Browsing by Author "Heemskerk, Idse"

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    Nodal is a short-range morphogen with activity that spreads through a relay mechanism in human gastruloids
    (Springer Nature, 2022) Liu, Lizhong; Nemashkalo, Anastasiia; Rezende, Luisa; Jung, Ji Yoon; Chhabra, Sapna; Guerra, M. Cecilia; Heemskerk, Idse; Warmflash, Aryeh
    Morphogens are signaling molecules that convey positional information and dictate cell fates during development. Although ectopic expression in model organisms suggests that morphogen gradients form through diffusion, little is known about how morphogen gradients are created and interpreted during mammalian embryogenesis due to the combined difficulties of measuring endogenous morphogen levels and observing development in utero. Here we take advantage of a human gastruloid model to visualize endogenous Nodal protein in living cells, during specification of germ layers. We show that Nodal is extremely short range so that Nodal protein is limited to the immediate neighborhood of source cells. Nodal activity spreads through a relay mechanism in which Nodal production induces neighboring cells to transcribe Nodal. We further show that the Nodal inhibitor Lefty, while biochemically capable of long-range diffusion, also acts locally to control the timing of Nodal spread and therefore of mesoderm differentiation during patterning. Our study establishes a paradigm for tissue patterning by an activator-inhibitor pair.
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    Rapid changes in morphogen concentration control self-organized patterning in human embryonic stem cells
    (eLife Sciences Publications, Ltd, 2019) Heemskerk, Idse; Burt, Kari; Miller, Matthew; Chhabra, Sapna; Guerra, M.Cecilia; Liu, Lizhong; Warmflash, Aryeh
    During embryonic development, diffusible signaling molecules called morphogens are thought to determine cell fates in a concentration-dependent way. Yet, in mammalian embryos, concentrations change rapidly compared to the time for making cell fate decisions. Here, we use human embryonic stem cells (hESCs) to address how changing morphogen levels influence differentiation, focusing on how BMP4 and Nodal signaling govern the cell-fate decisions associated with gastrulation. We show that BMP4 response is concentration dependent, but that expression of many Nodal targets depends on rate of concentration change. Moreover, in a self-organized stem cell model for human gastrulation, expression of these genes follows rapid changes in endogenous Nodal signaling. Our study shows a striking contrast between the specific ways ligand dynamics are interpreted by two closely related signaling pathways, highlighting both the subtlety and importance of morphogen dynamics for understanding mammalian embryogenesis and designing optimized protocols for directed stem cell differentiation.
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    Roadmap for the multiscale coupling of biochemical and mechanical signals during development
    (IOP Publishing, 2021) Lenne, Pierre-François; Munro, Edwin; Heemskerk, Idse; Warmflash, Aryeh; Bocanegra-Moreno, Laura; Kishi, Kasumi; Kicheva, Anna; Long, Yuchen; Fruleux, Antoine; Boudaoud, Arezki; Saunders, Timothy E.; Caldarelli, Paolo; Michaut, Arthur; Gros, Jerome; Maroudas-Sacks, Yonit; Keren, Kinneret; Hannezo, Edouard; Gartner, Zev J.; Stormo, Benjamin; Gladfelter, Amy; Rodrigues, Alan; Shyer, Amy; Minc, Nicolas; Maître, Jean-Léon; Talia, Stefano Di; Khamaisi, Bassma; Sprinzak, David; Tlili, Sham
    The way in which interactions between mechanics and biochemistry lead to the emergence of complex cell and tissue organization is an old question that has recently attracted renewed interest from biologists, physicists, mathematicians and computer scientists. Rapid advances in optical physics, microscopy and computational image analysis have greatly enhanced our ability to observe and quantify spatiotemporal patterns of signalling, force generation, deformation, and flow in living cells and tissues. Powerful new tools for genetic, biophysical and optogenetic manipulation are allowing us to perturb the underlying machinery that generates these patterns in increasingly sophisticated ways. Rapid advances in theory and computing have made it possible to construct predictive models that describe how cell and tissue organization and dynamics emerge from the local coupling of biochemistry and mechanics. Together, these advances have opened up a wealth of new opportunities to explore how mechanochemical patterning shapes organismal development. In this roadmap, we present a series of forward-looking case studies on mechanochemical patterning in development, written by scientists working at the interface between the physical and biological sciences, and covering a wide range of spatial and temporal scales, organisms, and modes of development. Together, these contributions highlight the many ways in which the dynamic coupling of mechanics and biochemistry shapes biological dynamics: from mechanoenzymes that sense force to tune their activity and motor output, to collectives of cells in tissues that flow and redistribute biochemical signals during development.