Research

Human Somitogenesis: In Vitro Reconstitution and Mechanical Models

Somite is a unique structure of early-stage vertebrate embryo, which later becomes our musculoskeletal system. It acquires a segmented morphology (just like our vertebrae) through a sequence of boundary formation dynamics on a continuous strip of cells called pre-somitic mesoderm. This segmented morphology also defines the discontinuous topology of our bones and muscles, which are separated by joints and interfaces and therefore facilitate mechanical flexibility. However, a variety of fundamental questions regarding the somites remain unanswered due the our lack of understanding towards the morphogenetic driving forces. For example, different vertebrate species can have significantly different number of somites (e.g. ~40 pairs in human and ~315 in corn snake) and hence vertebrae, yet little is known about the underlying mechanism. To address this challenge, I combined human pluripotent stem cells and microfluidic tools and successfully induced an in vitro spatially directed somite boundary formation dynamics. Further, I established a mechanics-based theoretical scaling law to predict the somite size, which is confirmed by both in vivo and in vitro data from multiple species. Based on this work, I will be able to further probe the mechanical and biological principles dictating the somite formation process, and fully unveil the topology regulation mechanism of our musculoskeletal system.

Related publications:

• Y. Liu#, Y.S. Kim, X. Xue, Y. Miao, N. Kobayashi, S. Sun, R.Z. Yan, Q. Yang, O. Pourquié & J. Fu#. A human pluripotent stem cell-based somitogenesis model using microfluidics. Cell Stem Cell 31, 1113-1126. e1116 (2024)

• Y. Liu#, X. Xue, S. Sun, N. Kobayashi, Y.S. Kim & J. Fu#. Morphogenesis beyond in vivo. Nature Reviews Physics 6, 28-44 (2024)

• X. Xue, Y. Liu & J. Fu. Bioengineering embryo models. Nature Reviews Bioengineering, 1-19 (2024).

• X. Xue, Y.S. Kim, A.I.P. Arias, R. O'laughlin, R.Z. Yan, N. Kobayashi, R.Y. Tshuva, Y.-H. Tsai, S. Sun, Y. Zheng, Y. Liu, F. Wong, A. Surani, J. Spence, H. Song, G.-L. Ming, O. Reiner & J. Fu. A patterned human neural tube model using microfluidics. Nature, 1-3 (2024).

• S. Sun, Y. Zheng, N. Kobayashi, Y.S. Kim, X. Xue, Y. Liu, Y. Xu, J. Zhai, H. Wang, & J. Fu. A transgene-free, human peri-gastrulation embryo model with trilaminar embryonic disc-, amnion- and yolk sac-like structures. bioRxiv (2024)

• Y. Zheng, R. Z. Yan, M. Kobayashi, L. Xiang, R. Yang, A. Goedel, Y. Kang, X. Xue, S. N. Esfahani, Y. Liu, A. M. R. Irizarry, W. Wu, Y. Li, W. Ji, Y. Niu, K. R. Chien, T. Li, T. Shioda & J. Fu. Single-cell analysis of embryoids reveals lineage diversification roadmaps of early human development. Cell Stem Cell 29, 1402-1419. e1408 (2022).

• K. Chen, Y. Zheng, X. Xue, Y. Liu, A. M. R. Irizarry, H. Tang & J. Fu. Branching development of early post-implantation human embryonic-like tissues in 3D stem cell culture. Biomaterials, 120898 (2021).

Viscoelastic Epicardial Patch for Myocardial Infarction Treatment

Cardiovascular diseases are currently one of the leading cause of mortality globally.  Cardiac patches, made from biomaterials or biological substances and sometimes in combination with cells or drugs, offer a potential treatment for severe myocardial infarction (MI) and subsequent heart failure with established efficacy through alleviating myocardium wall stress. However, the optimal patch design is still unknown. Through finite element simulation, I discovered that an optimal design requires a balance between the fluid properties and solid properties, a so-called gel-point viscoelastic trait, so as to both accommodate the dynamic heartbeat and provide mechanical support. Based on such design, a starch-based self-adaptive epicardial patch is developed by our collaborating teams with a near-optimal reliable efficacy in restraining ventricular dilatation and preventing adverse LV remodeling and cardiac failure after MI.

