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Biomechanical forces promote embryonic haematopoiesis

Abstract

Biomechanical forces are emerging as critical regulators of embryogenesis, particularly in the developing cardiovascular system1,2. After initiation of the heartbeat in vertebrates, cells lining the ventral aspect of the dorsal aorta, the placental vessels, and the umbilical and vitelline arteries initiate expression of the transcription factor Runx1 (refs 3–5), a master regulator of haematopoiesis, and give rise to haematopoietic cells4. It remains unknown whether the biomechanical forces imposed on the vascular wall at this developmental stage act as a determinant of haematopoietic potential6. Here, using mouse embryonic stem cells differentiated in vitro, we show that fluid shear stress increases the expression of Runx1 in CD41+c-Kit+ haematopoietic progenitor cells7, concomitantly augmenting their haematopoietic colony-forming potential. Moreover, we find that shear stress increases haematopoietic colony-forming potential and expression of haematopoietic markers in the para-aortic splanchnopleura/aorta–gonads–mesonephros of mouse embryos and that abrogation of nitric oxide, a mediator of shear-stress-induced signalling8, compromises haematopoietic potential in vitro and in vivo. Collectively, these data reveal a critical role for biomechanical forces in haematopoietic development.

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Figure 1: Shear stress induces haematopoietic commitment from ES-derived cells.
Figure 2: Nitric oxide production regulates the expansion of haematopoietic progenitors.
Figure 3: Shear stress induces haematopoiesis in PSp/AGM-embryo-derived cells.
Figure 4: Runx1 expression and c.f.u. activity are shear-stress-dependent.

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Acknowledgements

We thank G. Losyev for assistance with flow cytometry, S. Schmitt for critical help in optimizing AGM culture conditions, C. Lengerke and Y. Mukouyama for critical discussions. L.A. was partially funded by the Giovanni Armenise-Harvard Foundation. O.N. was partially funded by the Barrie de la Maza Foundation. G.G.-C. was supported by grants from the National Institutes of Health and G.Q.D was supported by grants from the National Institutes of Health (NIH), and the NIH Director’s Pioneer Award of the NIH Roadmap for Medical Research. G.Q.D. is a recipient of the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and is an Investigator of the Howard Hughes Medical Institute.

Author Contributions L.A., O.N, G.G.-C. and G.Q.D. conceived ideas, designed experiments, analysed results and wrote the manuscript. P.J.M. performed the haemodynamic shear stress estimation and programmed the biomechanical stimuli. L.A., O.N., P.L.W., J.G.-S., S.M.-F. and A.S.-D. performed experiments. M.W.L. conceived ideas and contributed to experimental design. M.Y. and M.C.Y. set up timed pregnancies and isolated Ncx1 null and wild-type mouse embryos. All authors edited and reviewed the final manuscript. G.Q.D. and G.G.-C. co-directed the project.

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Correspondence to Guillermo García-Cardeña or George Q. Daley.

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Adamo, L., Naveiras, O., Wenzel, P. et al. Biomechanical forces promote embryonic haematopoiesis. Nature 459, 1131–1135 (2009). https://doi.org/10.1038/nature08073

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