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J Biomed Biotechnol. 2012; 2012: 480289.
Published online Feb 13, 2012. doi:  10.1155/2012/480289
PMCID: PMC3303614
Autism Spectrum Disorders: Is Mesenchymal Stem Cell Personalized Therapy the Future?
Dario Siniscalco, 1 ,2 * Anna Sapone, 3 ,4 Alessandra Cirillo, 5 Catia Giordano, 1 Sabatino Maione, 1 and Nicola Antonucci 6
1Division of Pharmacology “L. Donatelli”, Department of Experimental Medicine, Second University of Naples, Via S. Maria di Costantinopoli, 16-80138 Napoli, Italy
2Centre for Autism, La Forza del Silenzio, Caserta, 80138 Naples, Italy
3Department of Internal and Experimental Medicine “Magrassi-Lanzara”, Second University of Naples, 80138 Naples, Italy
4Center for Celiac Research and Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
5Division of Biotechnology and Molecular Biology “A. Cascino”, Department of Experimental Medicine, Second University of Naples, 80138 Naples, Italy
6Biomedical Centre for Autism Research and Treatment, 70122 Bari, Italy
*Dario Siniscalco: dariosin/at/uab.edu
Academic Editor: Ken-ichi Isobe
Received July 11, 2011; Accepted September 29, 2011.
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.
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 [1416]. 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 [2123]. A plethora of behavioural strategies and social skill trainings have been used [2426]. 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].
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 [3133]. 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 [3436]. 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 [4043]. 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].
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].
Figure 1
Figure 1
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 (more ...)
It has been demonstrated that in postmortem brains from ASD patients there is evidence of abnormal functioning and cerebellum alterations [6163]. 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).
Table 1
Table 1
Potential ameliorative effects mediated by MSCs in ASD treatment.
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.
1. Fasano A. Intestine, leaky gut, autism and probiotics. In: Lyndhurst NJ, editor. Cutting Edge Therapies. Barnes & Noble; 2010. pp. 192–198.
2. Williams K, Wheeler DM, Silove N, Hazell P. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD) Cochrane Database of Systematic Reviews. 2010;8 Article ID CD004677. [PubMed]
3. Toro R, Konyukh M, Delorme R, et al. Key role for gene dosage and synaptic homeostasis in autism spectrum disorders. Trends in Genetics. 2010;26(8):363–372. [PubMed]
4. Bradstreet JJ, Smith S, Baral M, Rossignol DA. Biomarker-guided interventions of clinically relevant conditions associated with autism spectrum disorders and attention deficit hyperactivity disorder. Alternative Medicine Review. 2010;15(1):15–32. [PubMed]
5. Persico AM, Bourgeron T. Searching for ways out of the autism maze: genetic, epigenetic and environmental clues. Trends in Neurosciences. 2006;29(7):349–358. [PubMed]
6. Toro R, Konyukh M, Delorme R, et al. Key role for gene dosage and synaptic homeostasis in autism spectrum disorders. Trends in Genetics. 2010;26(8):363–372. [PubMed]
7. El-Fishawy P, State MW. The genetics of autism: key issues, recent findings, and clinical implications. Psychiatric Clinics of North America. 2010;33(1):83–105. [PMC free article] [PubMed]
8. Herbert MR. Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Current Opinion in Neurology. 2010;23(2):103–110. [PubMed]
9. Muhle R, Trentacoste SV, Rapin I. The genetics of autism. Pediatrics. 2004;113(5):e472–e486. [PubMed]
10. Levy SE, Mandell DS, Schultz RT. Autism. The Lancet. 2009;374(9701):1627–1638. [PMC free article] [PubMed]
