Age-Related Dysfunction in Mechanotransduction Impairs Differentiation of Human Mammary Epithelial Progenitors
Dysfunctional progenitor and luminal cells with acquired basal cell properties accumulate during human mammary epithelial aging for reasons not understood. Multipotent progenitors from women aged <30 years were exposed to a physiologically relevant range of matrix elastic modulus (stiffness). Inc...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2014-06-01
|
| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124714003969 |
| _version_ | 1818062201291800576 |
|---|---|
| author | Fanny A. Pelissier James C. Garbe Badriprasad Ananthanarayanan Masaru Miyano ChunHan Lin Tiina Jokela Sanjay Kumar Martha R. Stampfer James B. Lorens Mark A. LaBarge |
| author_facet | Fanny A. Pelissier James C. Garbe Badriprasad Ananthanarayanan Masaru Miyano ChunHan Lin Tiina Jokela Sanjay Kumar Martha R. Stampfer James B. Lorens Mark A. LaBarge |
| author_sort | Fanny A. Pelissier |
| collection | DOAJ |
| description | Dysfunctional progenitor and luminal cells with acquired basal cell properties accumulate during human mammary epithelial aging for reasons not understood. Multipotent progenitors from women aged <30 years were exposed to a physiologically relevant range of matrix elastic modulus (stiffness). Increased stiffness causes a differentiation bias towards myoepithelial cells while reducing production of luminal cells and progenitor maintenance. Lineage representation in progenitors from women >55 years is unaffected by physiological stiffness changes. Efficient activation of Hippo pathway transducers YAP and TAZ is required for the modulus-dependent myoepithelial/basal bias in younger progenitors. In older progenitors, YAP and TAZ are activated only when stressed with extraphysiologically stiff matrices, which bias differentiation towards luminal-like phenotypes. In vivo YAP is primarily active in myoepithelia of younger breasts, but localization and activity increases in luminal cells with age. Thus, aging phenotypes of mammary epithelia may arise partly because alterations in Hippo pathway activation impair microenvironment-directed differentiation and lineage specificity. |
| first_indexed | 2024-12-10T14:00:26Z |
| format | Article |
| id | doaj.art-4d6696dd5bbc480d88d3b8b0c1f5c4e5 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T14:00:26Z |
| publishDate | 2014-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-4d6696dd5bbc480d88d3b8b0c1f5c4e52022-12-22T01:45:48ZengElsevierCell Reports2211-12472014-06-01761926193910.1016/j.celrep.2014.05.021Age-Related Dysfunction in Mechanotransduction Impairs Differentiation of Human Mammary Epithelial ProgenitorsFanny A. Pelissier0James C. Garbe1Badriprasad Ananthanarayanan2Masaru Miyano3ChunHan Lin4Tiina Jokela5Sanjay Kumar6Martha R. Stampfer7James B. Lorens8Mark A. LaBarge9Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USALife Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USADepartment of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USALife Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USALife Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USALife Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USADepartment of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USALife Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USACenter for Cancer Biomarkers, Department of Biomedicine, University of Bergen, Bergen 5009, NorwayLife Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USADysfunctional progenitor and luminal cells with acquired basal cell properties accumulate during human mammary epithelial aging for reasons not understood. Multipotent progenitors from women aged <30 years were exposed to a physiologically relevant range of matrix elastic modulus (stiffness). Increased stiffness causes a differentiation bias towards myoepithelial cells while reducing production of luminal cells and progenitor maintenance. Lineage representation in progenitors from women >55 years is unaffected by physiological stiffness changes. Efficient activation of Hippo pathway transducers YAP and TAZ is required for the modulus-dependent myoepithelial/basal bias in younger progenitors. In older progenitors, YAP and TAZ are activated only when stressed with extraphysiologically stiff matrices, which bias differentiation towards luminal-like phenotypes. In vivo YAP is primarily active in myoepithelia of younger breasts, but localization and activity increases in luminal cells with age. Thus, aging phenotypes of mammary epithelia may arise partly because alterations in Hippo pathway activation impair microenvironment-directed differentiation and lineage specificity.http://www.sciencedirect.com/science/article/pii/S2211124714003969 |
| spellingShingle | Fanny A. Pelissier James C. Garbe Badriprasad Ananthanarayanan Masaru Miyano ChunHan Lin Tiina Jokela Sanjay Kumar Martha R. Stampfer James B. Lorens Mark A. LaBarge Age-Related Dysfunction in Mechanotransduction Impairs Differentiation of Human Mammary Epithelial Progenitors Cell Reports |
| title | Age-Related Dysfunction in Mechanotransduction Impairs Differentiation of Human Mammary Epithelial Progenitors |
| title_full | Age-Related Dysfunction in Mechanotransduction Impairs Differentiation of Human Mammary Epithelial Progenitors |
| title_fullStr | Age-Related Dysfunction in Mechanotransduction Impairs Differentiation of Human Mammary Epithelial Progenitors |
| title_full_unstemmed | Age-Related Dysfunction in Mechanotransduction Impairs Differentiation of Human Mammary Epithelial Progenitors |
| title_short | Age-Related Dysfunction in Mechanotransduction Impairs Differentiation of Human Mammary Epithelial Progenitors |
| title_sort | age related dysfunction in mechanotransduction impairs differentiation of human mammary epithelial progenitors |
| url | http://www.sciencedirect.com/science/article/pii/S2211124714003969 |
| work_keys_str_mv | AT fannyapelissier agerelateddysfunctioninmechanotransductionimpairsdifferentiationofhumanmammaryepithelialprogenitors AT jamescgarbe agerelateddysfunctioninmechanotransductionimpairsdifferentiationofhumanmammaryepithelialprogenitors AT badriprasadananthanarayanan agerelateddysfunctioninmechanotransductionimpairsdifferentiationofhumanmammaryepithelialprogenitors AT masarumiyano agerelateddysfunctioninmechanotransductionimpairsdifferentiationofhumanmammaryepithelialprogenitors AT chunhanlin agerelateddysfunctioninmechanotransductionimpairsdifferentiationofhumanmammaryepithelialprogenitors AT tiinajokela agerelateddysfunctioninmechanotransductionimpairsdifferentiationofhumanmammaryepithelialprogenitors AT sanjaykumar agerelateddysfunctioninmechanotransductionimpairsdifferentiationofhumanmammaryepithelialprogenitors AT martharstampfer agerelateddysfunctioninmechanotransductionimpairsdifferentiationofhumanmammaryepithelialprogenitors AT jamesblorens agerelateddysfunctioninmechanotransductionimpairsdifferentiationofhumanmammaryepithelialprogenitors AT markalabarge agerelateddysfunctioninmechanotransductionimpairsdifferentiationofhumanmammaryepithelialprogenitors |