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1.
Nat Commun ; 13(1): 7137, 2022 11 21.
Article in English | MEDLINE | ID: mdl-36414616

ABSTRACT

The lung's gas exchange surface is comprised of alveolar AT1 and AT2 cells that are corrupted in several common and deadly diseases. They arise from a bipotent progenitor whose differentiation is thought to be dictated by differential mechanical forces. Here we show the critical determinant is FGF signaling. Fgfr2 is expressed in the developing progenitors in mouse then restricts to nascent AT2 cells and remains on throughout life. Its ligands are expressed in surrounding mesenchyme and can, in the absence of exogenous mechanical cues, induce progenitors to form alveolospheres with intermingled AT2 and AT1 cells. FGF signaling directly and cell autonomously specifies AT2 fate; progenitors lacking Fgfr2 in vitro and in vivo exclusively acquire AT1 fate. Fgfr2 loss in AT2 cells perinatally results in reprogramming to AT1 identity, whereas loss or inhibition later in life triggers AT2 apoptosis and compensatory regeneration. We propose that Fgfr2 signaling selects AT2 fate during development, induces a cell non-autonomous AT1 differentiation signal, then continuously maintains AT2 identity and survival throughout life.


Subject(s)
Alveolar Epithelial Cells , Mesoderm , Animals , Mice , Cell Differentiation , Signal Transduction , Apoptosis
2.
Elife ; 72018 03 21.
Article in English | MEDLINE | ID: mdl-29560858

ABSTRACT

Non-malignant breast epithelial cells cultured in three-dimensional laminin-rich extracellular matrix (lrECM) form well organized, growth-arrested acini, whereas malignant cells form continuously growing disorganized structures. While the mechanical properties of the microenvironment have been shown to contribute to formation of tissue-specific architecture, how transient external force influences this behavior remains largely unexplored. Here, we show that brief transient compression applied to single malignant breast cells in lrECM stimulated them to form acinar-like structures, a phenomenon we term 'mechanical reversion.' This is analogous to previously described phenotypic 'reversion' using biochemical inhibitors of oncogenic pathways. Compression stimulated nitric oxide production by malignant cells. Inhibition of nitric oxide production blocked mechanical reversion. Compression also restored coherent rotation in malignant cells, a behavior that is essential for acinus formation. We propose that external forces applied to single malignant cells restore cell-lrECM engagement and signaling lost in malignancy, allowing them to reestablish normal-like tissue architecture.


Subject(s)
Breast/metabolism , Epithelial Cells/metabolism , Nitric Oxide/metabolism , Stress, Mechanical , Acinar Cells/drug effects , Acinar Cells/metabolism , Breast/cytology , Breast/drug effects , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line , Cell Line, Tumor , Epithelial Cells/drug effects , Extracellular Matrix/metabolism , Humans , Laminin/metabolism , Laminin/pharmacology , Microscopy, Confocal , Signal Transduction/drug effects , Time-Lapse Imaging/methods
3.
Science ; 359(6380): 1118-1123, 2018 03 09.
Article in English | MEDLINE | ID: mdl-29420258

ABSTRACT

Alveoli, the lung's respiratory units, are tiny sacs where oxygen enters the bloodstream. They are lined by flat alveolar type 1 (AT1) cells, which mediate gas exchange, and AT2 cells, which secrete surfactant. Rare AT2s also function as alveolar stem cells. We show that AT2 lung stem cells display active Wnt signaling, and many of them are near single, Wnt-expressing fibroblasts. Blocking Wnt secretion depletes these stem cells. Daughter cells leaving the Wnt niche transdifferentiate into AT1s: Maintaining Wnt signaling prevents transdifferentiation, whereas abrogating Wnt signaling promotes it. Injury induces AT2 autocrine Wnts, recruiting "bulk" AT2s as progenitors. Thus, individual AT2 stem cells reside in single-cell fibroblast niches providing juxtacrine Wnts that maintain them, whereas injury induces autocrine Wnts that transiently expand the progenitor pool. This simple niche maintains the gas exchange surface and is coopted in cancer.


