Summary

Our research is driven by important biological questions that cannot always be addressed with existing methods. To answer such questions, we develop new ways to measure complex biological phenomena. Rather than treating analytical tools as ends in themselves, we build platforms that can capture complex, heterogeneous, and dynamic biological processes, and then use those same platforms to generate new biological insights. Through this approach, we integrate mechanistic cell biology, bioengineering, and quantitative analysis in the study of systems such as extracellular vesicles, organoids, and spheroids.

Biological Studies that Shape Our Research Direction

Our research direction has been shaped by biological studies aimed at understanding how cells sense stress, regulate cell fate, and adapt their functions in changing environments. In this phase, we investigated ASK family signaling across stress responses, regulated cell death, and metabolic regulation, and established mechanistic links between signaling pathways and physiological outcomes. For example, we showed that ASK1 regulates the thermogenic gene program and function of brown and beige adipocytes through the PKA-ASK1-p38 axis (Nat. Commun., 2016), that β-adrenergic receptor signaling activates the PKA-ASK pathway in mature brown adipocytes through defined phosphorylation-dependent mechanisms (PLoS One, 2020), that PGAM5 suppresses energy consumption in brown adipocytes by repressing UCP1 expression (J. Biol. Chem., 2020), that severe cold stress induces ferroptosis through the ASK1-p38 pathway (EMBO Rep., 2017), and that ASK1 activity is regulated at the level of protein stability through β-TrCP-dependent degradation (BBA Gen. Subj., 2018). Together with our review work on the ASK family and its roles in stress signaling and disease, these studies established a foundation in mechanistic biology while also making clear that many important cellular responses are heterogeneous, context-dependent, and difficult to resolve with conventional bulk assays alone. That realization became a major driver of our later efforts to build new analytical platforms.

Selected publications

Original articles

Hattori, K., Naguro, I., Okabe, K., Funatsu, T., Furutani, S., Takeda, K., Ichijo, H.* ASK1 signalling regulates brown and beige adipocyte function. Nat. Commun. 7, 11158 (2016).

Hattori, K.# (co-first), Ishikawa, H.#, Sakauchi, C., Takayanagi, S., Naguro, I., Ichijo, H.* Cold stress-induced ferroptosis involves the ASK1-p38 pathway. EMBO Rep. 18, 2067-2078 (2017).

Cheng, R., Takeda, K., Naguro, I., Hatta, T., Iemura, S., Natsume, T., Ichijo, H.*, Hattori, K.* (co-corresponding) β-TrCP-dependent degradation of ASK1 suppresses the induction of the apoptotic response by oxidative stress. BBA Gen. Subj. 1862, 2271-2280 (2018).

Hattori, K.* (co-corresponding), Wakatsuki, H., Sakauchi, C., Furutani, S., Sugawara, S., Hatta, T., Natsume, T., Ichijo, H.* β-adrenergic receptor signaling evokes the PKA-ASK axis in mature brown adipocytes. PLoS One 15, e0232645 (2020).

Sugawara, S., Kanamaru, Y., Sekine, S., Maekawa, L., Takahashi, A., Yamamoto, T., Watanabe, K., Fujisawa, T., Hattori, K.* (co-corresponding), Ichijo, H.* The mitochondrial protein PGAM5 suppresses energy consumption in brown adipocytes by repressing expression of uncoupling protein 1. J. Biol. Chem. 295, 5588-5601 (2020).

Review articles

Hattori, K., Naguro, I., Runchel, C., Ichijo, H.* The roles of ASK family proteins in stress responses and diseases. Cell Commun. Signal. 7, 9 (2009).

Nishida, T., Hattori, K.* (co-corresponding), Watanabe, K.* The regulatory and signaling mechanisms of the ASK family. Adv. Biol. Regul. 66, 2-22 (2017).

Sakauchi, C., Wakatsuki, H., Ichijo, H.*, Hattori, K. Pleiotropic properties of ASK1. BBA Gen. Subj. 1861, 3030-3038 (2017).

