Heterogeneity in collective endothelial cell behavior is a driver of arterio-venous remodeling
Posted on: 2 October 2020
Preprint posted on 16 September 2020
Categories: cell biology, developmental biology, molecular biology
Background
The blood vasculature is an important conduit system that supplies oxygen and nutrients to our tissues, transports hormones, and metabolites around our bodies as well as removes tissue waste products. Formation of the vasculature occurs progressively through vasculogenesis and repeated rounds of angiogenesis (Hogan and Schulte-Merker, 2017; Moccia et al., 2019; Patel-Hett and D’Amore, 2011; Risau, 1997). This ultimately gives rise to distinct vessel subtypes such as arteries and veins.
Notably, during the process of vascular remodeling, vessels can be lined with both arterial and venous endothelial cells. Factors determining whether a vessel eventually adopts an arterial or venous identity are still being unraveled (Betz et al., 2016; Hogan and Schulte-Merker, 2017). Recent studies observed that the displacement of arterial endothelial cells by venous endothelial cells leads to vessels adopting a final venous identity, independent of endothelial trans-differentiation (Weijts et al., 2018). Also, a combination of Notch signaling and blood flow have been reported to specify endothelial cells early in development, resulting in the formation of vessels that are fated to take on either an arterial or venous identity (Geudens et al., 2019).
Importantly, vascular remodeling is a highly dynamic process involving cellular behaviors such as changes in polarity and cell migration (Betz et al., 2016). Whether collective cell dynamics affect the distribution of vessel subtypes and their relationship with early specification events remains unclear. In this new preprint, Jiang et al. tackled these questions using 1) a novel transgenic zebrafish line (arteriobow) for lineage tracing, 2) long-term high-resolution confocal time-lapse imaging and, 3) systematic cluster analysis.
Key findings
To study the behavior of endothelial cells during vessel formation, the authors chose to use zebrafish as their model organism. To this end, they generated arteriobow– an endothelial-specific Brainbow reporter zebrafish line. Briefly, the Brainbow cassette (Livet et al., 2007; Weissman and Pan, 2015) contains a promoter followed by 3 fluorescent proteins: dTomato, mCerulean, and eYFP. These fluorescent proteins are spectrally distinct and are flanked by 2 pairs of mutually incompatible loxp sites. This ensures that the irreversible Cre-mediated recombination occurs only once. In addition, colour diversity increases proportionally according to the number of Brainbow transgenes inserted into the fish genome. As the resulting colour combinations are unique to each cell that carries the Brainbow transgene, this allows individual cells to be identified and their progeny traced as vascular development occurs.
In addition, the authors also developed a method to measure colour distances between and within different groups of cells. This allows them to characterize endothelial cell lineage relationships and explore the range of behaviors employed by endothelial cells during vascular remodeling.
By imaging and tracking cells at intersomitic vessels from 30 hpf to 72 hpf, the authors discovered that endothelial cells formed cohesive cohorts and moved collectively. A thorough examination of individual endothelial cell collectives indicated that cells could adopt up to 10 types of collective cell behaviors. Remarkably, the authors also noticed a correlation between the type of collective cell behavior adopted and the eventual intersomitic vessel identity. For instance, Type I, VIII, and IX behaviors are associated with vessels that adopt an arterial identity.
Figure 1. Classification of endothelial cell behaviors across time. Adapted from Figure 2B from Jiang et al.
Notch signaling is involved in arterio-venous fate determination (Gridley, 2010; Lawson et al., 2001). In addition, inhibition of this pathway was shown to increase intersomitic vessels adopting a venous identity (Geudens et al., 2010; Hogan et al., 2009). Notably, when the authors pharmacologically inhibited Notch signalling using the γ-secretase inhibitor (DAPT), they observed a change in the frequency of collective cell behaviors. There was a reduction in behaviors associated with arterial vessel identity and an increase in behaviors associated with venous vessel identity.
Since blood flow has been implicated in modulating Notch activity (Geudens et al., 2019; Weijts et al., 2018), the authors further investigated the effects of blood flow on collective cell behaviors. Treating embryos with tricaine methanesulfonate to reduce blood flow and heart rate led to an increase in arterial compartment formation. In addition, there was a reduction in behaviors associated with venous vessel identity and an increase in behaviors associated with arterial vessel identity.
