Despite its importance in central nervous system development, development of the human nervous system remains poorly understood. We have developed the first completely patterned human neural tube model by engineering morphogen environments of human pluripotent stem cells. This neural tube model recaptulates key development landmarks, including the formation of a single continuous central lumen enclosed by neuronal progenitor cells, nested expression of HOX genes along rostral-caudal axis, patterned expression of canonical dorsal-ventral regional markers, and emergence of isthmic organizer, neural crest cells, and neuromesodermal progenitors. In addition to these technical breakthroughs, we have also revealed new biological insights in human neural development, including the pre-patterning of axial identities of neural crest cells and functional roles of neuromesodermal progenitors in trunk neural crest development.

In the future, we are interested in the following research directions:

• Develop next-generation neural organoids with improved interregional interactions and functional neural circuits.

• Study the etiology of neural developmental disorders such as autism spectrum disease and brain malformation by integrating spatially organized neural organoids with patient iPSCs, CRISPR screening and single cell sequencing.

• Decipher the molecular mechanism underlying the regional patterning of neural crest cells and craniofacial abnormalities.

• Develop high-throughput drug screening platform to test patient-specific drug response and toxicity in patient iPSC derived organoids.

Related publications:

1. Xufeng Xue, Yue Liu, and Jianping Fu. Cultivating advanced embryo models through bioengineering mastery. Nature Reviews Bioengineering, 2024, in press

2. Xufeng Xue, Yung Su Kim, Alfredo-Isaac Ponce-Arias, Richard O'Laughlin, Robin Zhexuan Yan, Norio Kobayashi, Rami Yair Tshuva, Yu-Hwai Tsai, Shiyu Sun, Yi Zheng, Yue Liu, Frederick C.K. Wong, Azim Surani, Jason Spence, Hongjun Song, Guo-Li Ming, Orly Reiner, and Jianping Fu. A patterned human neural tube model using microfluidic gradients. Nature, vol. 628, 391-399, 2024. DOI: 10.1038/s41586-024-07204-7

3. Shiyu Sun, Xufeng Xue, Jianping Fu. Modeling development using microfluidics: Bridging gaps to foster fundamental and translational research. Current Opinion in Genetics & Development, vol. 82, 102097, 2023. DOI: 10.1016/j.gde.2023.102097

4. Xufeng Xue, Ryan P. Wang, and Jianping Fu. Modeling of human neurulation using bioengineered pluripotent stem cell culture. Current Opinion in Biomedical Engineering, vol. 13, pp. 127-133, 2020. DOI: 10.1016/j.cobme.2020.02.002 

5. Yuanyuan Zheng#, Xufeng Xue#, Agnes M. Resto-Irizarry, Zida Li, Yue Shao, Yi Zheng, Gang Zhao, and Jianping Fu. Dorsal-ventral patterned neural cyst from human pluripotent stem cells in a biomimetic neurogenic niche. Science Advances, vol. 5, eaax5933, 2019. DOI: 10.1126/sciadv.aax5933

6. Xufeng Xue#, Yubing Sun#, Agnes M. Resto-Irizarry, Ye Yuan, Koh Meng Aw Yong, Yi Zheng, Shinuo Weng, Yue Shao, Yimin Chai, Lorenz Studer, and Jianping Fu. Mechanics-guided embryonic patterning of neuroectoderm tissue from human pluripotent stem cells. Nature Materials, vol. 17, pp. 633-641, 2018. DOI: 10.1038/s41563-018-0082-9

Classic embryological studies have successfully applied genetics and cell biology principles to understand embryonic development. However, it remains unresolved how mechanics, as an integral part for shaping development, is involved in controlling tissue-scale cell fate patterning. We hav developed a micropatterned human pluripotent stem cell (hPSC)-based neuroectoderm developmental model, wherein pre-pattered geometrical confinement induces emergent patterning of neuroepithelial (NE) cells and neural plate border (NPB) cells. Importantly, strong correlations between spatial regulations of cell shape, cytoskeletal contactility and BMP activity are observed during emergent neuroectoderm patterning of hPSC colonies. We further show that cell shape and mechanical force can directly activate BMP-SMAD signaling and thus repress NE but enhance NPB differentiation. This study provides a novel hPSC-based model to understand the biomechanical principles that guide neuroectoderm patterning, thereby useful for studing neural development and diseases.