Related articles

Naguro, I., Umeda, T., Kobayashi, Y., Maruyama, J., Hattori, K., Shimizu, Y., Kataoka, K., Kim-Mitsuyama, S., Uchida, S., Vandewalle, A., Noguchi, T., Nishitoh, H., Matsuzawa, A., Takeda, K., Ichijo, H.* ASK3 responds to osmotic stress and regulates blood pressure by suppressing WNK1-SPAK/OSR1 signaling in the kidney. Nat. Commun. 3, 1285 (2012).

Sekine, S.#, Yao, A.#, Hattori, K., Sugawara, S., Naguro, I., Koike, M., Uchiyama, Y., Takeda, K., Ichijo, H.* The ablation of mitochondrial protein phosphatase Pgam5 confers resistance against metabolic stress. EBioMedicine 5, 82-92 (2016).

Imamura, K., Yoshitane, H., Hattori, K., Yamaguchi, M., Yoshida, K., Okubo, T., Naguro, I., Ichijo, H., Fukada, Y.* ASK family kinases mediate cellular stress and redox signaling to circadian clock. Proc. Natl. Acad. Sci. U.S.A. 115, 3646-3651 (2018).

Kato, H., Okabe, K., Miyake, M., Hattori, K., Fukaya, T., Tanimoto, K., Beini, S., Mizuguchi, M., Torii, S., Arakawa, S., Ono, M., Saito, Y., Sugiyama, T., Funatsu, T., Sato, K., Shimizu, S., Oyadomari, S., Ichijo, H., Kadowaki, H., Nishitoh, H.* ER-resident sensor PERK is essential for mitochondrial thermogenesis in brown adipose tissue. Life Sci. Alliance 3, e201900576 (2020).

Nakamura, T., Ogawa, M., Kojima, K., Takayanagi, S., Ishihara, S., Hattori, K., Naguro, I., Ichijo, H. The mitochondrial Ca2+ uptake regulator, MICU1, is involved in cold stress-induced ferroptosis. EMBO Rep. 22, e51532 (2021).

Platform Development for Quantitative Analysis of Complex Biology

To address biological questions that are challenging to resolve with existing methods, we develop analytical platforms that enable quantitative and high-throughput analysis of complex biological systems. Our work in this area first established well-based screening platforms that transformed organoid models into scalable and quantitative assay systems (Nat. Biomed. Eng., 2022). We then developed microfluidics-based platforms that overcome the scale and handling limitations of conventional well-based approaches. These efforts include droplet array systems for long-term single-cell secretion analysis (Anal. Chem., 2022) and microcapsule technologies for the high-throughput generation of uniform 3D culture units as well as for bacterial culture and analysis (ACS Biomater. Sci. Eng., 2024; bioRxiv, 2025). In parallel, we established suspended-adherent 3D culture models that support high-throughput quantitative analysis of epithelial cell systems in 3D, together with compatible flow-based imaging readouts (Small Methods, 2024). Together, these studies define the technological core of our research program: platform development not as an end in itself but as a means to quantitative analysis of complex biology.

Selected publications

Original articles

Mead, B. E.#, Hattori, K.# (co-first), Levy, L., Imada, S., Goto, N., Vukovic, M., Sze, D., Kummerlowe, C., Matute, J. D., Duan, J., Langer, R., Blumberg, R. S., Ordovas-Montanes, J., Yilmaz, O. H., Karp, J. M., Shalek, A. K. Screening for modulators of the cellular composition of gut epithelia via organoid models of intestinal stem cell differentiation. Nat. Biomed. Eng. 6, 476-494 (2022).

Hattori, K., Goda, Y., Yamashita, M., Yoshioka, Y., Kojima, R., Ota, S.* Droplet array-based platform for parallel optical analysis of dynamic extracellular vesicle secretion from single cells. Anal. Chem. 94, 11209-11215 (2022).

Yamashita, M., Tamamitsu, M., Kirisako, H., Goda, Y., Chen, X., Hattori, K.* (co-corresponding), Ota, S.* High-Throughput 3D Imaging Flow Cytometry of Suspended Adherent 3D Cell Cultures. Small Methods 8, e2301318 (2024).

