechanisms of action of mesenchymal stem cells (MSCs) in autism spectrum disorder (ASD) treatment. In humans, ASDs are associated with immune alterations and pro-inflammatory cytokines (i.e., IL-1β) over-production. These cytokines are able to trigger pro-inflammatory cellular events. Data from in vitro models show that MSCs are able to affect not only T cells, but also other cells of the immune system (i.e., NK cells). Immunoregulatory properties of MSCs are through secretion of large amounts of several bioactive molecules (paracrine activity), that is, PGE-2, IL-10. These molecules cause the inhibition or the unresponsiveness of T-cell mediated responses.
It has been demonstrated that in postmortem brains from ASD patients there is evidence of abnormal functioning and cerebellum alterations [61–63]. Indeed, ASD subjects show a decreased number of Purkinje cells in the cerebellum [64]. These changes could reflect defective cortical organization in ASDs development. In addition, autism is associated with dysregulation in the maturation and plasticity of dendritic spine morphology [65]. Restoring injured brain functioning could be achieved by stem-cell-based cell replacement [66]. Indeed, transplanted MSCs are able to promote synaptic plasticity and functional recovery and rescue cerebellar Purkinje cells [67, 68]. Challenging newest study from Deng et al. suggests that granulocyte colony-stimulating factor (G-CSF) is able to mobilize MSCs into peripheral blood. These mobilized MSCs are incorporated and integrate into damaged brain in craniocerebral injured mice, ameliorating the effect of trauma [69]. It is noteworthy that MSC ability to migrate to the sites of injury and participate in the repair process is a key issue in tissue repair [70]. Also by this way, MSC therapy could restore the altered brain organization seen in autistic subjects (Table 1).
Potential ameliorative effects mediated by MSCs in ASD treatment.
ASD-induced changes in human brain
Potential MSC ameliorative roles seen in preclinical models
Abnormal functioning
Improving functional recovery
Cerebellum alterations
Integrating in altered brain and restoring damaged functions
Decreased number of Purkinje cells (PCs)
Restoring cerebellar PCs
Defective cortical organization
Reinforcing cortical plasticity
Altered plasticity of dendritic spine morphology
Promoting synaptic plasticity
A key dilemma in stem-cell-based therapy for autism treatment is whether endogenous or exogenous MSC administration is the best way of stem cell delivery. Endogenous strategy could be limited by the availability of MSCs. Exogenous MSCs could show low rate of engraftment to provide cellular replacement. It is unclear if differentiated cells are able to develop functional interconnections with the intrinsic cells of the recipient host [49]. Controversy, few exogenous MSCs are able to exert paracrine activity. Indeed, exogenously applied MSCs have been shown to home to injured tissues and repair them by producing chemokines, or by cell or nuclear fusion with host cells [71]. On the other hand, exogenous culture-expanded MSCs could address endogenous MSCs in order to activate them and guide intrinsic repair [72]. In addition, exogenous delivery bypasses surgical intervention on the autistic child.
Cellular therapy could represent a new frontier in the treatment of several diseases. Despite the fact that MSCs have been enrolled in several clinical trials, long-term safety of MSC-based therapies is not yet well established; this fact could be one major limitation to clinical translation [73]. At the present, there are no preclinical studies on the use of MSCs in ASD models. There is just one clinical trial (NCT01343511 http://www.clinicaltrial.gov/) concerning the safety and efficacy of human umbilical cord mesenchymal stem cells (hUC-MSCs) and human cord blood mononuclear cells (hCB-MNCs) transplantation in patients with autism by Shenzhen Beike Bio-Technology Co., China. Results are not yet posted.
However, personalized stem cell therapy will be the most effective treatment for a specific autistic child, opening a new era in autism management in the next future.
Acknowledgments
The authors gratefully thank Mr. Enzo Abate, Ms. Giovanna Gallone, and the nonprofit organizations “La Forza del Silenzio” and “Cancellautismo,” Italy for their useful assistance. The authors thank the Autism Research Institute, USA (ARI grant “Research that makes a difference” 2010) for financial support of this study.
