Yuchuan Miao, Ph.D.

Unravelling human development with stem cells

During development, numerous cells adopt various fates and organize 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 harnessing the power of stem cells. We use human pluripotent stem cells to build organoids that recapitulate essential features of developmental processes. With these simplified in vitro models, we dive deep into mechanisms that integrate gene regulation, cellular dynamics, and tissue-level cues to precisely pattern the body plan. We in turn leverage on this knowledge to enhance technologies of tissue engineering. Altogether, we aim to advance human developmental biology, understand congenital diseases, and promote regenerative medicine.

Current focus

We are fascinated by the development of our vertebral column, including somite formation in the early embryo and the subsequent organogenesis. Somites are repeated epithelial blocks flanking the neural tube and they go on to form our axial skeleton and skeletal muscles. Using human iPSCs, we have established organoid models, called “segmentoid” and “somitoid”, which recapitulate key features of somite formation, from rhythmicity to patterning to morphogenesis. We combine live imaging, functional genomics, and cell engineering to uncover fundamental principles of multicellular systems and human development:

(1) How do cells coordinate? During somite formation, gene expression in individual cells are coordinated as tissue-level wave patterns, whose spatiotemporal features are essential to ensure developmental precision. We 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 leverage on this breakthrough framework to answer the longstanding question of somite polarity and advance a multi-scale view of developmental patterning.

(3) How do cells build organs? In further development, the ventral part of each somite undergoes series of re-organization to establish the primordia of vertebrae and intervertebral discs of the spine. This complex process is poorly understood even in animal embryo models. We will use tissue engineering, functional genomics, and live imaging to illuminate the molecular and cellular mechanisms of human spine organogenesis. This will also help us understand and combat disc degeneration and back pain associated with aging.

Outlook

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

Further Information

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