RESUMO
Neural stem cells are multipotent cells with the ability to differentiate into neurons, astrocytes, and oligodendrocytes. Lineage specification is strongly sensitive to the mechanical properties of the cellular environment. However, molecular pathways transducing matrix mechanical cues to intracellular signaling pathways linked to lineage specification remain unclear. We found that the mechanically gated ion channel Piezo1 is expressed by brain-derived human neural stem/progenitor cells and is responsible for a mechanically induced ionic current. Piezo1 activity triggered by traction forces elicited influx of Ca(2+), a known modulator of differentiation, in a substrate-stiffness-dependent manner. Inhibition of channel activity by the pharmacological inhibitor GsMTx-4 or by siRNA-mediated Piezo1 knockdown suppressed neurogenesis and enhanced astrogenesis. Piezo1 knockdown also reduced the nuclear localization of the mechanoreactive transcriptional coactivator Yes-associated protein. We propose that the mechanically gated ion channel Piezo1 is an important determinant of mechanosensitive lineage choice in neural stem cells and may play similar roles in other multipotent stem cells.
Assuntos
Sinalização do Cálcio/fisiologia , Ativação do Canal Iônico/fisiologia , Canais Iônicos/metabolismo , Mecanotransdução Celular/fisiologia , Células-Tronco Multipotentes/metabolismo , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Diferenciação Celular/fisiologia , Células Cultivadas , Feminino , Técnicas de Silenciamento de Genes , Humanos , Canais Iônicos/genética , Masculino , Células-Tronco Multipotentes/citologia , Células-Tronco Neurais/citologiaRESUMO
As human and chimpanzee genomes show high homology for IGF1 and PRL, we analyzed the sera of 367 healthy chimpanzees obtained during routine physical examinations in a single colony and measured chimpanzee insulin-like growth factor (IGF)-1 and prolactin (PRL) levels across the lifespan using standard human immunoassays. Assuming chimpanzee IGF-1 levels peak during puberty as in humans, we randomly defined puberty as the age at which most IGF-1 levels were equal to or above the 90th percentile for each sex (males, ages ≥7.00 but <9.20 years; females, ≥5.00 but <8.00 years). IGF-1 levels steadily increased at a similar rate in juvenile males and females and peaked in puberty, strongly correlating with age, then slowly decreased faster in adult males than in adult females. As a group, males had a higher mean IGF-1 level than did females, but comparison by age category showed similar mean IGF-1 levels in males and females. PRL levels increased with age in females more than in males and levels were twice as high in females than in males. One pubertal male reported to have short stature had lower IGF-1 and weight compared with other males in the age group, confirming suspected growth hormone deficiency; a second male of normal height but low IGF-1 may have had delayed puberty. Overall, results show that differences in IGF-1 levels over the lifespan in this cohort of chimpanzees largely mimic those seen in humans, while patterns of PRL changes are less similar.