Mesenchymal Stem Cell Transplantation Promotes Neurogenesis and Ameliorates Autism Related Behaviors in BTBR Mice

Abstract

Autism spectrum disorders (ASD) are characterized by social communication deficits, cognitive rigidity, and repetitive stereotyped behaviors. Mesenchymal stem cells (MSC) have a paracrine regenerative effect, and were speculated to be a potential therapy for ASD. The BTBR inbred mouse strain is a commonly used model of ASD as it demonstrates robust behavioral deficits consistent with the diagnostic criteria for ASD. BTBR mice also exhibit decreased brain-derived neurotrophic factor (BDNF) signaling and reduced hippocampal neurogenesis. In the current study, we evaluated the behavioral and molecular effects of intracerebroventricular MSC transplantation in BTBR mice. Transplantation of MSC resulted in a reduction of stereotypical behaviors, a decrease in cognitive rigidity and an improvement in social behavior. Tissue analysis revealed elevated BDNF protein levels in the hippocampus accompanied by increased hippocampal neurogenesis in the MSC-transplanted mice compared with sham treated mice. This might indicate a possible mechanism underpinning the behavioral improvement. Our study suggests a novel therapeutic approach which may be translatable to ASD patients in the future.

Transplantation of mesenchymal stem cells reverses behavioural deficits and impaired neurogenesis caused by prenatal exposure to valproic acid

“…Such potentially therapeutic effect of MSC on similar behavioural traits has been reported in the BTBR genetic mice model for autism and even in humans [13, 28]. Similarly, we have previously shown that transplantation of MSC (neural stem cells) can restore neurobehavioral deficits caused by developmental exposure to organophosphates [29].…”

“…These studies clearly indicated that, following stem cell treatment, the changes in neurogenesis coincide well with behavioural changes. Yet, an important point is that the engrafted MSC do not differentiate to new neurons but rather paracrinely support endogenous neurogenesis [12, 13, 30]. Indeed, in previous studies we observed that MSC injected to the lateral ventricle engraft adjacent to neurogenic niche sites including hippocampal molecular layer, DG hilus and ventricle choroid plexus, without any signs of differentiation [12, 31].…”

The BTBR mouse model of idiopathic autism – Current view on mechanisms

“…Intracerebroventricular transplantation of human mesenchymal stem cells (MSC: Segal-Gavish et al 2016) resulted in increased sociability of BTBR mice, including improved social approach and increased social novelty preference in the three-chambered apparatus as well as increased social sniffing in reciprocal dyadic interactions, it also reduced stereotypic digging behavior and excessive grooming as compared with sham-operated mice. Given the choice of running in a jammed wheel and interacting with a stranger mouse, MSC treated BTBR mice also showed greater preference for social interaction than the sham-operated mice, as well as reduced cognitive rigidity in a water t-maze task.…”

Hypoxic and ischemic effects on gene and protein expression levels of paracrine factors by human olfactory mucosa mesenchymal-like stem cells

“…49,50 MSCs are a potent source of VEGF, which is a promoter and regulator of angiogenesis. 2,51 Neurons exposed to hypoxic conditions exhibited neuronal apoptosis, but the combined hypoxia-inducible VEGF and MSCs treatment indicated a significant increase in VEGF expression and decreased neuronal apoptosis.…”