Subject(s)
Cell Transdifferentiation , Pulmonary Alveoli/cytology , Stem Cell Niche/physiology , Stem Cells/cytology , Wnt Signaling Pathway , Animals , Fibroblasts/cytology , Fibroblasts/metabolism , Lung/physiology , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mice, Inbred C57BL , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Pulmonary Alveoli/metabolism , Stem Cells/metabolism
4.
Nature ; 507(7491): 190-4, 2014 Mar 13.
Article in English | MEDLINE | ID: mdl-24499815

ABSTRACT

Alveoli are gas-exchange sacs lined by squamous alveolar type (AT) 1 cells and cuboidal, surfactant-secreting AT2 cells. Classical studies suggested that AT1 arise from AT2 cells, but recent studies propose other sources. Here we use molecular markers, lineage tracing and clonal analysis to map alveolar progenitors throughout the mouse lifespan. We show that, during development, AT1 and AT2 cells arise directly from a bipotent progenitor, whereas after birth new AT1 cells derive from rare, self-renewing, long-lived, mature AT2 cells that produce slowly expanding clonal foci of alveolar renewal. This stem-cell function is broadly activated by AT1 injury, and AT2 self-renewal is selectively induced by EGFR (epidermal growth factor receptor) ligands in vitro and oncogenic Kras(G12D) in vivo, efficiently generating multifocal, clonal adenomas. Thus, there is a switch after birth, when AT2 cells function as stem cells that contribute to alveolar renewal, repair and cancer. We propose that local signals regulate AT2 stem-cell activity: a signal transduced by EGFR-KRAS controls self-renewal and is hijacked during oncogenesis, whereas another signal controls reprogramming to AT1 fate.


Subject(s)
Lung Neoplasms/pathology , Lung/cytology , Lung/growth & development , Multipotent Stem Cells/cytology , Multipotent Stem Cells/pathology , Pulmonary Alveoli/cytology , Regeneration , Animals , Cell Differentiation , Cell Division , Cell Lineage , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Cells, Cultured , Cellular Reprogramming , Clone Cells/cytology , ErbB Receptors/metabolism , Female , Lung/embryology , Lung/pathology , Lung Neoplasms/metabolism , Male , Mice , Models, Biological , Multipotent Stem Cells/metabolism , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Signal Transduction
5.
Curr Biol ; 23(8): 703-9, 2013 Apr 22.
Article in English | MEDLINE | ID: mdl-23562267

ABSTRACT

For decades, the work of cell and developmental biologists has demonstrated the striking ability of the mesenchyme and the stroma to instruct epithelial form and function in the mammary gland, but the role of extracellular matrix (ECM) molecules in mammary pattern specification has not been elucidated. Here, we show that stromal collagen I (Col-I) fibers in the mammary fat pad are axially oriented prior to branching morphogenesis. Upon puberty, the branching epithelium orients along these fibers, thereby adopting a similar axial bias. To establish a causal relationship from Col-I fiber to epithelial orientation, we embedded mammary organoids within axially oriented Col-I fiber gels and observed dramatic epithelial co-orientation. Whereas a constitutively active form of Rac1, a molecule implicated in cell motility, prevented a directional epithelial response to Col-I fiber orientation, inhibition of the RhoA/Rho-associated kinase (ROCK) pathway did not. However, time-lapse studies revealed that, within randomly oriented Col-I matrices, the epithelium axially aligns fibers at branch sites via RhoA/ROCK-mediated contractions. Our data provide an explanation for how the stromal ECM encodes architectural cues for branch orientation as well as how the branching epithelium interprets and reinforces these cues through distinct signaling processes.


Subject(s)
Collagen Type I/metabolism , Mammary Glands, Animal/metabolism , Neuropeptides/metabolism , rac1 GTP-Binding Protein/metabolism , Animals , Epithelium/metabolism , Extracellular Matrix/metabolism , Female , Mesoderm/metabolism , Mice , Mice, Inbred BALB C , Microscopy, Confocal , Sexual Maturation , Signal Transduction , rho GTP-Binding Proteins/metabolism , rho-Associated Kinases/metabolism , rhoA GTP-Binding Protein
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