Tenascin-C deficiency impairs alveolarization and microvascular maturation during postnatal lung development.

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.