BME Seminar Series - Todd McDevitt, UCSF

Friday, March 1, 2019
11:00 AM - 12:00 PM
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Engineering human pluripotent stem cell morphogenesis to control organoid
development

Human pluripotent stem cells (PSCs) provide a unique substrate to study fundamental principles
of developmental biology including the morphogenesis of multicellular aggregates into functional
tissues commonly referred to as “organoids”. We are particularly interested in understanding
how form and function arise in complex multicellular systems in order to engineer tissues from
human PSCs. Using an inducible CRISPRi system in iPSCs, we examined the effects of
silencing E-cadherin or ROCK1 to impact intercellular adhesion or cortical tension, respectively.
We found that knock-down of both molecules rapidly silenced their expression and upon mixing
CRISPRi cells with wild type hiPSCs, unique multicellular patterns were formed without
adversely affecting pluripotency. However, upon treatment with morphogenic stimuli, divergent
patterns of cell fate commitment were observed. Furthermore, we created a data-driven
computational model of iPSC self-organization and performed pattern optimization studies in
silico that predicted precise experimental conditions capable of yielding unique, previously
unobserved patterns. Experimental validation of the predicted patterns demonstrated the
powerful ability to combine cell engineering with computational modeling to predictably control
the morphogenic behaviors of human PSCs. In addition to studying early symmetry breaking
events, we are engineering cardiac microtissues from human PSCs using either 1) forced
aggregation of multiple differentiated cell types or 2) cardiac organotypic methods. These
complementary routes to create microscale models of cardiac tissue ex vivo offer some distinct
advantages with respect to each other and together yield new insights into the phenotypic and
functional effects of heterotypic culture on developing tissues. Examples of cardiac microtissues
and organoids created by our lab will be contrasted and discussed. Robust and reproducible
methods of directing human PSC morphogenesis should enable new fundamental discoveries
about human embryogenesis and yield functional tissue constructs for biomedical therapy
development.
Event Contact Information:
Natalie Chee
[email protected]
LOCATION:
  • Morningside
TYPE:
  • Lecture
CATEGORY:
  • Engineering
EVENTS OPEN TO:
  • Faculty
  • Postdocs
  • Graduate Students
  • Students
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