Maekawa, R.#, Hattori, K.#* (co-first/co-corresponding), Kirisako, H., Iwamoto, Y., Kawasaki, F., Yoneshiro, T., Sakai, J., Ota, S.* Large-scale generation of uniform sub-100 μm adipocyte spheroids in hydrogel microcapsules using a flow-focusing microfluidic device. bioRxiv 2024.06.08.597376 (2024). Accepted in ACS Biomater. Sci. Eng.

Xu, B.#, Kim, S.#, Hinode, K., Hattori, K.* (co-corresponding), Ota, S.* Space-efficient method for high-throughput generation of uniform cell-laden hollow agarose microcapsules. bioRxiv 2025.10.19.683215 (2025).

Review articles

Hattori, K., Iwamoto, Y., Kojima, R., Yoshioka, Y., Ota, S.* High dimensional cytometry for studying heterogeneous small particles. In Extracellular Fine Particles, 243-260 (2025).

Hattori, K.* Cell assays in microcompartments driven by droplet microfluidics and hydrogel technologies. J. Biochem. (2026).

Related articles

Tsuyama, Y., Xu, B., Hattori, K., Baek, S., Yoshioka, Y., Kojima, R., Cho, Y., Laurell, T., Kim, S., Ota, S.*, Lee, S.* A 50 µm acoustic resonator microchannel enables focusing 100 nm polystyrene beads and sub-micron bioparticles. Sens. Actuators B Chem. 376, 132918 (2023).

Kunitake, K., Mizuno, T., Hattori, K., Oneyama, C., Kamiya, M., Ota, S., Urano, Y., Kojima, R.* Barcoding of small extracellular vesicles with CRISPR-gRNA enables comprehensive, subpopulation-specific analysis of their biogenesis and release regulators. Nat. Commun. 15, 9777 (2024).

Biological Discoveries Enabled by Our Platforms

Because we develop and apply these platforms within the same research program, platform development directly feeds into biological discovery. Using organoid-based screening, we identified pathways and compounds that modulate the cellular composition of the intestinal epithelium and uncovered regulators of Paneth cell differentiation (Nat. Biomed. Eng., 2022). Using droplet-based single-cell secretion analysis, we revealed heterogeneity in extracellular vesicle secretion dynamics within clonal cell populations and found that CD9-positive extracellular vesicle secretion increases around the time of cell division (Anal. Chem., 2022). In parallel, suspended adherent 3D culture models and compatible flow-based imaging readout enabled quantitative analysis of morphology and cell state in large populations of epithelial 3D culture systems (Small Methods, 2024). Together, these studies illustrate how our platforms are used not only to improve measurement but also to uncover biological principles that are difficult to resolve with conventional approaches.

Selected publications (repeated from Section 2)

Original articles

Mead, B. E.#, Hattori, K.# (co-first), Levy, L., Imada, S., Goto, N., Vukovic, M., Sze, D., Kummerlowe, C., Matute, J. D., Duan, J., Langer, R., Blumberg, R. S., Ordovas-Montanes, J., Yilmaz, O. H., Karp, J. M., Shalek, A. K. Screening for modulators of the cellular composition of gut epithelia via organoid models of intestinal stem cell differentiation. Nat. Biomed. Eng. 6, 476-494 (2022).

Hattori, K., Goda, Y., Yamashita, M., Yoshioka, Y., Kojima, R., Ota, S.* Droplet array-based platform for parallel optical analysis of dynamic extracellular vesicle secretion from single cells. Anal. Chem. 94, 11209-11215 (2022).

Yamashita, M., Tamamitsu, M., Kirisako, H., Goda, Y., Chen, X., Hattori, K.* (co-corresponding), Ota, S.* High-Throughput 3D Imaging Flow Cytometry of Suspended Adherent 3D Cell Cultures. Small Methods 8, e2301318 (2024).

Review articles

Hattori, K.* Cell assays in microcompartments driven by droplet microfluidics and hydrogel technologies. J. Biochem. (2026).