Tristan, C. | bioRxiv Science

bioRxiv2024

Satellite glial contact enhances differentiation and maturation of human induced sensory neurons

Sensory neurons generated from induced pluripotent stem cells (iSNs) are used to model human peripheral neuropathies, however current differentiation protocols produce sensory neurons with an embryonic phenotype. Peripheral glial cells contact sensory neurons early in development and contribute to formation of the canonical pseudounipolar morphology, but these signals are not encompassed in current iSN differentiation protocols. Here, we show that terminal differentiation of iSNs in co-culture with rodent Dorsal Root Ganglion satellite glia (rSG) advances their differentiation and maturation. Co-cultured iSNs develop a pseudounipolar morphology through contact with rSGs. This transition depends on semaphorin-plexin guidance cues and on glial gap junction signaling. In addition to morphological changes, iSNs terminally differentiated in co-culture exhibit enhanced spontaneous action potential firing, more mature gene expression, and increased susceptibility to paclitaxel induced axonal degeneration. Thus, iSNs differentiated in coculture with rSGs provide a better model for investigating human peripheral neuropathies.

neuroscience↗

bioRxiv2019

Nuclear GAPDH signaling mediates pathological cardiac hypertrophy

Here we report that stress-induced nuclear translocation of GAPDH mediates heart hypertrophy via Brahma-Related-Gene-1 (BRG1)-associated chromatin remodelling. In response to pressure overload elicited by transverse aortic constriction, we observed nuclear translocation of GAPDH in the mouse heart. We also demonstrated a robust nuclear localization of GAPDH in cardiomyocytes from patients with dilated hypertrophic cardiomyopathy, whereas negligible GAPDH in the nucleus in control subjects. This is the first demonstration of disease-associated nuclear GAPDH directly in living patients. Using immunohistochemical methods and a pharmacological way that selectively blocks GAPDH nuclear translocation (RR compound), we proved the causal involvement of GAPDH cysteine-150 modification in this translocation in Gq-induced cell model for heart hypertrophy. Accordingly, both pharmacological and genetic interventions proved that the same mechanism played a causal role for heart hypertrophy and dysfunction in vivo. We discovered that, upon nuclear translocation, GAPDH augmented the protein interaction of BRG1 and histone deacetylase 2 (HDAC2), which further facilitated the Myh7/Myh6 isoform ratio from the mature to immature status, an essential mechanism for heart hypertrophy. Beyond medical implications, we provide a novel mechanism of stress-induced reversion of a cellular phenotype from adult to fetal state, which is mediated by a "moonlighting" function of GAPDH.

molecular biology↗