People

Academic Titles

Assistant Professor (Incoming)

Research Topic

Design principles of human body plan development

Background and Vision

One of nature’s most elegant wonders is embryo development, where numerous cells adopt various fates and organize themselves into a constellation of patterns and shapes generating the intricate body plan. Elucidating the underlying design principles is key not only to treating congenital disorders but also to manufacturing tissues and organs for regenerative medicine. Whereas classical studies enriched our knowledge at the molecular scale with a focus on gene regulation, how molecular information is integrated with cell-scale and tissue-scale controls to build complex body structures are less understood. Meanwhile, detailed investigation of our own species is hindered by limited access to human embryos and ethical concerns. The understudied multi-scale integration and human-specific mechanisms directly restrict the extent to which we can correct diseased states or engineer functional tissues.

We aim to fill these knowledge gaps by reconstructing and deconstructing human body plan development using pluripotent stem cells (PSCs). “Reconstruction” – we are interested in creating human PSC-based models to reconstitute developmental processes in vitro. These models will provide unlimited experimental materials while bypassing ethical concerns.  They will also allow quantitative characterization and sophisticated perturbations to comprehend human development at all scales. “Deconstruction” – we are using these tractable models to illuminate design principles of human development with a cell-centered conceptual framework. We view cells as the central building blocks of the body and examine how cell behaviors are integrated with intracellular states (e.g. gene expression, organelle dynamics) and tissue-level regulations (e.g. signaling gradients, tissue mechanics) to sculpt the human body plan.

Current focus

We are fascinated by the development of our spinal column, including somite formation in the early embryo and the subsequent organogenesis. Somites are repeated epithelial blocks flanking the neural tube and they give rise to our vertebrae and skeletal muscles. Owing to its remarkable spatiotemporal characteristics, somite formation has long served as a paradigm to decode design principles of body plan development. Using human iPSCs, we have established two model systems in 3D, called “segmentoid” and “somitoid”, which recapitulate key features of somite formation, from rhythmicity to patterning to morphogenesis. We are using these organoid systems to ask fundamental questions regarding multicellular systems and human developmental biology:

(1) How do cells coordinate? During somite formation, gene expression in individual cells are coordinated as tissue-level wave patterns, whose stereotypical features are essential to ensure developmental precision. We will use live imaging to quantitatively determine molecular and cellular parameters governing wave features (e.g. speed, range, amplitude, etc.), as well as adopt tools of synthetic biology to control wave dynamics, to together illuminate how cells communicate and cooperate in living systems.

(2) How do cells make patterns? Each somite is sub-divided into an anterior and posterior half, which is essential to guide the segmental organization of our spine and peripheral nervous system. We previously discovered that cell sorting, instead of gene expression modulation as conventionally postulated, underlies the symmetry breaking of somite polarity. We will leverage on this breakthrough framework to solve the longstanding question of somite polarity and advance a multi-scale view of developmental patterning.

(3) How do cells build organs? In further development, somites will go through a process called “resegmentation” to establish the vertebrae and intervertebral disks of the spine. This complex process is poorly understood even in animal embryo models. We will use tissue engineering approaches to recapitulate human spinal organogenesis in vitro and investigate the interactions of different cell types in building mature tissues.

Outlook

We are also applying our in vitro approach and conceptual framework to other systems of body plan development, including human limbs. Together, we will seize the opportunities provided by stem cells and advance both technology development and mechanistic understanding, towards the long-term goal of making tissues and organs in vitro for regenerative medicine.

Further Information

Featured interview by the Development journal: https://doi.org/10.1242/dev.202265

Perspectives

Miao Y & Pourquié O. Mapping mouse axial progenitor dynamics in vitro. Developmental Cell (2024). PMID: 38889690

Miao Y. In preprints: tick, tick, somite – an intrinsic time regulates segmentation. Development (2024). PMID: 38293868

Miao Y & Pourquié O. Modeling human trunk development. Nature Biotechnology (2023). PMID: 37974011

Agarwal P, Cadart C, Fort L, Gahan J, Greenspan L, Juan T, Kameneva P, Miao Y. Pathway to Independence: the future of developmental biology. Development (2023). PMID: 37812057