Wnt/β‐catenin signaling pathway is involved in early dopaminergic differentiation of trabecular meshwork‐derived mesenchymal stem cells

Abstract

Permanent degeneration and loss of dopaminergic (DA) neurons in substantia nigra is the main cause of Parkinson's disease. Considering the therapeutic application of stem cells in neurodegeneration, we sought to examine the neurogenic differentiation potential of the newly introduced neural crest originated mesenchymal stem cells (MSCs), namely, trabecular meshworkderived mesenchymal stem cells (TM-MSCs) compared to two other sources of MSCs, adipose tissue-derived stem cells (ADSCs) and bone marrow-derived mesenchymal stem cells (BM-MSCs). The three types of cells were therefore cultured in the presence and absence of a neural induction medium followed by the analysis of their differentiation potentials. Our results showed that TM-MSCs exhibited enhanced neural morphologies as well as higher expressions of MAP2 as the general neuron marker and Nurr-1 as an early DA marker compared to the adipose tissue-derived mesenchymal stem cells (AD-MSCs) and bone marrow-derived stem cells (BMSCs). Also, analysis of Nurr-1 immunostaining showed more intense Nurr-1 stained nuclei in the neurally induced TM-MSCs compared to those in the AD-MSCs, BMSCs, and noninduced control TM-MSCs. To examine if Wnt/beta-catenin pathway drives TM-MSCs towards a DA fate, we treated them with the Wnt agonist (CHIR, 3 μM) and the Wnt antagonist (IWP-2, 3 μM). Our results showed that the expressions of Nurr-1 and MAP2, as well as the Wnt/beta-catenin target genes, c-Myc and Cyclin D1, were significantly increased in the CHIR-treated TM-MSCs, but significantly reduced in those treated with IWP-2. Altogether, we declare first a higher neural potency of TM-MSCs compared to the more commonly used MSCs, BMSCs and ADSCs, and second that Wnt/beta-catenin activation directs the neurally induced TM-MSCs towards a DA fate.

Molecular regulation after mucosal injury and regeneration in ulcerative colitis

“…By inhibiting the phosphorylation of β-catenin, β-catenin accumulates in the cytoplasm and translocates to the nucleus, eventually binding to LEF/TCFs to replace transcriptional inhibitors on the promoter of target genes, thereby regulating the transcription of downstream target genes and stimulating signal transduction cascades in one or more cells. The target genes of Wnt include c-Myc, Cyclin D1 and LGR5, among which c-Myc and Cyclin D1 promote the proliferation of IECs, and LGR5 enhances the activity of ISCs ( Sahebdel et al, 2022 ). In contrast, in the absence of Wnt ligands, β-catenin is phosphorylated by degradation complexes and is recognized and degraded by ubiquitin proteasomes.…”