Defining a mesenchymal progenitor niche at single-cell resolution
INTRODUCTION In most vertebrate organs, epithelial tubes or sacs are surrounded by
support and stromal tissues—including smooth muscle, cartilage, pericytes, fibroblasts, and
mesothelium—that form during development from a loose collection of undifferentiated
progenitor cells called mesenchyme. Although the behavior and regulation of epithelial
progenitors and their niches have begun to be elucidated, much less is known about the
identity and behavior of the progenitors of support and stromal tissues. This is critical not …
support and stromal tissues—including smooth muscle, cartilage, pericytes, fibroblasts, and
mesothelium—that form during development from a loose collection of undifferentiated
progenitor cells called mesenchyme. Although the behavior and regulation of epithelial
progenitors and their niches have begun to be elucidated, much less is known about the
identity and behavior of the progenitors of support and stromal tissues. This is critical not …
INTRODUCTION
In most vertebrate organs, epithelial tubes or sacs are surrounded by support and stromal tissues—including smooth muscle, cartilage, pericytes, fibroblasts, and mesothelium—that form during development from a loose collection of undifferentiated progenitor cells called mesenchyme. Although the behavior and regulation of epithelial progenitors and their niches have begun to be elucidated, much less is known about the identity and behavior of the progenitors of support and stromal tissues. This is critical not only because of the key cell types that they form but also because support and stromal cells can signal to epithelial stem cells and tumors and contribute to other serious diseases such as fibrosis and asthma. Mesenchyme cells are generally thought to represent highly proliferative, migratory, and multipotent cells that condense around epithelia to generate support and stromal cell types and do not form organized progenitor pools. Elucidating their behavior has been limited by the inability to track the fate of individual mesenchymal cells in development.
Diverse mechanisms generate mesenchymal cell derivatives. (Top) Single mesenchyme cells are labeled early in lung development. The labeled cell (green) proliferates, and daughter cells disperse to seed progenitor “niches” that generate support and stromal cell types. (Bottom) Photomicrographs of individual clones and schematics of mesenchymal niches, highlighting the distinct modes of recruitment. Airway epithelium, white (schematic), blue (photomicrographs); mesenchyme, light gray (schematic); mesothelium, dark gray (schematic outline); smooth muscle, red (schematic); endothelium, blue (schematic). Scale bars, 10 μm. Diverse mechanisms generate mesenchymal cell derivatives. (Top) Single mesenchyme cells are labeled early in lung development. The labeled cell (green) proliferates, and daughter cells disperse to seed progenitor “niches” that generate support and stromal cell types. (Bottom) Photomicrographs of individual clones and schematics of mesenchymal niches, highlighting the distinct modes of recruitment. Airway epithelium, white (schematic), blue (photomicrographs); mesenchyme, light gray (schematic); mesothelium, dark gray (schematic outline); smooth muscle, red (schematic); endothelium, blue (schematic). Scale bars, 10 μm.
RATIONALE
We adapted clonal cell labeling strategies with multicolor reporters in mice to probe the behavior and potential of individual and sibling mesenchyme cells in lung development. This was used to define the proliferation, migration, and differentiation behavior of individual mesenchyme cells and to map the locations and behavior of mesenchymal progenitors at single-cell resolution.
RESULTS
We show that although mesenchymal cells are highly proliferative, as classical studies suggested, there is a surprising diversity of mesenchymal progenitor populations with different locations, patterns of migration, recruitment mechanisms, and lineage boundaries. We focus on airway smooth muscle progenitors, which map exclusively to the mesenchyme just ahead of budding and bifurcating airway branches. Progenitors are recruited from these tip pools to the branch stalk, where they differentiate into circumferentially oriented airway smooth muscle cells. There is a lineage boundary that prevents mesenchymal cells surrounding airway stalks from becoming airway smooth muscle from branch sides, but this stalk mesenchyme can be induced in the presence of a newly budded airway branch to generate a new smooth muscle progenitor pool dedicated to the new branch. Micrografting experiments show that the airway tip alone is …
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