We develop microfabrication, computational and genetic tools to promote, modulate and analyse the self-organizing behaviors of mammalian stem cells and embryos.
We created the first in vitro model of the blastocyst that we termed blastoid, which recapitulates aspects of early development and implants in utero.
Stem cells have the inherent capacity to self-organise and recapitulate development. Capitalising on this, we guided stem cells to form the first model of a blastocyst in-a-dish (blastoids). Blastoids form through the assembly of trophoblast and embryonic stem cells, and morphologically and transcriptionally resemble the mouse pre-implantation blastocyst. Upon transfer in utero, blastoids implant and initiate a pregnancy. Blastoids are scientific models that reveal the design principles of development. Up to now, they exposed that, at this early stage, the embryonic cells produce numerous inductive signals that guide the development and the in utero implantation of the trophoblast cells (the future placenta). Blastoids draw general principles for promoting stem cell self-organisation in a dish, and could contribute to understand and test solutions to problems of infertility, pregnancy failure or the embryonic origin of diseases.
1: Embryonic signals perpetuate polar-like trophoblast stem cells and pattern the blastocyst axis. Frias-Aldeguer J, Kip M, Vivié J, Li L, Alemany A, Korving J, Darmis F, van Oudenaarden A, Van Blitterswijk CA, Geijsen N, Rivron NC*. BioRxiv 510362; doi: https://doi.org/10.1101/510362
2: Chemically-defined induction of a primitive endoderm and epiblast-like niche supports post-implantation progression from blastoids. Vrij EJ, Scholte op Reimer YS, Frias Aldeguer J, Misteli Guerreiro I, Kind J, Koo BK, van Blitterswijk CA, Rivron NC*. BioRxiv 510396; doi: https://doi.org/10.1101/510396.
3: Blastocyst-like structures generated solely from stem cells. Nicolas C Rivron [corresponding author], Javier Frias-Aldeguer, Erik J Vrij, Jean-Charles Boisset, Jeroen Korving, Judith Vivié, Roman K Truckenmüller, Alexander van Oudenaarden, Clemens A van Blitterswijk †, Niels Geijsen † [† equal contribution]. Nature. 2018.
4: In vitro generation of blastoids from trophoblast and embryonic stem cells. Nicolas C Rivron. Protocol exchange. 2018.
5: Kicheva A, Rivron NC. Creating to understand - developmental biology meets engineering in Paris. Development. 2017 Mar 1;144(5):733-736. doi:10.1242/dev.144915. PubMed PMID: 28246208.
Self-organization is a fascinating family of mechanisms underlying the formation of patterns of behaviors in populations. It has been mathematically resolved to explain the behaviour of populations of animals (e.g., ants, bees). For example, fish schools, ant colonies and bird flocks coordinate their collective behaviors to control the emergence and progression of patterns and functions. This broad range of decentralized, adaptive behaviors based on local interactions is called self-organization. However, it remains unknown to which extent the same mechanisms apply to multicellular development. We explore how self-organization complements traditional hierarchical genetic (e.g., HOX genes collinearity) and molecular (e.g., morphogen gradients) processes to shape the mammalian organism.
Unleashing the intrinsic potential for stem cells to spontaneously organize in-a-dish requires to precisely control simple boundary conditions (e.g., cell number, confinment, multicellular geometry). We developed microfabrication, computational, and genetic technologies to establish these boundary conditions, modulate and monitor behaviours at the single cell level. These tools increase the reproducibility, throughput, and prediction of stem cell behaviours, and are thus empowering for scientific discoveries.
1: Kicheva A, Rivron NC. Creating to understand - developmental biology meets engineering in Paris. Development. 2017 Mar 1;144(5):733-736. doi:10.1242/dev.144915. PubMed PMID: 28246208.
2: Vrij E, Rouwkema J, LaPointe V, van Blitterswijk C, Truckenmüller R, Rivron N. Directed Assembly and Development of Material-Free Tissues with Complex Architectures. Adv Mater. 2016 Jun;28(21):4032-9. doi: 10.1002/adma.201505723. Epub 2016 Mar 22. PubMed PMID: 27000493.
3: Vrij EJ, Espinoza S, Heilig M, Kolew A, Schneider M, van Blitterswijk CA, Truckenmüller RK, Rivron NC. 3D high throughput screening and profiling of embryoid bodies in thermoformed microwell plates. Lab Chip. 2016 Feb 21;16(4):734-42. doi: 10.1039/c5lc01499a. Epub 2016 Jan 18. PubMed PMID:26775648.
4: Leferink A, Schipper D, Arts E, Vrij E, Rivron N, Karperien M, Mittmann K, van Blitterswijk C, Moroni L, Truckenmüller R. Engineered micro-objects as scaffolding elements in cellular building blocks for bottom-up tissue engineering approaches. Adv Mater. 2014 Apr 23;26(16):2592-9. doi: 10.1002/adma.201304539. Epub 2014 Jan 7. PubMed PMID: 24395427.
5: Fennema E, Rivron N, Rouwkema J, van Blitterswijk C, de Boer J. Spheroid culture as a tool for creating 3D complex tissues. Trends Biotechnol. 2013 Feb;31(2):108-15. doi: 10.1016/j.tibtech.2012.12.003. Epub 2013 Jan 18. Review. PubMed PMID: 23336996.
6: Rivron NC, Vrij EJ, Rouwkema J, Le Gac S, van den Berg A, Truckenmüller RK, van Blitterswijk CA. Tissue deformation spatially modulates VEGF signaling and angiogenesis. Proc Natl Acad Sci U S A. 2012 May 1;109(18):6886-91. doi:10.1073/pnas.1201626109. Epub 2012 Apr 17. PubMed PMID: 22511716; PubMed Central PMCID: PMC3344996.
7: Rivron NC, Raiss CC, Liu J, Nandakumar A, Sticht C, Gretz N, Truckenmüller R, Rouwkema J, van Blitterswijk CA. Sonic Hedgehog-activated engineered blood vessels enhance bone tissue formation. Proc Natl Acad Sci U S A. 2012 Mar 20;109(12):4413-8. doi: 10.1073/pnas.1117627109. Epub 2012 Mar 2. PubMed PMID:22388744; PubMed Central PMCID: PMC3311342.
8: Rouwkema J, Rivron NC, van Blitterswijk CA. Vascularization in tissue engineering. Trends Biotechnol. 2008 Aug;26(8):434-41. doi:10.1016/j.tibtech.2008.04.009. Epub 2008 Jun 26. Review. PubMed PMID: 18585808.
9: Rivron NC, Rouwkema J, Truckenmüller R, Karperien M, De Boer J, Van Blitterswijk CA. Tissue assembly and organization: developmental mechanisms in microfabricated tissues. Biomaterials. 2009 Oct;30(28):4851-8. doi:10.1016/j.biomaterials.2009.06.037. Epub 2009 Jul 9. PubMed PMID: 19592088.