Robust Control of the Stem Cell Niche

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Overview The interdisciplinary lab focuses an overarching question: how biological controls manage heterogeneity and achieve robustness, and how subversion of such mechanisms heightens risk for disease. To address this question, the lab studies fundamental mechanisms and develops new technology to probe such processes in live animals at high spatiotemporal resolution: 1) The lab has discovered that non-coding RNA (ncRNA) such as long non-coding RNA (lncRNA) and microRNA can initiate asymmetric cell division and limit plasticity. Not essential for healthy tissue, ncRNA can be triggered to turn on asymmetric division to safeguard tissue integrity during inflammation-induced reparative regeneration. 2) The lab discovered that fast- and slow-cycling intestinal stem cells can directly interconvert via asymmetric division, representing an optimal survival strategy for the tissue. 3) To address the limitation of current engraftment models, the lab developed a novel chemokine-targeting technology to engraft human cells into immunocompetent mouse hosts by manipulating cell migration via embryonic thymus to build central immune tolerance. 4) A new device integrating an abdominal window, a 3D-printed scaffold, and a transparent graphene sensor has been designed to demonstrate live recording of the enteric nervous system for the first time. Goals In the next five years, the lab will explore three areas: Goal 1. Elucidating the ncRNA mechanisms that regulate asymmetric division and safeguard tissue integrity, e.g., to understand their mechanism of asymmetric segregation and to identify such lncRNAs and microRNAs in a systematic way. Goal 2. Understanding the spatiotemporal dynamics of the intestinal stem cell niche using intravital imaging, laser ablation, and multiscale stochastic modeling. Goal 3. Epigenetic profiling and reprogramming of intestinal cell lineages using ATAC-seq and CRISPR-Cas9- based epigenome editing. Vision With a background in electrical engineering, the PI has always been intrigued by the ability of biological circuits to perform robust functions with very imprecise components and seemingly messy architectures, in contrast to man-made electrical circuits which rely on precise devices and carefully laid-out designs. The proposed study attempts to deepen our understanding of tissue homeostasis and highlights the sophistication of underlying biological circuitry in terms of dynamics and robustness. The lab will also develop new tools for the research community to ask the kind of questions that are impossible right now. The study will provide new insight into disease conditions and contribute to future regenerative medicine.