Editors' ChoiceRegeneration

BASCing in the Presence of Endothelial Cells

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Sci. Signal.  18 Feb 2014:
Vol. 7, Issue 313, pp. ec47
DOI: 10.1126/scisignal.2005179

Lung development and regeneration in response to injury could depend on the interaction between lung epithelial progenitor cells and the surrounding stromal environment. Multiple types of progenitor cells reside in the lung epithelium, including bronchioalveolar stem cells (BASCs) positioned at the junction between the bronchial ducts and alveoli. Lee et al. found that signals from lung endothelial cells promote self-renewal and differentiation of BASCs. When grown in the presence of murine lung endothelial cells (luMECs) in three-dimensional culture, primary murine BASCs but not alveolar type 2 cells (AT2Cs), another type of progenitor cell found in the lung, gave rise to colonies that could be continuously grown in culture. Clonal analysis of individual, fluorescently labeled BASCs in culture revealed that single BASCs could produce bronchiolar and alveolar cells as well as new BASCs, indicating that BASCs are multipotent and can self-renew. When injected subcutaneously in mice, BASC-luMEC, but not AT2C-luMEC, cocultures produced multilineage tube-like lung epithelial structures. Thombospondin-1 (TSP1) is an antiangiogenic glycoprotein in lung endothelial cells that increases during developmental alveolar cell proliferation and differentiation, and TSP1 expression was increased in response to alveolar injury. Coculture of BASCs with luMECs from TSP1-deficient (TSP1–/–) mice produced more bronchiolar cells and fewer alveolar cells in culture and when transplanted in mice. These effects were reversed by treating BASC-TSP1–/–luMEC cocultures with conditioned media from wild-type luMECs or recombinant TSP1. After alveolar injury, the lungs of TSP1–/– mice had fewer regenerated alveolar cells but more BASCs. The expression of the gene encoding bone morphogenetic protein 4 (BMP4) was also increased after alveolar injury in wild-type mice. BMP4 treatment increased alveolar and decreased bronchiolar differentiation in BASC-luMEC cocultures but not in BASC-TSP1–/–luMEC cocultures. In contrast, treating BASC-luMEC cocultures with the BMP-inhibitor Noggin or establishing BASC cocultures with luMECs deficient for the type 1a BMP receptor produced the opposite effect on differentiation. Recombinant BMP4 induced calcineurin-dependent nuclear translocation of the transcriptional activator NFATc1 and binding of NFATc1 to the promoter of TSP1, and increased expression of TSP1 in luMECs. Thus, in response to alveolar injury, BMP4 signals to lung endothelial cells to activate NFATc1-dependent production of TSP1, which stimulates alveolar differentiation of BASCs. This signaling pathway could be therapeutically targeted in patients with lung injury or disease.

J.-H. Lee, D. H. Bhang, A. Beede, T. L. Huang, B. R. Stripp, K. D. Bloch, A. J. Wagers, Y.-H. Tseng, S. Ryeom, C. F. Kim, Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-thrombospondin-1 axis. Cell 156, 440–455 (2014). [PubMed]