Abstract
After the airways have been formed by branching morphogenesis the gas exchange area of the developing lung is enlarged by the formation of new alveolar septa (alveolarization). The septa themselves mature by a reduction of their double-layered capillary networks to single-layered ones (microvascular maturation). Alveolarization in mice is subdivided into a first phase (postnatal days 4–21, classical alveolarization), where new septa are lifted off from immature preexisting septa, and a second phase (day 14 to adulthood, continued alveolarization), where new septa are formed from mature septa. Tenascin-C (TNC) is a multidomain extracellular matrix protein contributing to organogenesis and tumorigenesis. It is highly expressed during classical alveolarization, but afterward its expression is markedly reduced. To study the effect of TNC deficiency on postnatal lung development, the formation and maturation of the alveolar septa were followed stereologically. Furthermore, the number of proliferating (Ki-67-positive) and TUNEL-positive cells was estimated. In TNC-deficient mice for both phases of alveolarization a delay and catch-up were observed. Cell proliferation was increased at days 4 and 6; at day 7, thick septa with an accumulation of capillaries and cells were observed; and the number of TUNEL-positive cells (dying cells or DNA repair) was increased at day 10. Whereas at days 15 and 21 premature microvascular maturation was detected, the microvasculature was less mature at day 60 compared with wild type. No differences were observed in adulthood. We conclude that TNC contributes to the formation of new septa, to microvascular maturation, and to cell proliferation and migration during postnatal lung development.NEW & NOTEWORTHY Previously, we showed that the extracellular matrix protein tenascin-C takes part in prenatal lung development by controlling branching morphogenesis. Now we report that tenascin-C is also important during postnatal lung development, because tenascin-C deficiency delays the formation and maturation of the alveolar septa during not only classical but also continued alveolarization. Adult lungs are indistinguishable from wild type because of a catch-up formation of new septa.
Highlights
Starting from the lung buds the conducting airways and parts of the respiratory airways are formed by continuous cycles of branching and growth into the surround-ing mesenchyme [branching morphogenesis [65, 83]]
An additional question arising is why the anlage of new alveolar septa and septal surface area observed in adult TNCdeficient animals is identical to wild type
In parallel with the prolonged alveolarization a decrease in the fraction of the septal surface area characterized by a single-layered capillary network was observed between days 36 and 60 in TNC-deficient lungs (Fig. 5A)
Summary
Starting from the lung buds (lung anlage) the conducting airways and parts of the respiratory airways are formed by continuous cycles of branching and growth into the surround-ing mesenchyme [branching morphogenesis [65, 83]]. The newly formed septa increase in height and subdivide the existing air spaces into smaller units (septation), called alveoli. Whereas alveolarization focuses on the formation of new air spaces (alveoli), septation focuses on the formation of new walls (septa) that subdivide the existing air spaces. Classical alveolarization (days 4 –21 in mice and rats) is characterized by the lifting off/folding up of new septa from immature preexisting septa containing a double-layered capillary network, whereas during continued alveolarization [day 14 to adulthood (roughly days 36 – 60) in mice and rats], new septa are lifted off/folded up from mature preexisting septa containing a single-layered capillary network [1, 50, 70]. Alveolarization is considered to start before birth and last up to young adulthood, and microvascular maturation is regarded to last until 2–3 yr of age [65, 66, 83]
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