Research

Despite its importance in central nervous system development, development of the human neural tube remains poorly understood, given the challenges of studying human embryos, and the developmental divergence between humans and animal models. We developed the first completely patterned synthetic human neural tube tissues using stem cells in which key early human neural tube development landmarks can be recapitulated in a highly controllable and reproducible fashion. These neural tubedevelopmental events include 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 rostral-caudal and dorsal-ventral regional markers, and emergence of isthmic organizer and neuromesodermal progenitors.

Leveraging the in vitro human neural tube models, we investigated the following biological problems which are very difficult to study in humans:

• Studying the rostral-caudal axis dependent neural crest development

• Elucidate how NMPs contribute to spinal cord and neural crest development

• Modeling defective neural crest development in CHARGE syndrome using 3D microfluidic neural tube models

• Modeling NDE1 madiated microlissencephaly using 3D microfluidic neural tube models

Related publications:

1. Xufeng Xue, Robin Zhexuan Yan, Yi Zheng, Yue Liu, Frederick C.F. Wong, Azim Surani, Orly Reiner, and Jianping Fu. A patterned human neural tube model using microfluidics. Nature, accepted.

2. 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.

We report a dorsal-ventrally (DV) patterned human spinal cord development model. Neuroepithelial (NE) cysts, which are generated in a bioengineered neurogenic environment through self-organization of human pluripotent stem cells (hPSCs), exhibit spontaneous symmetry breaking and pattern formation, featuring sequential emergence of the ventral floor plate, P3, and pMN domains in discrete, adjacent regions and a dorsal territory progressively restricted to the opposite dorsal pole, mimicking the DV patterning of the spinal cord in vivo. This hPSC-based, DV patterned NE cyst system will be useful for understanding the self-organizing principles that guide NT patterning and for investigations of neural development and neural disease.

Related publications:

1. 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

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. Here we report 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.

Related publications:

1. 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.

2.  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.

3. 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.

I 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), the 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. Over the last few years, I have utilizedthe ATC technological platform for biomechanical stimulations of mechano-sensitive and -responsive human stem cells including human mesenchymal stem cells, and  human pluripotent stem cells (hPSCs).

Related publications:

1. 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.

2. 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.

3. 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.

4. 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.