In the future, we are interested in the following research directions:

• Develop region-specific neural tube folding model using hPSCs and study the roles of genetic and environmental factors in human neural tube defects including anencephaly and spina bifida.

• Mechanobiology of neural crest delamination and migration.

Related publications:

1. Jonathon Muncie, Nadia Ayad, Johnathon Lakins, Xufeng Xue, Jianping Fu, Calerie Weaver. Mechanical Tension Promotes Formation of Gastrulation-like Nodes and Patterns Mesoderm Specification in Human Embryonic Stem Cells. Developmental Cell, vol. 55, pp. 679-694, 2020. DOI: 10.1016/j.devcel.2020.10.015

2. Xufeng Xue#, Yubing Sun#, Agnes M. Resto-Irizarry, Ye Yuan, Koh Meng Aw Yong, Yi Zheng, Shinuo Weng, Yue Shao, Yimin Chai, Lorenz Studer, and Jianping Fu. Mechanics-guided embryonic patterning of neuroectoderm tissue from human pluripotent stem cells. Nature Materials, vol. 17, pp. 633-641, 2018. DOI: 10.1038/s41563-018-0082-9 

3.  Feng Lin, Yue Shao, Xufeng Xue, Yi Zheng, Zida Li, Chunyang Xiong, Jianping Fu. Biophysical phenotypes and determinants of anterior vs. posterior primitive streak cells derived from human pluripotent stem cells. Acta Biomaterialia, vol. 86, pp. 125-134, 2018. DOI: 10.1016/j.actbio.2019.01.017 

We have developed a novel, acoustics-based cellular biomechanics tool, the acoustic tweezing cytometry (ATC), that can apply controlled, targeted subcellular forces to single live mammalian cells through cell surface receptors. Compared to other exiting cellular biomechanics tool (such as magnetic and optical tweezers), ATC offers several unique advantages, including its scalability and high-throughput operation and its compatibility with both 2D and 3D tissue cultures and even in vivo translational applications. We have utilizes ATC for biomechanical stimulations and phenotyping of human stem cells including human mesenchymal stem cells, and  human pluripotent stem cells (hPSCs).

Related publications:

1. Zhaoyi Xu#, Shiying Liu#, Xufeng Xue#, Weiping Li, Jianping Fu, and Cheri X. Deng. Rapid responses of human pluripotent stem cells to cyclic mechanical strains applied to integrin by acoustic tweezing cytometry. Scientific Reports, vol. 12, 18030, 2023. DOI: 10.1038/s41598-023-45397-5

2. Weiping Li, Jiatong Guo, Eric C Hobson, Xufeng Xue, Qingjiang Li, Jianping Fu, Cheri X Deng, and Zhongwu Guo. Metabolic-glycoengineering-enabled molecularly specific acoustic tweezing cytometry for targeted mechanical stimulation of cell surface sialoglycans. Angewandte Chemie, vol. 63, e202401921, 2024. DOI: 10.1002/anie.202401921

3. Zhenzhen Fan, Xufeng Xue, Jianping Fu, and Cheri X. Deng. Visualization and quantification of dynamic intercellular coupling in human embryonic stem cells using single cell sonoporation. Scientific Reports, vol. 10, 18253, 2020. DOI: 10.1038/s41598-020-75347-4a 

4. Zhenzhen Fan#, Xufeng Xue#, Reshani Perera, Sajedeh Nasr Esfahani, Agata A. Exner, Jianping Fu and Cheri X. Deng. Acoustic actuation of integrin-bound microbubbles for mechanical phenotyping during differentiation and morphogenesis of human embryonic stem cells. Small, vol. 14, 1803137, 2018. DOI: 10.1002/smll.201803137 

5. Tugba Topal#, Xiaowei Hong#, Xufeng Xue, Zhenzhen Fan, Ninad Kanetkar, Joe T. Nguyen, Jianping Fu, Cheri X. Deng, and Paul H. Krebsbach. Acoustic tweezing cytometry induces rapid initiation of human embryonic stem cell differentiation. Scientific Reports, vol. 8, 12977, 2018. DOI: 10.1038/s41598-018-30939-z 

6. Xufeng Xue, Xiaowei Hong, Zida Li, Cheri X. Deng, and Jianping Fu. Acoustic tweezing cytometry enhances osteogenesis of human mesenchymal stem cells through cytoskeletal contractility and YAP activation. Biomaterials, vol. 134, pp. 22-30, 2017. DOI: 10.1016/j.biomaterials.2017.04.039