Stem cell therapy in autism: recent insights
An article from 2018.
"Fetal stem cells
FSCs have the ability to secrete various neurotrophic and immunomodulatory factors that promote neuronal growth and suppress the action of proinflammatory cytokines that make them a potential candidate for treating ASDs and various neurodegenerative diseases.
A clinical trial in younger human Parkinson’s patients also showed promising results when dopamine neurons from fetal neural tissues were transplanted.36 An open-labeled clinical trial that examined the safety and efficacy of FSCs in autistic children revealed no adverse events and a significant difference in the improvement of autistic symptoms (detailed in Stem cells and autism: animal models section).
Bone marrow-derived stem cells
Mesenchymal stem cells (MSCs)
Different mechanisms were hypothesized for using MSCs for treating ASDs that include inducing plasticity, secretion of anti-inflammatory and survival-promoting factors, and engrafting into neural network.45
Also, in vivo, in different animal models of neurodegeneration, MSCs exert neuroprotection mainly by secretion of various neurotrophic and immunomodulatory factors, thus facilitating the recruitment of endogenous stem cells to promote regeneration and by downregulating T cells, B cells, and NK cells of immune system.46 Owing to these properties, MSCs were highly preferred candidates for clinical trials for various neurologic diseases. Clinical trials using MSCs are ongoing for diseases like multiple sclerosis (MS), stroke, Parkinson’s disease (PD), Huntington’s disease (HD), Alzheimer’s disease (AD), and systemic autoimmune diseases.47 For ASDs, several studies using stem cells have been conducted in humans (detailed in Stem cells and autism: animal models section); a study by Lv et al analyzed the safety and efficacy of using human cord blood mononuclear cells (CBMNCs) and umbilical cord-derived mesenchymal stem cells (UCMSCs) in treating children with autism.48 They reported safe and statistically significant improvements in the Childhood Autism Rating Scale (CARS), Clinical Global Impression (CGI) scale, and Aberrant Behavior Checklist (ABC) in the children treated combinedly with CBMNCs and UCMSCs when compared to the control group.
Adipo-stem cells
Along with being multipotent, ASCs secrete various trophic factors and are immunosuppressive and hypoimmunogenic, making them an attractive candidate for cellular therapies. ASCs have been used in various clinical trials targeting a wide range of indications ranging from immune disorders, myocardial infarction, bone defects, and neurodegenerative diseases. Although no reports have been found on the use of ASCs for treating ASDs, ASCs have been proven effective in other neurologic preclinical models, as in the mouse model of middle cerebral artery occlusion, human ASCs partially rescue the stroke syndromes by forming new neurons and blood vessels and increasing the viability of endogenous neurons.
Umbilical cord- and amniotic fluid-derived stem cells
These cells from perinatal, extraembryonic tissue have potential for future applications in ASDs.22 There are no ethical controversy and risk of teratoma formation, and they could also be used for autologous transplantation after banking in later stages of life.55
NSCs
The NSCs that can be extracted from two major regions of the brain, namely, the subventricular zone of lateral ventricles and subgranular zone of hippocampus, can be cultured.57,58 The culture-expanded NSCs are multipotent, have the ability to differentiate into various neuronal cell types, secrete neurotrophic factors, integrate into neural tissue, maintain homeostasis, and are neuroprotective, making them an ideal candidate for treating ASDs. Indeed, impairments in excitatory and inhibitory cortical neurons lead to minicolumn structure abnormalities in ASDs.56 Synaptic-related genes show multiple rare variants in some ASD subjects.59 Given that, transplantation of NSCs could be effective in ASDs, as transplanted cells can promote neural tissue repair and homeostasis through integration in damaged areas and secretion of factors that enhance brain repair and plasticity.60 The definitive use of NSCs for clinical applications in neurodegenerative diseases still requires addressing some critical issues: autologous reliable source of sufficient amount of stem cells needs to be identified; post-transplanted neural plasticity and differentiation, if any, must be further defined.60 However, though NSCs have been used in various preclinical and clinical studies against different neurologic conditions like PD, HD, AD, amyotrophic lateral sclerosis (ALS), MS, stroke, and spinal cord injury (SCI), the outcome is not definitive as expected and is hindered by several points to be further elucidated: the absence of homogenous cell population, stability, and long-term survival of neurons after transplantation.61,62
Different methods have been tried to enhance the capabilities of NSCs, like immortalizing the NSCs by gene manipulation techniques to create a homogenous, long-surviving cell that is capable of differentiating into neurons and glial cells when transplanted into normal or damaged brain.58
Hematopoietic stem cells (HSCs)
HSCs are mainly resident in bone marrow and also in blood and umbilical cord.63 Self-renewal, multipotency, and homing/mobility activities are very high. This type of stem cells is able to differentiate in myeloid and lymphoid lineages. Their paracrine activity, releasing bioactive molecules, and their ability to quickly traffic to the site of inflammation gained them a lot of attention for their use in ASD therapy.63 Several clinical trials have been performed with the use of CD34+ stem cells in autism (detailed in Stem cells and autism: animal models section).
iPSCs: the new frontier for cell therapy
There are several in vivo studies that prove the efficiency of iPSCs in treating neurodegenerative disorders, cardiovascular disease, and sickle cell anemia. For example, in contusive SCI model in nonobese diabetic severe combined immunodeficient mice, injection of neurospheres derived from human iPSCs leads to recovery of locomotor function without formation of any tumors.67 The differentiation capabilities of injected neurospheres into neurons, astrocytes, and oligodendrocytes along with induction of angiogenesis, axonal regeneration, and local-circuitry reconstruction may contribute to the recovery in SCI model.67 When autologous iPSCs-derived dopamine neurons were transplanted in PD model of cynomolgus monkey, the neurons engraft and survive for prolonged time of 2 years leading to improvement in the motor function in the nonhuman primate model.68 iPSCs have also been used effectively against HD and ALS by their capability to differentiate into desired neuronal lineages.
iPSC applications gain much attention also for autism research.73 Successful reprogramming of peripheral blood-derived mononuclear cells from autistic child into iPSCs has been performed by transgene-free delivery system.74 Customized iPSCs will help in elucidating the pathogenic mechanisms of ASDs,75 also for neuronal differentiation and maturation.76
Indeed, iPSC-derived neurons from autistic subjects show aberrant cation channels expression, voltage-gated currents, and changes in synaptic functions.77,78 Autistic patient-derived stem cells display an altered developmental neuronal phenotype: alteration in cell bodies, branched neurites, and motility compared with those derived from controls.79 Using iPSCs to generate three-dimensional models of neurons and brain structures could also be useful to model autism pathophysiology.