FasanoA.LyndhurstN. J.Intestine, leaky gut, autism and probiotics2010Barnes & Noble192198WilliamsK.WheelerD. M.SiloveN.HazellP.Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD)201082-s2.0-77955951729CD004677ToroR.KonyukhM.DelormeR.LeblondC.ChasteP.FauchereauF.ColemanM.LeboyerM.GillbergC.BourgeronT.Key role for gene dosage and synaptic homeostasis in autism spectrum disorders20102683633722-s2.0-7795509305810.1016/j.tig.2010.05.007BradstreetJ. J.SmithS.BaralM.RossignolD. A.Biomarker-guided interventions of clinically relevant conditions associated with autism spectrum disorders and attention deficit hyperactivity disorder201015115322-s2.0-77952501114PersicoA. M.BourgeronT.Searching for ways out of the autism maze: genetic, epigenetic and environmental clues20062973493582-s2.0-3374631483210.1016/j.tins.2006.05.010ToroR.KonyukhM.DelormeR.LeblondC.ChasteP.FauchereauF.ColemanM.LeboyerM.GillbergC.BourgeronT.Key role for gene dosage and synaptic homeostasis in autism spectrum disorders20102683633722-s2.0-7795509305810.1016/j.tig.2010.05.007El-FishawyP.StateM. W.The genetics of autism: key issues, recent findings, and clinical implications2010331831052-s2.0-7704912017310.1016/j.psc.2009.12.002HerbertM. R.Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders20102321031102-s2.0-7794936854110.1097/WCO.0b013e328336a01fMuhleR.TrentacosteS. V.RapinI.The genetics of autism20041135e472e4862-s2.0-3442894480LevyS. E.MandellD. S.SchultzR. T.Autism20093749701162716382-s2.0-7044952143210.1016/S0140-6736(09)61376-3CDCSurveillance summaries200756128MainP. A.AngleyM. T.ThomasP.O'DohertyC. E.FenechM.Folate and methionine metabolism in autism: a systematic review2010916159816202-s2.0-7795303390410.3945/ajcn.2009.29002ReiersenA. M.ToddR. D.Co-occurrence of ADHD and autism spectrum disorders: phenomenology and treatment2008846576692-s2.0-4224909917210.1586/14737175.8.4.657McCrackenJ. T.Safety issues with drug therapies for autism spectrum disorders200566supplement 1032372-s2.0-31144434282TandonM.PruettJ. R.Jr.An overview of the use of antidepressants in children and adolescents2008105179852-s2.0-40949151959NevelsR. M.DehonE. E.AlexanderK.GontkovskyS. T.Psychopharmacology of aggression in children and adolescents with primary neuropsychiatric disorders: a review of current and potentially promising treatment options20101821842012-s2.0-7795287225910.1037/a0018059DhosscheD. M.ShahA.WingL.Blueprints for the assessment, treatment, and future study of catatonia in autism spectrum disorders2006722672842-s2.0-3364625092510.1016/S0074-7742(05)72016-XRossignolD. A.Novel and emerging treatments for autism spectrum disorders: a systematic review20092142132362-s2.0-75649107225ŞenelH. G.Parents' views and experiences about complementary and alternative medicine treatments for their children with autistic spectrum disorder20104044945032-s2.0-7795445859610.1007/s10803-009-0891-4WongV. C.SunJ. G.Randomized controlled trial of acupuncture versus sham acupuncture in autism spectrum disorder20101655455532-s2.0-7795257042010.1089/acm.2007.0768FilipekP. A.Steinberg-EpsteinR.BookT. M.Intervention for autistic spectrum disorders2006322072162-s2.0-3364613140610.1016/j.nurx.2006.01.014VismaraL. A.RogersS. J.Behavioral