title: Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells.
abstract: 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.
authors.affiliation: Departments of Physiology and Biophysics, medhap@uci.edu ftombola@uci.edu.
authors.forename: Medha M
authors.initials: MM
authors.lastname: Pathak
authors.affiliation: Neurology, and Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA 92697; and.
authors.forename: Jamison L
authors.initials: JL
authors.lastname: Nourse
authors.affiliation: Departments of Physiology and Biophysics.
authors.forename: Truc
authors.initials: T
authors.lastname: Tran
authors.affiliation: Departments of Physiology and Biophysics.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hwe
authors.affiliation: Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA 92697; and Biomedical Engineering and.
authors.forename: Janahan
authors.initials: J
authors.lastname: Arulmoli
authors.affiliation: Departments of Physiology and Biophysics.
authors.forename: Dai Trang T
authors.initials: DT
authors.lastname: Le
authors.affiliation: Section of Dermatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104.
authors.forename: Elena
authors.initials: E
authors.lastname: Bernardis
authors.affiliation: Neurology, and Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, CA 92697; and Biomedical Engineering and.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Flanagan
authors.affiliation: Departments of Physiology and Biophysics, medhap@uci.edu ftombola@uci.edu.
authors.forename: Francesco
authors.initials: F
authors.lastname: Tombola
mesh_terms: D020013:Calcium Signaling / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*
chemical_list: D007473:Ion Channels; C515204:PIEZO1 protein, human
keywords: Yap/Taz; blebbistatin; calcium signaling; matrix mechanics; myosin II