Related publications:

• X. Lin*, Y. Liu*, A. Bai*, H. Cai*, Y. Bai, W. Jiang, H. Yang, X. Wang, L. Yang, N. Sun & H. Gao. A viscoelastic adhesive epicardial patch for treating myocardial infarction. Nature Biomedical Engineering 3, 632-643 (2019).

• X. Shi, Y. Liu, K. M. Copeland, S. R. McMahan, S. Zhang, J. R. Butler, Y. Hong, M. Cho, P. Bajona & H. Gao. Epicardial prestrained confinement and residual stresses: a newly observed heart ventricle confinement interface. Journal of the Royal Society Interface 16, 20190028 (2019).

• X. Shi, S. Zhang, Y. Liu, B. Brazile, J. Cooley, J.R. Butler, S.R. McMahan, K. Peltz, Y. Hong, K. Nguyen, P. Bajona, M. Peltz, H. Gao & J. Liao. Spatial distribution and network morphology of epicardial, endocardial, and interstitial elastin fibers in porcine left ventricle. Bioactive Materials 19, 348-359 (2023).

Membrane-Targeting Nanomedicine

When subjected to antibiotics, bacteria can enter a dormant state and become the so-called "persisters" with high resistance against conventional antibiotics. Such persisters can lead to a looming global crisis of antimicrobial resistance that can cause ten million deaths worldwide every year by 2050 if no measure is taken. Recently a new class of membrane-targeting antibiotics (MTAs) were designed to degrade the mechanical integrity of bacterial membrane and as such can effectively kill bacteria, even the persisters. With theoretical studies, I developed the critical condition where the bending energy and the free energy of mixing of MTAs can lead to domain aggregation on bacterial membrane. Further, the bending energy and the domain boundary line tension are shown to assist the pore growth by reducing the energy barrier. I also performed coarse-grained molecular dynamics simulations to validate such domain aggregation and associated pore formation. This study sheds light on how lipid membranes can be damaged through molecular domain aggregation and contributes to establish a theoretical foundation for the next-generation membrane-targeting nanomedicine.

Related publications:

• Y. Liu, G. Zou & H. Gao. Domain aggregation and associated pore growth in lipid membranes. ACS Nano 15, 604-613 (2021). 

• G. Zou, Y. Liu & H. Gao. EML webinar overview: Simulation-assisted discovery of membrane targeting nanomedicine. Extreme Mechanics Letters 39, 100817 (2020). 

Limpet Teeth with Auxeticity and High Strength

Negative Poisson's ratio, or auxeticity, is a peculiar mechanical property with abundant potential engineering applications. When stretched in one direction, an auxetic material will expand, instead of shrinking, in the transverse direction. Most engineering materials/structures incorporate voids to attain auxeticity and thus inevitably reduces their strength and/or stiffness. In contrast, by analyzing the straining data contributed by our collaborating team, I found that limpet teeth can unite auxeticity and high stiffness and strength through their unique microstructure. With DIC analysis, I identified a rotation-dominated deformation mechanism. Based on these discoveries, I further characterized the microstructure with micropolar elasticity modeling and successfully recapitulated the auxeticity. 

Related publications:

• S. Oh∗, J.-K. Kim∗, Y. Liu∗, M. Wurmshuber, X.-L. Peng, J. Seo, J. Jeong, Z. Wang, J. Wilmers, C. Soyarslan, J. Kim, J. Jeong, H.-J. Kim, Y. H. Huh, D. Kiener, S. Bargmann, & H. Gao. Limpet teeth microstructure unites auxeticity with extreme strength and high stiffness. Science Advances 8, eadd4644 (2022).