What I like about this preprint
In this study, the authors addressed the question of whether collective cellular behaviors displayed during vascular remodeling could act as a predictive feature for vessel identity. Using a novel transgenic zebrafish line and an unbiased clustering analysis approach, they discovered that heterogeneous collective endothelial cell behaviors are associated with distinct vessel identity. Finally, the authors adopted a systematic approach to investigate what could easily be viewed as noise or stochastic behaviors. I find this to be an inspiring example of how to approach what seems to be biological ‘chaos’ and to make sense from it.
Questions for the authors
- Since this study focused specifically on behaviors displayed by arterial endothelial cell populations, would you expect similar or unique collective behaviors to be seen in venous endothelial cells?
- The observation that up to 10 distinct collective cell behaviors can be employed by arterial endothelial cells is fascinating! Could collective behaviors alone be sufficient to predict vessel identity independent of signaling pathways such as Notch? Are there any approaches one could use to modulate these behaviors to test this?
References:
Betz, C., Lenard, A., Belting, H.G., and Affolter, M. (2016). Cell behaviors and dynamics during angiogenesis. Development 143, 2249-2260.
Geudens, I., Coxam, B., Alt, S., Gebala, V., Vion, A.C., Meier, K., Rosa, A., and Gerhardt, H. (2019). Artery-vein specification in the zebrafish trunk is pre-patterned by heterogeneous Notch activity and balanced by flow-mediated fine-tuning. Development 146.
Geudens, I., Herpers, R., Hermans, K., Segura, I., Ruiz de Almodovar, C., Bussmann, J., De Smet, F., Vandevelde, W., Hogan, B.M., Siekmann, A., et al. (2010). Role of delta-like-4/Notch in the formation and wiring of the lymphatic network in zebrafish. Arterioscler Thromb Vasc Biol 30, 1695-1702.
Gridley, T. (2010). Notch signaling in the vasculature. Curr Top Dev Biol 92, 277-309.
Hogan, B.M., Herpers, R., Witte, M., Helotera, H., Alitalo, K., Duckers, H.J., and Schulte-Merker, S. (2009). Vegfc/Flt4 signalling is suppressed by Dll4 in developing zebrafish intersegmental arteries. Development136, 4001-4009.
Hogan, B.M., and Schulte-Merker, S. (2017). How to Plumb a Pisces: Understanding Vascular Development and Disease Using Zebrafish Embryos. Dev Cell 42, 567-583.
Lawson, N.D., Scheer, N., Pham, V.N., Kim, C.H., Chitnis, A.B., Campos-Ortega, J.A., and Weinstein, B.M. (2001). Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128, 3675-3683.
Livet, J., Weissman, T.A., Kang, H., Draft, R.W., Lu, J., Bennis, R.A., Sanes, J.R., and Lichtman, J.W. (2007). Transgenic strategies for combinatorial expression of fluorescent proteins in the nervous system. Nature 450, 56-62.
Moccia, F., Negri, S., Shekha, M., Faris, P., and Guerra, G. (2019). Endothelial Ca(2+) Signaling, Angiogenesis and Vasculogenesis: just What It Takes to Make a Blood Vessel. Int J Mol Sci 20.
Patel-Hett, S., and D’Amore, P.A. (2011). Signal transduction in vasculogenesis and developmental angiogenesis. Int J Dev Biol 55, 353-363.
Risau, W. (1997). Mechanisms of angiogenesis. Nature 386, 671-674.
Weijts, B., Gutierrez, E., Saikin, S.K., Ablooglu, A.J., Traver, D., Groisman, A., and Tkachenko, E. (2018). Blood flow-induced Notch activation and endothelial migration enable vascular remodeling in zebrafish embryos. Nat Commun 9, 5314.
Weissman, T.A., and Pan, Y.A. (2015). Brainbow: new resources and emerging biological applications for multicolor genetic labeling and analysis. Genetics 199, 293-306.
doi: https://doi.org/10.1242/prelights.25012
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