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Coordination of heart and lung co-development by a multipotent cardiopulmonary progenitor

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Abstract

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.

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Figure 1: The pulmonary vasculature develops in the absence of lung specification.
Figure 2: Wnt2+ and Gli1+ cells define a cardiopulmonary progenitor and generate mesoderm derivatives of the lung and cardiac inflow tract.
Figure 3: Clonal analysis reveals that CPPs generate related lineages within the cardiopulmonary system.
Figure 4: Hedgehog signalling is required in CPPs to coordinate the vascular connection between the heart and lung.

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Acknowledgements

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.

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T.P. and E.E.M. designed the experiments. T.P., Y.T., C.J.B., M.M.L., R.S.K. and K.M.S. performed experiments. S.M.E. provided animal lines and expertise. T.P. and E.E.M. wrote the manuscript.

Corresponding author

Correspondence to Edward E. Morrisey.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-14 and Supplementary Tables 1-4. (PDF 11318 kb)

Three-dimensional CD31 immunostained control embryo (Shhcre)

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)

Three-dimensional CD31 immunostained lung agenesis mutant (Shhcre:Ctnnb1flox/flox)

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)

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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

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