Mechanoreceptor Piezo1 Is Downregulated in Multiple Sclerosis Brain and Is Involved in the Maturation and Migration of Oligodendrocytes in vitro

Abstract

Mechanical properties of the brain such as intracranial pressure or stiffness of the matrix play an important role in the brain’s normal physiology and pathophysiology. The physical properties are sensed by the cells through mechanoreceptors and translated into ion currents which activate multiple biochemical cascades allowing the cells to adapt and respond to changes in their microenvironment. Piezo1 is one of the first identified mechanoreceptors. It modulates various central nervous system functions such as axonal growth or activation of astrocytes. Piezo1 signaling was also shown to play a role in the pathophysiology of Alzheimer’s disease. Here, we explore the expression of the mechanoreceptor Piezo1 in human MO3.13 oligodendrocytes and human MS/non-MS patients’ brains and investigate its putative effects on oligodendrocyte proliferation, maturation, and migration. We found that Piezo1 is expressed in human oligodendrocytes and oligodendrocyte progenitor cells in the human brain and that its inhibition with GsMTx4 leads to an increment in proliferation and migration of MO3.13 oligodendrocytes. Activation of Piezo1 with Yoda-1 induced opposite effects. Further, we observed that expression of Piezo1 decreased with MO3.13 maturation in vitro. Differences in expression were also observed between healthy and multiple sclerosis brains. Remarkably, the data showed significantly lower expression of Piezo1 in the white matter in multiple sclerosis brains compared to its expression in the white matter in healthy controls. There were no differences in Piezo1 expression between the white matter plaque and healthy-appearing white matter in the multiple sclerosis brain. Taken together, we here show that Piezo1-induced signaling can be used to modulate oligodendrocyte function and that it may be an important player in the pathophysiology of multiple sclerosis.

The proton-activated receptor TDAG8 is upregulated in oligodendrocytes during maturation and under acidic conditions

“…Whether acidic pH indeed inhibits oligodendrocyte maturation and/or maintains OPCs in an undifferentiated state (PDGFRα expression), and whether TDAG8 is involved in these processes needs to be investigated further. Low pH could act on other receptors that have been shown to regulate OPC differentiation and migration, such as EBI2 or the mechanosensing ion channel Piezo1, which is inhibited in pH under 6.9 [29,38,43,44]. Nevertheless, looking at myelination in vivo in untreated TDAG8 KO mice, our explorations demonstrate that TDAG8-mediated signalling is not required for normal myelination in the mouse CNS.…”

“…Our explorations culminated in experiments using human material from MS patients where we found that TDAG8 is upregulated in MS plaques. Differentiation of the MO3.13 oligodendrocytes in vitro can be achieved by stimulation with either PMA or by culturing in SFM [37,38]. The cell maturation is indicated by reduced expression of the OPC or pre-oligodendrocyte markers and an increase in mature and myelinating oligodendrocyte markers [29,39].…”

The epigenetic landscape of oligodendrocyte lineage cells

“…In the oligodendrocyte lineage cells, Piezo1 is highly expressed in OPCs, where its activation decreases both proliferation and migration. 166,189 The transcriptional coactivators YAP and TAZ with the PDZ domain encoded by the gene WWTR1 are part of the Hippo (named after the Hpo/MTS1/2 kinase) pathway cascade, which regulates organ size by modulating cell proliferation and apoptosis (Figure 3). In the unphosphorylated state, the coactivators YAP and TAZ are nuclear and favor proliferation due to the transcription of cell cycle genes.…”

“…It is expressed in neurons, astrocytes, and microglial cells at low levels. In the oligodendrocyte lineage cells, Piezo1 is highly expressed in OPCs, where its activation decreases both proliferation and migration 166,189 …”

Piezo1 mechanosensing regulates integrin-dependent chemotactic migration in human T cells

“…A role of Piezo1 in cellular migration has been explored in different contexts, viz. cancer cells, fibroblasts, mesenchymal stem cells, keratinocytes, oligodendrocytes and macrophages, which show differential involvement of Piezo1 depending on contexts (Hung et al, 2016; Chubinskiy Nadezhdin et al, 2019; Mousawi et al; 2020, Wang et al, 2021; Gao et al, 2021; Holt et al, 2021; He Y et al, 2022; Velasco-Estevez et al, 2022). The previous studies point to the possibility of a role of Piezo1 in confinement sensing and integrin activation in moving cells, while it deters integrin-independent cell motility, usually referred to as amoeboid movement (McHugh et al, 2010; Hung et al, 2016).…”