11. CDC. Surveillance summaries. Morbidity and Mortality Weekly Report. 2007;56:1–28. [PubMed]
12. Main PA, Angley MT, Thomas P, O’Doherty CE, Fenech M. Folate and methionine metabolism in autism: a systematic review. American Journal of Clinical Nutrition. 2010;91(6):1598–1620. [PubMed]
13. Reiersen AM, Todd RD. Co-occurrence of ADHD and autism spectrum disorders: phenomenology and treatment. Expert Review of Neurotherapeutics. 2008;8(4):657–669. [PubMed]
14. McCracken JT. Safety issues with drug therapies for autism spectrum disorders. Journal of Clinical Psychiatry. 2005;66(supplement 10):32–37. [PubMed]
15. Tandon M, Pruett JR., Jr. An overview of the use of antidepressants in children and adolescents. Missouri Medicine. 2008;105(1):79–85. [PubMed]
16. Nevels RM, Dehon EE, Alexander K, Gontkovsky ST. Psychopharmacology of aggression in children and adolescents with primary neuropsychiatric disorders: a review of current and potentially promising treatment options. Experimental and Clinical Psychopharmacology. 2010;18(2):184–201. [PubMed]
17. Dhossche DM, Shah A, Wing L. Blueprints for the assessment, treatment, and future study of catatonia in autism spectrum disorders. International Review of Neurobiology. 2006;72:267–284. [PubMed]
18. Rossignol DA. Novel and emerging treatments for autism spectrum disorders: a systematic review. Annals of Clinical Psychiatry. 2009;21(4):213–236. [PubMed]
19. Şenel HG. Parents’ views and experiences about complementary and alternative medicine treatments for their children with autistic spectrum disorder. Journal of Autism and Developmental Disorders. 2010;40(4):494–503. [PubMed]
20. Wong VC, Sun JG. Randomized controlled trial of acupuncture versus sham acupuncture in autism spectrum disorder. Journal of Alternative and Complementary Medicine. 2010;16(5):545–553. [PubMed]
21. Filipek PA, Steinberg-Epstein R, Book TM. Intervention for autistic spectrum disorders. NeuroRx. 2006;3(2):207–216. [PubMed]
22. Vismara LA, Rogers SJ. Behavioral treatments in autism spectrum disorder: what do we know? Annual Review of Clinical Psychology. 2010;6:447–468. [PubMed]
23. Kasari C, Lawton K. New directions in behavioral treatment of autism spectrum disorders. Current Opinion in Neurology. 2010;23(2):137–143. [PubMed]
24. Murdock LC, Hobbs JQ. Picture me playing: increasing pretend play dialogue of children with autism spectrum disorders. Journal of Autism and Developmental Disorders. 2011;41:870–878. [PubMed]
25. Frankel F, Whitham C. Parent-assisted group treatment for friendship problems of children with autism spectrum disorders. Brain Research. 2011;1380:240–245. [PubMed]
26. Valenti M, Cerbo R, Masedu F, De Caris M, Sorge G. Intensive intervention for children and adolescents with autism in a community setting in Italy: a single-group longitudinal study. Child and Adolescent Psychiatry and Mental Health. 2010;4, article no. 23 [PMC free article] [PubMed]
27. Ospina MB, Seida JK, Clark B, et al. Behavioural and developmental interventions for autism spectrum disorder: a clinical systematic review. PLoS One. 2008;3(11) Article ID e3755. [PMC free article] [PubMed]
28. Stahmer AC, Schreibman L, Cunningham AB. Toward a technology of treatment individualization for young children with autism spectrum disorders. Brain Research. 2011;1380:229–239. [PubMed]
29. Coury D. Medical treatment of autism spectrum disorders. Current Opinion in Neurology. 2010;23(2):131–136. [PubMed]
30. Siniscalco D, Sullo N, Maione S, Rossi F, D’Agostino B. Stem cell therapy: the great promise in lung disease. Therapeutic Advances in Respiratory Disease. 2008;2(3):173–177. [PubMed]
31. Brooke G, Cook M, Blair C, et al. Therapeutic applications of mesenchymal stromal cells. Seminars in Cell and Developmental Biology. 2007;18(6):846–858. [PubMed]
