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Research Projects

Stem Cell Biology

Stem cells continuously perceive and adapt to various signals to sustain their biological fitness. Intestinal stem cells (ISCs), situated at the critical interface between external and internal environments, integrate a wide range of inputs—including nutrients, microbes, cytokines, immune cells, and neural signals—to maintain tissue homeostasis. This positions ISCs as an excellent model for studying adult stem cell biology, tissue regeneration, and tumorigenesis. Drosophila ISCs share numerous similarities with their mammalian counterparts, encompassing general anatomical structure, cellular physiology, lineage hierarchy, and key regulatory pathways such as Notch, JNK, JAK/STAT, Insulin, Hippo, Wg, and EGF signaling. These conserved features endow findings from fly ISCs with significant translational relevance for understanding human physiology and disease.

 

We identified Piezo—a stretch-activated ion channel—as a key regulator of pre-enteroendocrine (pre-EE) differentiation, mediated by its direct response to mechanical stimuli (Nature, 2018). This mechanosensitive role closely mirrors Piezo’s function in human neural stem cells. Subsequent studies from other groups have further showed that mammalian Piezo1 and 2 also play similar functions in mouse ISCs both in vitro and in vivo (Cell Stem Cell, 2023; Science, 2024).

Currently, we are employing fluorescence-activated cell sorting (FACS) followed by RNA sequencing (RNA-seq) to profile pre-EE cells, aiming to establish a comprehensive dataset of the signaling networks that govern early enteroendocrine fate determination. This dataset will serve as a foundation for subsequent targeted RNA interference (RNAi) screens within the pre-EE cell population.

 

 

Additionally, through a genetic screen in intestinal stem cells (ISCs), we identified a novel protein that regulates mitochondrial dynamics and mtDNA homeostasis via the formation of distinct mitochondrial subdomains (Nat. Cell Biol., 2025). Building on this finding, we are now investigating the biological function of these mitochondrial subdomains in both fly and mouse models, as well as their potential relevance to various human diseases.

Visualize the Dynamics

By leveraging novel optical tools and techniques, we aim to investigate and understand the dynamically changing biological systems at cellular and molecular levels. Two major research directions currently pursued in our laboratory are:

First, we are establishing a new live-imaging platform that enables the observation of living tissues previously difficult to study. Using our latest ultrafast multicolor Thunder imaging system, we plan to track multiple key molecules within complex developing organs with high spatiotemporal resolution. This will allow us to identify new cellular behaviors, uncover interactions between different signaling pathways, and explore communication not only between cells but also across organs.

Second, we are developing new molecular probes to reveal dynamic information in vivo. Previously, we created a transcriptional timer capable of encoding temporal information into a color ratio (eLife, 2019). This tool facilitated the discovery of several new genes expressed in a subpopulation of Drosophila intestinal stem cells, including the mechanosensitive channel Piezo (Nature, 2018).

We are currently developing novel tools to label aged proteins and organelles in order to study their temporal dynamics in developing and aging tissues. 

 

 

 

 

 

 

 

 

In parallel, we have employed live-cell imaging of Ca²⁺ dynamics in Drosophila to investigate metabolic activity in vivo, revealing how amino acid consumption regulates lipid metabolism through brain–adipose tissue communication (Nat. Commun. 2025).

 

 

Furthermore, we identified an intriguing phenomenon in which specific sulfur-containing amino acids—methionine and cysteine—strongly upregulate the peroxisome-related gene PEX11G, specifically within adipose tissue (CMLS, 2024). This upregulation further leads to a significant reduction in triacylglycerol (TAG) levels in fat cells. We are now exploring whether similar mechanisms operate in mammalian systems.

Organ Morphogenesis

As one of the three basic questions in developmental biology, studying morphogenesis not only provides the fundamental knowledge about life, but also pave the way for tissue engineering and regenerative medicine.  Our lab is interested in understanding how specific cytoskeleton component is spatially and temporally regulated in individual cell to dictate the global tissue shape.

Previously, we identified a globally organized basal actomyosin contraction that promotes tissue elongation during fly oogenesis (Nat. Cell Bio. 2010).

And this global effect of actomyosin contraction can be revealed by acute removal of the basement membrane by collagenase (Mol. Bio. of the Cell, 2014).

Using this in vivo model, we are looking for new regulators that control the position and property of these contracting cells. We are also trying to identify the key switch that turn on this machinery, and test if the system can be engineered to create novel organ structures.  

Synthetic Biology/Genetic Tools

 

Traditional developmental biology is a “top-down” study that dissects the complex system into individual parts. However, information about how these biological parts connect to each other, and what are the minimal core components is usually missing. Meanwhile, many biological processes are hard to track due to the lack of a good read-out. To solve these problems, we take a “bottom-up” approach, which is to understand biology by reassembling the machinery and building de novo functions. With the development of the latest protein and genome engineering technology, we are now able to design novel molecules and test its effect in complex multicellular organisms such as the fly.

Previously, we designed a synthetic Notch receptor (Dev. Cell, 2015) and applied it in detecting direct cell-cell interaction as well as triggering tumor and wild-type cell competition in vivo (PNAS, 2017). This approach has been further adopted and test functional in mammlain system (Science, 2023).

Now, we are directly modifying the endogenous signaling molecule to create synthetic bio-parts, which will allow us to build a new signaling circuit that can visualize and trigger the target biological activity.