RECODE: Functional characterization of human skin organoids

University Of California-Irvine, Irvine CA

Investigators

Abstract

Do skin organoid cultures, essentially growing human skin in a dish, accurately reflect how normal skin develops? This project aims to use cutting-edge technologies in biology, engineering, and mathematics to define how human epidermal stem cells differentiate at the single cell level. The major benefits will reveal new insights into developmental biology, adult homeostasis, disease modeling, and provide a platform for preclinical drug testing. New computational tools for analyzing cells at the single cell level will be developed by integrating dynamic modeling with the cell’s spatial position to reconstruct how cells transition from one state to another, how they communicate, and how cells interact at the single cell to tissue levels. The broader societal impacts include developing an interdisciplinary training program to enhance research, diversity, and outreach at the interface between mathematical, physical, and biological sciences. A major challenge in organoid biology is defining stem cell states and their interactions that lead to differentiation of the tissue. The goal of this RECODE project is to define human skin equivalent organoids to address how to faithfully reproduce the differentiation of human epidermal stem cells and generate fully functioning in vitro stratified human skin. This project will integrate single cell RNA-sequencing with spatial imaging data using new mathematical and computational tools applied to primary human epithelial progenitors undergoing active differentiation on engineered substrates in an in vitro organoid culture. Novel computational tools will be developed to connect dynamic spatial models with novel data analytics and these tools will reveal transition cell states, cell-cell communication, and cell-cell spatial maps – three important but underexplored areas in cell fate analysis. The new multiscale models will define when, where, and how human keratinocytes acquire their fates and robustly differentiate to establish stratified epidermis. This RECODE award is co-funded by the Physiological and Structural Systems Cluster in the Division of Integrative Organismal Systems and the Engineering Biology and Health Cluster in the Division of Chemical, Bioengineering, Environmental, and Transport Systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.