Induction of PLXNA4 Gene during Neural Differentiation in Human Umbilical-Cord-Derived Mesenchymal Stem Cells by Low-Intensity Sub-Sonic Vibration

Abstract

Human umbilical-cord-derived mesenchymal stem cells (hUC-MSC) are a type of mesenchymal stem cells and are more primitive than other MSCs. In this study, we identify novel genes and signal-activating proteins involved in the neural differentiation of hUC-MSCs induced by Low-Intensity Sub-Sonic Vibration (LISSV). RNA sequencing was used to find genes involved in the differentiation process by LISSV. The changes in hUC-MSCs caused by LISSV were confirmed by PLXNA4 overexpression and gene knockdown through small interfering RNA experiments. The six genes were increased among genes related to neurons and the nervous system. One of them, the PLXNA4 gene, is known to play a role as a guide for axons in the development of the nervous system. When the PLXNA4 recombinant protein was added, neuron-related genes were increased. In the PLXNA4 gene knockdown experiment, the expression of neuron-related genes was not changed by LISSV exposure. The PLXNA4 gene is activated by sema family ligands. The expression of SEMA3A was increased by LISSV, and its downstream signaling molecule, FYN, was also activated. We suggest that the PLXNA4 gene plays an important role in hUC-MSC neuronal differentiation through exposure to LISSV. The differentiation process depends on SEMA3A-PLXNA4-dependent FYN activation in hUC-MSCs.

Case report of PLXNA4 variant associated with hyper-response to phentermine/topiramate pharmacotherapy: Potential genetic basis for superior weight loss response?

“…To our knowledge, there are no studies in the literature examining the relationship between the mechanisms of phentermine/topiramate and the PLXNA4 gene. However, the PLXNA4 product (plexin A4) is known to function with semaphorin 6A and itself is localized in the hypothalamus [ 8 , 22 ]. Semaphorins function as signaling proteins necessary for development and maintenance of organs and tissues by regulating morphology and motility [ 7 , 8 ].…”

“…However, the PLXNA4 product (plexin A4) is known to function with semaphorin 6A and itself is localized in the hypothalamus [ 8 , 22 ]. Semaphorins function as signaling proteins necessary for development and maintenance of organs and tissues by regulating morphology and motility [ 7 , 8 ]. They are in turn regulated by plexin A4 to prevent abnormal mossy fiber projection in the hippocampus [ 7 ].…”

“…While there are many pathways through which weight and homeostasis are regulated, in this case, the pathway of interest includes PLXNA4. PLXNA4 is one of several receptors involved in semaphorin signaling within the hypothalamus [ 7 , 8 ]. Heterozygous missense mutations in PLXNA4 have also been linked to severe, early-onset obesity [ 9 ].…”

The pig pangenome provides insights into the roles of coding structural variations in genetic diversity and adaptation

“…Furthermore, we found that three of the candidate TE insertions affected the expression of corresponding genes (SVIL, PLXNA4, and NELL2), which are more likely to be the actual targets of positive selection. PLXNA4 is known to play a role as a guide for axons in the development of the nervous system and in the positive regulation of axonogenesis (Cho et al 2022), whereas NELL2 is multifunctional in neural cell growth and is strongly linked to the urinary tract disease (Liu et al 2021).…”