32. Arthur A, Zannettino A, Gronthos S. The therapeutic applications of multipotential mesenchymal/stromal stem cells in skeletal tissue repair. Journal of Cellular Physiology. 2009;218(2):237–245. [PubMed]
33. Chagastelles PC, Nardi NB, Camassola M. Biology and applications of mesenchymal stem cells. Science Progress. 2010;93(2):113–127. [PubMed]
34. Short B, Brouard N, Occhiodoro-Scott T, Ramakrishnan A, Simmons PJ. Mesenchymal stem cells. Archives of Medical Research. 2003;34(6):565–571. [PubMed]
35. Beyer Nardi N, da Silva Meirelles L. Mesenchymal stem cells: isolation, in vitro expansion and characterization. Handbook of Experimental Pharmacology. 2006;(174):249–282. [PubMed]
36. Sethe S, Scutt A, Stolzing A. Aging of mesenchymal stem cells. Ageing Research Reviews. 2006;5(1):91–116. [PubMed]
37. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–317. [PubMed]
38. Giordano A, Galderisi U, Marino IR. From the laboratory bench to the patient’s bedside: an update on clinical trials with mesenchymal stem cells. Journal of Cellular Physiology. 2007;211(1):27–35. [PubMed]
39. Pricola KL, Kuhn NZ, Haleem-Smith H, Song Y, Tuan RS. Interleukin-6 maintains bone marrow-derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism. Journal of Cellular Biochemistry. 2009;108(3):577–588. [PMC free article] [PubMed]
40. Le Blanc K, Pittenger MF. Mesenchymal stem cells: progress toward promise. Cytotherapy. 2005;7(1):36–45. [PubMed]
41. Beggs KJ, Lyubimov A, Borneman JN, et al. Immunologic consequences of multiple, high-dose administration of allogeneic mesenchymal stem cells to baboons. Cell Transplantation. 2006;15(8-9):711–721. [PubMed]
42. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nature Reviews Immunology. 2008;8(9):726–736. [PubMed]
43. Aronin CEP, Tuan RS. Therapeutic potential of the immunomodulatory activities of adult mesenchymal stem cells. Birth Defects Research Part C Embryo Today. 2010;90(1):67–74. [PubMed]
44. Siniscalco D. Transplantation of human mesenchymal stem cells in the study of neuropathic pain. Methods in Molecular Biology. 2010;617:337–345. [PubMed]
45. Sotiropoulou PA, Papamichail M. Immune properties of mesenchymal stem cells. Methods in Molecular Biology. 2007;407:225–243. [PubMed]
46. Newman RE, Yoo D, LeRoux MA, Danilkovitch-Miagkova A. Treatment of inflammatory diseases with mesenchymal stem cells. Inflammation and Allergy. 2009;8(2):110–123. [PubMed]
47. Meyerrose T, Olson S, Pontow S, et al. Mesenchymal stem cells for the sustained in vivo delivery of bioactive factors. Advanced Drug Delivery Reviews. 2010;62(12):1167–1174. [PMC free article] [PubMed]
48. Ksiazek K. A comprehensive review on mesenchymal stem cell growth and senescence. Rejuvenation Research. 2009;12(2):105–116. [PubMed]
49. Siniscalco D, Giordano C, Galderisi U, et al. Intra-brain microinjection of human mesenchymal stem cells decreases allodynia in neuropathic mice. Cellular and Molecular Life Sciences. 2010;67(4):655–669. [PubMed]
50. Majumdar MK, Thiede MA, Mosca JD, Moorman M, Gerson SL. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. Journal of Cellular Physiology. 1998;176(1):57–66. [PubMed]
51. da Silva Meirelles L, Fontes AM, Covas DT, Caplan AI. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine and Growth Factor Reviews. 2009;20(5-6):419–427. [PubMed]
52. Giuliani M, Fleury M, Vernochet A, et al. Long-lasting inhibitory effects of fetal liver mesenchymal stem cells on T-lymphocyte proliferation. PLoS One. 2011;6(5) Article ID e19988. [PMC free article] [PubMed]
53. Hoogduijn MJ, Popp F, Verbeek R, et al. The immunomodulatory properties of mesenchymal stem cells and their use for immunotherapy. International Immunopharmacology. 2010;10(12):1496–1500. [PubMed]
54. Nicola MD, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838–3843. [PubMed]