treatments in autism spectrum disorder: what do we know?201064474682-s2.0-7795290965510.1146/annurev.clinpsy.121208.131151KasariC.LawtonK.New directions in behavioral treatment of autism spectrum disorders20102321371432-s2.0-7794936092810.1097/WCO.0b013e32833775cdMurdockL. C.HobbsJ. Q.Picture me playing: increasing pretend play dialogue of children with autism spectrum disorders2011418708782-s2.0-7795687382410.1007/s10803-010-1108-6FrankelF.WhithamC.Parent-assisted group treatment for friendship problems of children with autism spectrum disorders201113802402452-s2.0-7795772423910.1016/j.brainres.2010.09.047ValentiM.CerboR.MaseduF.De CarisM.SorgeG.Intensive intervention for children and adolescents with autism in a community setting in Italy: a single-group longitudinal study20104, article no. 232-s2.0-7795647073610.1186/1753-2000-4-23OspinaM. B.SeidaJ. K.ClarkB.KarkhanehM.HartlingL.TjosvoldL.VandermeerB.SmithV.Behavioural and developmental interventions for autism spectrum disorder: a clinical systematic review20083112-s2.0-5664911570310.1371/journal.pone.0003755e3755StahmerA. C.SchreibmanL.CunninghamA. B.Toward a technology of treatment individualization for young children with autism spectrum disorders201113802292392-s2.0-7795759281410.1016/j.brainres.2010.09.043CouryD.Medical treatment of autism spectrum disorders20102321311362-s2.0-7794940631610.1097/WCO.0b013e32833722faSiniscalcoD.SulloN.MaioneS.RossiF.D'AgostinoB.Stem cell therapy: the great promise in lung disease2008231731772-s2.0-6574908303710.1177/1753465808092340BrookeG.CookM.BlairC.HanR.HeazlewoodC.JonesB.KambourisM.KollarK.McTaggartS.PelekanosR.RiceA.RossettiT.AtkinsonK.Therapeutic applications of mesenchymal stromal cells20071868468582-s2.0-3624895928010.1016/j.semcdb.2007.09.012ArthurA.ZannettinoA.GronthosS.The therapeutic applications of multipotential mesenchymal/stromal stem cells in skeletal tissue repair200921822372452-s2.0-5814926573410.1002/jcp.21592ChagastellesP. C.NardiN. B.CamassolaM.Biology and applications of mesenchymal stem cells20109321131272-s2.0-7795408177710.3184/003685010X12708175591515ShortB.BrouardN.Occhiodoro-ScottT.RamakrishnanA.SimmonsP. J.Mesenchymal stem cells20033465655712-s2.0-034700467810.1016/j.arcmed.2003.09.007Beyer NardiN.da Silva MeirellesL.Mesenchymal stem cells: isolation, in vitro expansion and characterization20061742492822-s2.0-33644796337SetheS.ScuttA.StolzingA.Aging of mesenchymal stem cells200651911162-s2.0-3134447337910.1016/j.arr.2005.10.001DominiciM.Le BlancK.MuellerI.Slaper-CortenbachI.MariniF. C.KrauseD. S.DeansR. J.KeatingA.ProckopD. J.HorwitzE. M.Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement2006843153172-s2.0-3374771324610.1080/14653240600855905GiordanoA.GalderisiU.MarinoI. R.From the laboratory bench to the patient's bedside: an update on clinical trials with mesenchymal stem cells2007211127352-s2.0-3384761702110.1002/jcp.20959PricolaK. L.KuhnN. Z.Haleem-SmithH.SongY.TuanR. S.Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism200910835775882-s2.0-7035015067710.1002/jcb.22289Le BlancK.PittengerM. F.Mesenchymal stem cells: progress toward promise20057136452-s2.0-1744441034710.1080/14653240510018118BeggsK. J.LyubimovA.BornemanJ. N.BartholomewA.MoseleyA.DoddsR.ArchambaultM. P.SmithA. K.McIntoshK. R.Immunologic consequences of multiple, high-dose administration of allogeneic mesenchymal stem cells to baboons2006158-97117212-s2.0-33846229305UccelliA.MorettaL.PistoiaV.Mesenchymal stem cells in health and disease2008897267362-s2.0-5024915851110.1038/nri2395AroninC. E. P.TuanR. S.Therapeutic potential of the immunomodulatory activities of adult mesenchymal stem cells201090167742-s2.0-7794969153510.1002/bdrc.20174SiniscalcoD.Transplantation of human mesenchymal stem cells in the study of neuropathic pain20106173373452-s2.0-7795311387910.1007/978-1-60327-323-7_25SotiropoulouP. A.PapamichailM.Immune properties of mesenchymal stem cells20074072252432-s2.0-44649158408NewmanR. E.YooD.LeRouxM. A.Danilkovitch-MiagkovaA.Treatment of inflammatory diseases with mesenchymal stem cells2009821101232-s2.0-7034950166610.2174/187152809788462635MeyerroseT.OlsonS.PontowS.KalomoirisS.JungY.AnnettG.BauerG.NoltaJ. A.Mesenchymal stem cells for the sustained in vivo delivery of bioactive factors20106212116711742-s2.0-7865017683910.1016/j.addr.2010.09.013KsiazekK.A comprehensive review on mesenchymal stem cell growth and senescence20091221051162-s2.0-6614916307110.1089/rej.2009.0830SiniscalcoD.GiordanoC.GalderisiU.LuongoL.AlessioN.Di BernardoG.De NovellisV.RossiF.MaioneS.Intra-brain microinjection of human mesenchymal stem cells decreases allodynia in neuropathic mice20106746556692-s2.0-7564909943510.1007/s00018-009-0202-4MajumdarM. K.ThiedeM. A.MoscaJ. D.MoormanM.GersonS. L.Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells1998176157662-s2.0-0031861531da Silva MeirellesL.FontesA. M.CovasD. T.CaplanA. I.Mechanisms involved in the therapeutic properties of mesenchymal stem cells2009205-64194272-s2.0-7084910392410.1016/j.cytogfr.2009.10.002GiulianiM.giulianimas@hotmail.comFleuryM.VernochetA.KetroussiF.ClayD.AzzaroneB.LatailladeJ. J.DurrbachA.Long-lasting inhibitory effects of fetal liver mesenchymal stem cells on T-lymphocyte proliferation201165e1998810.1371/journal.pone.0019988HoogduijnM. J.PoppF.VerbeekR.MasoodiM.NicolaouA.BaanC.DahlkeM. H.The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy20101012149615002-s2.0-7865002630910.1016/j.intimp.2010.06.019NicolaM. D.Carlo-StellaC.MagniM.MilanesiM.LongoniP. D.MatteucciP.GrisantiS.GianniA. M.Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli20029910383838432-s2.0-003709305810.1182/blood.V99.10.3838BeythS.BorovskyZ.MevorachD.LiebergallM.GazitZ.AslanH.GalunE.RachmilewitzJ.Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness20051055221422192-s2.0-1494433917410.1182/blood-2004-07-2921DazziF.Marelli-BergF. M.Mesenchymal stem cells for graft-versus-host disease: close encounters with T cells2008386147914822-s2.0-4964911941710.1002/eji.200838433AshwoodP.CorbettB. A.KantorA.SchulmanH.Van de WaterJ.AmaralD. G.In search of cellular immunophenotypes in the blood of children with autism201165e19299SuzukiK.k-suzuki@hama-med.ac.jpMatsuzakiH.IwataK.KamenoY.ShimmuraC.KawaiS.YoshiharaY.WakudaT.TakebayashiK.TakagaiS.MatsumotoK.TsuchiyaK. J.IwataY.NakamuraK.TsujiiM.SugiyamaT.MoriN.Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders201165e2047010.1371/journal.pone.0020470GuptaS.SamraD.AgrawalS.Adaptive and innate immune responses in autism: rationale for therapeutic use of intravenous immunoglobulin201030supplement 1S90S962-s2.0-7795618465210.1007/s10875-010-9402-9EnstromA. M.OnoreC. E.Van de WaterJ. A.AshwoodP.Differential monocyte responses to TLR ligands in children with autism spectrum disorders201024164712-s2.0-7174909450510.1016/j.bbi.2009.08.001OblakA. L.RoseneD. L.KemperT. L.BaumanM. L.BlattG. J.Altered posterior cingulate cortical cyctoarchitecture, but normal density of neurons and interneurons in the posterior cingulate cortex and fusiform gyrus in autism20114200211WhitneyE. R.KemperT. L.RoseneD. L.BaumanM. L.BlattG. J.Density of cerebellar basket and stellate cells in autism: evidence for a late developmental loss of Purkinje cells20098710224522542-s2.0-6924922983710.1002/jnr.22056CourchesneE.KarnsC. M.DavisH. R.ZiccardiR.CarperR. A.TigueZ. D.ChisumH. J.MosesP.PierceK.LordC.LincolnA. J.PizzoS.SchreibmanL.HaasR. H.AkshoomoffN. A.CourchesneR. Y.Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study20015722452542-s2.0-0035943033BaumanM. L.KemperT. L.Neuroanatomic observations of the brain in autism: a review and future directions2005232-31831872-s2.0-1464439560510.1016/j.ijdevneu.2004.09.006FortinD. A.SrivastavaT.SoderlingT. R.Structural modulation of dendritic spines during synaptic plasticityNeuroscientist. In pressSørensenA. T.andreas.toft_sorensen@med.lu.seRogeliusN.nina.rogelius@genovis.comLundbergC.cecilia.lundberg@med.lu.seKokaiaM.merab.kokaia@med.lu.seActivity-dependent long-term plasticity of afferent synapses on grafted stem/progenitor cell-derived neurons2011229227428110.1016/j.expneurol.2011.02.008Rodrigues HellR. C.Silva CostaM. M.GoesA. M.OliveiraA. L.Local injection of BDNF producing mesenchymal stem cells increases neuronal survival and synaptic stability following ventral root avulsion20093322903002-s2.0-5814949252910.1016/j.nbd.2008.10.017ChangY. K.imrter@yahoo.com.twChenM. H.meanshine1982mhc@gmail.comChiangY. H.chia3260@ms11.hinet.netChenY. F.chenyufan0251@gmail.comMaW. H.horse0317@gmail.comTsengC. Y.candybox0713@gmail.comSoongB. W.bwsoong@vghtpe.gov.twHoJ. H.wh9801@yahoo.com.twLeeO. K.kslee@vghtpe.gov.twMesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells201118, article 54110.1186/1423-0127-18-54DengJ.ZouZ. M.ZhouT. L.SuY. P.suyp2003@yahoo.com.cnAiG. P.WangJ. P.XuH.DongS. W.Bone marrow mesenchymal stem cells can be mobilized into peripheral blood by G-CSF in vivo and integrate into traumatically injured cerebral tissue201132464165110.1007/s10072-011-0608-2LiL.JiangJ.Regulatory factors of mesenchymal stem cell migration into injured tissues and their signal transduction mechanisms201153339ProckopD. J.GregoryC. A.SpeesJ. L.One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues2003100111917119232-s2.0-014148304710.1073/pnas.1834138100AugelloA.KurthT. B.De BariC.Mesenchymal stem cells: a perspective from in vitro cultures to in vivo migration and niches2010201211332-s2.0-77957133737MominE. N.MohyeldinA.ZaidiH. A.VelaG.Quiñones-HinojosaA.Mesenchymal stem cells: new approaches for the treatment of neurological diseases2010543263442-s2.0-7864998494810.2174/157488810793351631