Co-development of the cardiovascular and pulmonary systems is a recent evolutionary adaption to terrestrial life that couples cardiac output with the gas exchange function of the lung1. Here we show that the murine pulmonary vasculature develops even in the absence of lung development. We have identified a population of multipotent cardiopulmonary mesoderm progenitors (CPPs) within the posterior pole of the heart that are marked by the expression of Wnt2, Gli1 and Isl1. We show that CPPs arise from cardiac progenitors before lung development. Lineage tracing and clonal analysis demonstrates that CPPs generate the mesoderm lineages within the cardiac inflow tract and lung including cardiomyocytes, pulmonary vascular and airway smooth muscle, proximal vascular endothelium, and pericyte-like cells. CPPs are regulated by hedgehog expression from the foregut endoderm, which is required for connection of the pulmonary vasculature to the heart. Together, these studies identify a novel population of multipotent cardiopulmonary progenitors that coordinates heart and lung co-development that is required for adaptation to terrestrial existence.
This is a preview of subscription content
Subscription info for Chinese customers
We have a dedicated website for our Chinese customers. Please go to naturechina.com to subscribe to this journal.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Peng, T. & Morrisey, E. E. Development of the pulmonary vasculature: current understanding and concepts for the future. Pulm Circ 3, 176–178 (2013)
Goss, A. M. et al. Wnt2/2b and β-catenin signaling are necessary and sufficient to specify lung progenitors in the foregut. Dev. Cell 17, 290–298 (2009)
Harris-Johnson, K. S., Domyan, E. T., Vezina, C. M. & Sun, X. β-Catenin promotes respiratory progenitor identity in mouse foregut. Proc. Natl Acad. Sci. USA 106, 16287–16292 (2009)
Cai, C. L. et al. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev. Cell 5, 877–889 (2003)
Moses, K. A., DeMayo, F., Braun, R. M., Reecy, J. L. & Schwartz, R. J. Embryonic expression of an Nkx2–5/Cre gene using ROSA26 reporter mice. Genesis 31, 176–180 (2001)
Goss, A. M. et al. Wnt2 signaling is necessary and sufficient to activate the airway smooth muscle program in the lung by regulating myocardin/Mrtf-B and Fgf10 expression. Dev. Biol. 356, 541–552 (2011)
Tian, Y. et al. Characterization and in vivo pharmacological rescue of a Wnt2–Gata6 pathway required for cardiac inflow tract development. Dev. Cell 18, 275–287 (2010)
Hoffmann, A. D., Peterson, M. A., Friedland-Little, J. M., Anderson, S. A. & Moskowitz, I. P. Sonic hedgehog is required in pulmonary endoderm for atrial septation. Development 136, 1761–1770 (2009)
Wang, Y. et al. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465, 483–486 (2010)
Red-Horse, K., Ueno, H., Weissman, I. L. & Krasnow, M. A. Coronary arteries form by developmental reprogramming of venous cells. Nature 464, 549–553 (2010)
Snippert, H. J. et al. Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134–144 (2010)
Lavine, K. J., Long, F., Choi, K., Smith, C. & Ornitz, D. M. Hedgehog signaling to distinct cell types differentially regulates coronary artery and vein development. Development 135, 3161–3171 (2008)
White, A. C., Lavine, K. J. & Ornitz, D. M. FGF9 and SHH regulate mesenchymal Vegfa expression and development of the pulmonary capillary network. Development 134, 3743–3752 (2007)
Lin, L., Bu, L., Cai, C. L., Zhang, X. & Evans, S. Isl1 is upstream of sonic hedgehog in a pathway required for cardiac morphogenesis. Dev. Biol. 295, 756–763 (2006)
Morrisey, E. E. et al. GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev. 12, 3579–3590 (1998)
Bai, L. Y. et al. Differential expression of Sonic hedgehog and Gli1 in hematological malignancies. Leukemia 22, 226–228 (2008)
Harfe, B. D. et al. Evidence for an expansion-based temporal Shh gradient in specifying vertebrate digit identities. Cell 118, 517–528 (2004)
Jeong, J., Mao, J., Tenzen, T., Kottmann, A. H. & McMahon, A. P. Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. Genes Dev. 18, 937–951 (2004)
Lepore, J. J. et al. High-efficiency somatic mutagenesis in smooth muscle cells and cardiac myocytes in SM22α-Cre transgenic mice. Genesis 41, 179–184 (2005)
Long, F., Zhang, X. M., Karp, S., Yang, Y. & McMahon, A. P. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development 128, 5099–5108 (2001)
Sun, Y. et al. Islet 1 is expressed in distinct cardiovascular lineages, including pacemaker and coronary vascular cells. Dev. Biol. 304, 286–296 (2007)
Shu, W., Jiang, Y. Q., Lu, M. M. & Morrisey, E. E. Wnt7b regulates mesenchymal proliferation and vascular development in the lung. Development 129, 4831–4842 (2002)
Snippert, H. J., Schepers, A. G., Delconte, G., Siersema, P. D. & Clevers, H. Slide preparation for single-cell-resolution imaging of fluorescent proteins in their three-dimensional near-native environment. Nature Protocols 6, 1221–1228 (2011)
Morrisey, E. E., Ip, H. S., Lu, M. M. & Parmacek, M. S. GATA-6: a zinc finger transcription factor that is expressed in multiple cell lineages derived from lateral mesoderm. Dev. Biol. 177, 309–322 (1996)
Yokomizo, T. et al. Whole-mount three-dimensional imaging of internally localized immunostained cells within mouse embryos. Nature Protocols 7, 421–431 (2012)
The authors appreciate the input of M. Kahn and J. Epstein in these studies. The authors are grateful to A. Stout for help in imaging. L. Guo provided assistance with figure illustrations. These studies were supported by funds from the National Institutes of Health (HL110942, HL100405, HL087825 to E.E.M. and HL117649 to S.M.E.) and the American Heart Association Jon DeHaan Myogenesis Center. T.P. is supported by T32 HL07586-23. C.J.B. is supported by P30 NS047101.
The authors declare no competing financial interests.
This file contains Supplementary Figures 1-14 and Supplementary Tables 1-4. (PDF 11318 kb)
This is a 3D stack of confocal images of a Shhcre embryo showing the pulmonary arteries and veins extending from the early heart at E10.5. (AVI 1460 kb)
This is a 3D stack of confocal images of a Shhcre:Ctnnb1flox/flox embryo showing the persistence of pulmonary arteries and veins extending from the early heart in the absence of lung development at E10.5. (AVI 1259 kb)
About this article
Cite this article
Peng, T., Tian, Y., Boogerd, C. et al. Coordination of heart and lung co-development by a multipotent cardiopulmonary progenitor. Nature 500, 589–592 (2013). https://doi.org/10.1038/nature12358
A right pulmonary vein abnormality treated with 3D CT assistance in thoracoscopic surgery for esophageal cancer: a case report
Surgical Case Reports (2022)
Nature Reviews Cardiology (2022)
Journal of Perinatology (2021)
Communications Biology (2021)
Single cell transcriptomics identifies a signaling network coordinating endoderm and mesoderm diversification during foregut organogenesis
Nature Communications (2020)