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BMP signaling and cellular dynamics during regeneration of airway epithelium from basal progenitors.

ABSTRACT: The pseudostratified epithelium of the lung contains ciliated and secretory luminal cells and basal stem/progenitor cells. To identify signals controlling basal cell behavior we screened factors that alter their self-renewal and differentiation in a clonal organoid (tracheosphere) assay. This revealed that inhibitors of the canonical BMP signaling pathway promote proliferation but do not affect lineage choice, whereas exogenous Bmp4 inhibits proliferation and differentiation. We therefore followed changes in BMP pathway components in vivo in the mouse trachea during epithelial regeneration from basal cells after injury. The findings suggest that BMP signaling normally constrains proliferation at steady state and this brake is released transiently during repair by the upregulation of endogenous BMP antagonists. Early in repair, the packing of epithelial cells along the basal lamina increases, but density is later restored by active extrusion of apoptotic cells. Systemic administration of the BMP antagonist LDN-193189 during repair initially increases epithelial cell number but, following the shedding phase, normal density is restored. Taken together, these results reveal crucial roles for both BMP signaling and cell shedding in homeostasis of the respiratory epithelium.

SUBMITTER: Tadokoro T

PROVIDER: S-EPMC4813333 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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BMP signaling and cellular dynamics during regeneration of airway epithelium from basal progenitors.

Tadokoro Tomomi T Gao Xia X Hong Charles C CC Hotten Danielle D Hogan Brigid L M BL

Development (Cambridge, England) 20160125 5

The pseudostratified epithelium of the lung contains ciliated and secretory luminal cells and basal stem/progenitor cells. To identify signals controlling basal cell behavior we screened factors that alter their self-renewal and differentiation in a clonal organoid (tracheosphere) assay. This revealed that inhibitors of the canonical BMP signaling pathway promote proliferation but do not affect lineage choice, whereas exogenous Bmp4 inhibits proliferation and differentiation. We therefore follow ...[more]

PMID: 26811382

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Project description:BackgroundThe airways of mammalian lung are lined with highly specialized cell types that are the target of airborne toxicants and injury. Several epithelial cell types and bone marrow-derived mesenchymal stem cells have been identified to serve as stem cells during injury repair. However, the contributions of endogenous mesenchymal cells to recruitment, expansion or differentiation of stem cells, and repair and reestablishment of the normal composition of airway epithelium following injury have not been addressed.MethodsThe role of mouse pulmonary mesenchymal cells was investigated by lineage tracing using Dermo1-Cre; ROSAmTmG mice. In experimental models of lung injury by lipopolysaccharide and naphthalene, GFP-labeled Dermo1+ mesenchymal cells were traced during injury repair. In vitro lung explant culture treated with or without lipopolysaccharide was also used to verify in vivo data.ResultsDuring injury repair, a subgroup of GFP-labeled Dermo1+ mesenchymal cells were found to contribute to normal repair of the airway epithelium and differentiated into Club cells, ciliated cells, and goblet cells. In Club cell-specific naphthalene injury model, the process of Dermo1+ stem cell regenerating epithelial cells was dissected. The Dermo1+ stem cells was migrated into the airway epithelium layer sooner after injury, and sequentially differentiated transitionally to epithelial stem cells, such as neuroendocrine cells, and finally to newly differentiated Club cells, ciliated cells, and goblet cells in injury repair.ConclusionIn this study, a population of Dermo1+ mesenchymal stem cell was identified to serve as stem cells in airway epithelial cell regeneration during injury repair. The Dermo1+ mesenchymal stem cell differentiated into epithelial stem cells before reestablishing various epithelial cells. These findings have implications for understanding the regulation of lung repair and the potential for usage of mesenchymal stem cells in therapeutic strategies for lung diseases.

Project description:BackgroundIn syllids (Annelida, Syllidae), the regenerative blastema was subject of many studies in the mid and late XXth century. This work on syllid regeneration showed that the blastema is developed by a process of dedifferentiation of cells near the wound, followed by their proliferation and redifferentiation (cells differentiate to the original cell type) or, in some specific cases, transdifferentiation (cells differentiate to a cell type different from the original). Up to date, participation of stem cells or pre-existing proliferative cells in the blastema development has never been observed in syllids. This study provides the first comprehensive description of Syllis malaquini's regenerative capacity, including data on the cellular proliferation dynamics by using an EdU/BrdU labelling approach, in order to trace proliferative cells (S-phase cells) present before and after operation.ResultsSyllis malaquini can restore the anterior and posterior body from different cutting levels under experimental conditions, even from midbody fragments. Our results on cellular proliferation showed that S-phase cells present in the body before bisection do not significantly contribute to blastema development. However, in some specimens cut at the level of the proventricle, cells in S-phase located in the digestive tube before bisection participated in regeneration. Also, our results showed that nucleus shape allows to distinguish different types of blastemal cells as forming specific tissues. Additionally, simultaneous and sequential addition of segments seem to occur in anterior regeneration, while only sequential addition was observed in posterior regeneration. Remarkably, in contrast with previous studies in syllids, sexual reproduction was not induced during anterior regeneration of amputees lacking the proventricle, a foregut organ widely known to be involved in the stolonization control.ConclusionsOur findings led us to consider that although dedifferentiation and redifferentiation might be more common, proliferative cells present before injury can be involved in regenerative processes in syllids, at least in some cases. Also, we provide data for comparative studies on resegmentation as a process that differs between anterior and posterior regeneration; and on the controversial role of the proventricle in the reproduction of different syllid lineages.

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BMP signaling and cellular dynamics during regeneration of airway epithelium from basal progenitors.

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BMP signaling and cellular dynamics during regeneration of airway epithelium from basal progenitors.

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