55. Beyth S, Borovsky Z, Mevorach D, et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood. 2005;105(5):2214–2219. [PubMed]
56. Dazzi F, Marelli-Berg FM. Mesenchymal stem cells for graft-versus-host disease: close encounters with T cells. European Journal of Immunology. 2008;38(6):1479–1482. [PubMed]
57. Ashwood P, Corbett BA, Kantor A, Schulman H, Van de Water J, Amaral DG. In search of cellular immunophenotypes in the blood of children with autism. PLoS One. 2011;6(5) Article ID e19299. [PMC free article] [PubMed]
58. Suzuki K, Matsuzaki H, Iwata K, et al. Plasma cytokine profiles in subjects with high-functioning autism spectrum disorders. PLoS One. 2011;6(5) Article ID e20470. [PMC free article] [PubMed]
59. Gupta S, Samra D, Agrawal S. Adaptive and innate immune responses in autism: rationale for therapeutic use of intravenous immunoglobulin. Journal of Clinical Immunology. 2010;30(supplement 1):S90–S96. [PubMed]
60. Enstrom AM, Onore CE, Van de Water JA, Ashwood P. Differential monocyte responses to TLR ligands in children with autism spectrum disorders. Brain, Behavior, and Immunity. 2010;24(1):64–71. [PMC free article] [PubMed]
61. Oblak AL, Rosene DL, Kemper TL, Bauman ML, Blatt GJ. Altered posterior cingulate cortical cyctoarchitecture, but normal density of neurons and interneurons in the posterior cingulate cortex and fusiform gyrus in autism. Autism Research. 2011;4:200–211. [PMC free article] [PubMed]
62. Whitney ER, Kemper TL, Rosene DL, Bauman ML, Blatt GJ. Density of cerebellar basket and stellate cells in autism: evidence for a late developmental loss of Purkinje cells. Journal of Neuroscience Research. 2009;87(10):2245–2254. [PMC free article] [PubMed]
63. Courchesne E, Karns CM, Davis HR, et al. Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study. Neurology. 2001;57(2):245–254. [PubMed]
64. Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism: a review and future directions. International Journal of Developmental Neuroscience. 2005;23(2-3):183–187. [PubMed]
65. Fortin DA, Srivastava T, Soderling TR. Structural modulation of dendritic spines during synaptic plasticity. Neuroscientist. In press. [PubMed]
66. Sørensen AT, Rogelius N, Lundberg C, Kokaia M. Activity-dependent long-term plasticity of afferent synapses on grafted stem/progenitor cell-derived neurons. Experimental Neurology. 2011;229(2):274–281. [PubMed]
67. Rodrigues Hell RC, Silva Costa MM, Goes AM, Oliveira AL. Local injection of BDNF producing mesenchymal stem cells increases neuronal survival and synaptic stability following ventral root avulsion. Neurobiology of Disease. 2009;33(2):290–300. [PubMed]
68. Chang YK, Chen MH, Chiang YH, et al. Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells. Journal of Biomedical Science. 2011;18, article 54(1) [PMC free article] [PubMed]
69. Deng J, Zou ZM, Zhou TL, et al. Bone marrow mesenchymal stem cells can be mobilized into peripheral blood by G-CSF in vivo and integrate into traumatically injured cerebral tissue. Neurological Sciences. 2011;32(4):641–651. [PubMed]
70. Li L, Jiang J. Regulatory factors of mesenchymal stem cell migration into injured tissues and their signal transduction mechanisms. Frontier Medical. 2011;5:33–39. [PubMed]
71. Prockop DJ, Gregory CA, Spees JL. One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(1):11917–11923. [PubMed]
72. Augello A, Kurth TB, De Bari C. Mesenchymal stem cells: a perspective from in vitro cultures to in vivo migration and niches. European Cells and Materials. 2010;20:121–133. [PubMed]
73. Momin EN, Mohyeldin A, Zaidi HA, Vela G, Quiñones-Hinojosa A. Mesenchymal stem cells: new approaches for the treatment of neurological diseases. Current Stem Cell Research and Therapy. 2010;5(4):326–344. [PubMed]
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