Assessing Neural Structural and Functional Deficits and Validating Human Mesenchymal Stem Cells Therapy in the Reduced Uterine Perfusion Pressure Rat Model of Fetal Growth Restriction

Abstract

Fetal growth restriction (FGR) is a failure of a fetus to reach its full genetic growth potential, with placental insufficiencies as the leading cause. FGR has been associated with a number of neural structural deficits that result in short- and long-term functional dysregulations. As of yet, no effective treatments have been developed to mitigate these effects. Human mesenchymal stem cells (hMSCs) have emerged as a promising new intervention for FGR infants. The paper at hand aims to characterize vascular/structural and functional outcomes in the reduced uterine perfusion pressure (RUPP) model, using immunohistochemical (laminin staining) and behavioral methods (eye opening, negative geotaxis, turning reflex, nest seeking, and grip strength) respectively. The RUPP model mimics the FGR phenotype by reducing blood flow to the fetuses through partial clipping of the lower abdominal aorta and both ovarian arcades on embryonic day 14 (E14). Additionally, the paper aims to evaluate the optimal timing for hMSCs therapy by comparing immunohistochemistry (brain area, corpus callosum thickness, cortical myelination, and cortical thickness) and use this optimal treatment timepoint to validate hMSCs therapy in FGR pups by assessing the effect of hMSCs on the earlier defined behavioral paradigms affected in the FGR pups. No significant differences in vascular/structural outcomes were found between RUPP and sham animals. Differences in behavioral task performance between the two groups was mainly on tasks measuring motor and vestibular function. An earlier timepoint of hMSCs administration was found to be more effective, but only in combating cortical myelination abnormalities. hMSCs therapy administered at this early timepoint did not result in any improvements in the previously mentioned behavioral/functional deficits. In conclusion, the RUPP model was successful in reproducing some, but not all, of the structural and functional deficits seen in FGR infants, namely changes in myelination and motor function. However, no evidence was found for the effectiveness of hMSCs in treating behavioral/functional deficits commonly seen in FGR and modelled using RUPP. Potential therapeutic effects of hMSCs were seen with early administration, specifically in combating myelin abnormalities.