Tissue Engineering: Bridging Developmental Biology and Regenerative Medicine

Stem cells offer a window into embryonic development and provide new avenues for tissue engineering and regenerative medicine. Our approach focuses on developing methods for directed differentiation of stem cells, a process that allows controlled production of specific cell types.

We have successfully developed protocols to differentiate mouse and human embryonic stem cells into spinal cord cells, notochord cells, and paraxial mesoderm cells. These cell types originate from a group of precursors in the posterior of the elongating embryo, known as the caudal epiblast and neuromesodermal progenitors (NMPs). By replicating the signaling environment of NMPs in embryos, we generate NMPs from pluripotent stem cells in vitro. These in vitro NMPs exhibit characteristics similar to their in vivo counterparts, co-expressing the neural factor Sox2 and the mesodermal factor TBXT/Brachyury. They can be directed to differentiate into either neural or mesodermal tissue. The neural cells produced from these NMPs possess spinal cord identity and can further differentiate into spinal cord motor neurons. This system serves as a platform to investigate NMP biology, focusing on the mechanisms governing the choice between spinal cord and mesoderm fates, and the control of cell identity in differentiating cells.

To advance our stem cell approaches, we are developing micropatterning methods and optogenetic tools to control gene expression. Constraining stem cell differentiation on micropatterns with defined geometries results in reproducible, self-organized tissues with consistent morphology and cell type patterning. This physically and genetically tractable system allows us to investigate the interplay between molecular and mechanical mechanisms underlying morphological processes.

Complementing our micropatterning work, we have established optogenetic systems to study developmental patterning in vitro. Using a tunable light-inducible gene expression system, we generate long-range signalling gradients that pattern neural progenitors into spatially distinct domains, mimicking the arrangement of neural progenitors in the vertebrate neural tube. This system allows the quantitative control and interrogation of patterning processes, which we use to dissect the interactions between molecular cues, mechanical processes, and geometric organization that underpin developmental patterning.

The combination of stem cell differentiation with bioengineering technology provides an in vitro experimental paradigm for studying tissue development. This approach allows us to take synthetic biology and constructionist approaches to understand fundamental mechanisms in developmental biology. By reconstructing developmental processes in vitro, we can isolate and manipulate individual components of complex biological systems, leading to new insights into the principles governing embryonic development.

This has implications beyond basic developmental biology. The methods and insights we develop are relevant to tissue engineering and regenerative medicine. By understanding how to generate specific cell types and tissues in vitro, we pave the way for potential therapeutic applications, such as cell replacement therapies or the creation of tissue models for drug testing. The intersection of stem cell biology, developmental biology, and bioengineering represents a frontier in biological research, with the potential to transform our understanding of human development and our approach to treating disease.

SELECTED PUBLICATIONS

  • Dirk Benzinger, James Briscoe (2024)
    Illuminating morphogen and patterning dynamics with optogenetic control of morphogen production
    bioRxiv 2024.06.11.598403
  • Tiago Rito, Ashley R.G. Libby, Madeleine Demuth, James Briscoe (2023)
    Notochord and axial progenitor generation by timely BMP and NODAL inhibition during vertebrate trunk formation
    bioRxiv 2023.02.27.530267
  • Gouti, M; Delile, J; Stamataki, D; Wymeersch, FJ; Huang, Y; Kleinjung, J; Wilson, V and Briscoe, J (2017)
    A gene regulatory network balances neural and mesoderm specification during vertebrate trunk development.
    Developmental Cell 41, 243-261