Engineered human development models using stem cells

Biomedical research has traditionally focused on only a handful of model organisms. Scientists believe that studies on these species also help us understand ourselves (human being). The logic is built on the fundamental idea that biological mechanisms are evolutionarily conserved. However, there is growing realization that the information obtained from other animal models does not completely reflect human physiology. Human pluripotent stem cell-derived multicellular tissues can offer novel experimental approaches that bridge the gap between animal models and human beings, which will potentially revolutionize the researches on human disease and development. Dr. Zheng has successfully developed a stem cell-derived microfluidic amniotic sac embryoid (┬ÁPASE), which recapitulates, in a highly controllable and scalable fashion, several landmarks of human post-implantation embryonic development. The long-term goal of the Zheng Lab is to establish synthetic biosystems closely mimicking certain human developmental and pathological processes, and to apply these biosystems to reveal the unique and fundamental mechanisms of human systems. We combine approaches from synthetic biology, developmental/stem cell biology, microengineering, and bioinformatics to build and quantitatively analyze these biosystems.

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5. Zheng Y*, Yan RZ, Sun S, Kobayashi M, Xiang L, Yang R, Goedel A, Kang Y, Xue X, Esfahani SN, Liu Y, Resto Irizarry AM, Wu W, Li Y, Ji W, Niu Y, Chien KR, Li T, Shioda T, Fu J. Single-cell analysis of embryoids reveals lineage diversification roadmaps of early human development. Cell Stem Cell. 2022;29(9):1402-1419.e8. (featured by Cell Stem Cell)
4. Chen K, Zheng Y, Xue X, Liu Y, Resto Irizarry AM, Tang H, Fu J. Branching development of early post-implantation human embryonic-like tissues in 3D stem cell culture. Biomaterials. 2021;275:120898.
3. Zheng Y, Shao Y, Fu J. A microfluidics-based stem cell model of early post-implantation human development. Nature Protocols. 2021;16(1):309-326.
2. Zheng Y, Xue X, Shao Y, Wang S, Esfahani SN, Li Z, Muncie JM, Lakins JN, Weaver VM, Gumucio DL, Fu J. Controlled modelling of human epiblast and amnion development using stem cells. Nature. 2019;573(7774):421-425.
1. Zheng Y, Xue X, Resto-Irizarry AM, Li Z, Shao Y, Zheng Y, Zhao G, Fu J. Dorsal-ventral patterned neural cyst from human pluripotent stem cells in a neurogenic niche. Science Advances. 2019;5(12):eaax5933.

Biomimetic tumor microenvironment for cancer biology

Despite the advances in biomedical science, cancer still remains a major health issue. The complexity and heterogeneity of tumors and their microenvironments necessitate the development of novel biomimetic disease models with the capability of recapitulating key features of native tumors. During metastasis, cancer cells disseminate to other parts of the body through bloodstream, and then extravasate at metastatic sites by attaching to endothelial cells and crossing the vessel walls. The location of metastatic sites is postulated to be tightly related to chemo-attractant molecules secreted by organ-specific tissues and the physical interaction between cancer cells and blood vessels (typically small capillaries) formed through angiogenesis. Thus, it has been well established that angiogenesis plays a critical role for the local progression and metastasis spread of tumors. The Zheng Lab leverages 3D microengineered platforms, in conjunction with advanced nanobiosensors to systematically study the mechanisms of angiogenesis in organ-specific metastatic microenvironments.

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2. Zheng Y$, Wang S$, Xue X, Xu A, Liao W, Deng A, Dai G, Liu AP, Fu J. Notch signaling in regulating angiogenesis in a 3D biomimetic environment. Lab on a Chip. 2017;17(11):1948-1959.
1. Zheng Y, Sun Y, Yu X, Shao Y, Zhang P, Dai G, Fu J. Angiogenesis in Liquid Tumors: An In Vitro Assay for Leukemic-Cell-Induced Bone Marrow Angiogenesis. Advanced Healthcare Materials. 2016;5(9):1014-1024.

Integrated microsystems for biophysical profiling of single cells

Deformability of normal red blood cells (RBCs) is critical for gas transfer and nutrient transportation. Pathological conditions may lead to reorganization of the membrane cytoskeletal protein network, and consequently compromise RBC deformability. Conventional systems for RBC deformability characterization lack the resemblance of the in-vivo circulation system. The low measurement speed also makes them infeasible to obtain statistically significant information for the highly heterogeneous RBC population. Leveraging microfluidics, high-speed imaging and electrical sensing, the Zheng Lab develops integrated microsystems for deformability characterization of RBCs, featuring a human-capillary-like microenvironment, interaction between RBCs and endothelium, and the capacity of gas exchange. These systems offer high-throughout and multiparametric profiling capabilities, which facilitates the discovery of new biochemical and biophysical phenotypes for a broad-spectrum enrichment and detection.

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4. Zheng Y, Wen J, Nguyen J, Cachia MA, Wang C, Sun Y. Decreased deformability of lymphocytes in chronic lymphocytic leukemia. Scientific Reports. 2015;5(1):7613.
3. Zheng Y, Cachia MA, Ge J, Xu Z, Wang C, Sun Y. Mechanical differences of sickle cell trait (SCT) and normal red blood cells. Lab on a Chip. 2015;15(15):3138-3146.
2. Zheng Y, Chen J, Cui T, Shehata N, Wang C, Sun Y. Characterization of red blood cell deformability change during blood storage. Lab on a Chip. 2014;14(3):577-583.
1. Zheng Y, Shojaei-Baghini E, Wang C, Sun Y. Microfluidic characterization of specific membrane capacitance and cytoplasm conductivity of single cells. Biosensors and Bioelectronics. 2013;42:496-502.