Solving the challenges for large scale liver regeneration

At this moment, the culture of many tissues like liver cells and organoids is based on Matrigel, a suboptimal substance due to its poor chemical characterization and animal origin. In order to overcome these disadvantages, Shicheng Ye spent his PhD developing an alternative hydrogel for liver organoid cultivation, which culminated in his defense on November 14th.

His project proved challenging. ‘To engineer human liver tissues,’ Ye says, ‘two fundamental things or materials are needed. One is liver cells, and the other is supporting materials. The most promising and popular of these used for tissue engineering are hydrogels.’ 

Matrigel is a suboptimal substance

Until recently though, the cultivation of liver organoids relied on Matrigel, a substance derived from the extracellular matrix of Engelbreth-Holm-Swarm mouse sarcoma. Ye: ‘In Matrigel there are thousands of small molecules or peptides that you can’t exactly determine or measure.’ This makes it unreliable, and its clinical applications are limited by its xenogeneic origin, poor chemical characterization, and considerable batch-to-batch variability.  

To solve this issue, Shicheng Ye developed a synthetic, chemically defined hydrogel for human liver organoid expansion and differentiation. ‘It’s chemically defined, so we know exactly what is in this hydrogel,’ he says. With the help of his collaborators and supervisors Ye developed a hydrogel based on polyisocyanopeptides (PIC) and laminin-11. Organoids cultured in those hybrid hydrogels showed an overall trend of improved differentiation, which indicates the potential of this hydrogel for engineering functional liver tissues. 

Producing a large number of cells proves difficult

Given that the liver is the largest internal organ, liver engineering requires an extremely high amount of liver cells, necessitating their large-scale and rapid production. Ye explains his solution: ‘We established a protocol for the large-scale production of liver organoids in suspension using commercial spinner flasks. It bridges the gap between the tedious static organoid culture in hydrogel droplets and the need for an abundant supply of organoids for tissue engineering and research and development.’ 

The improvement in the key components required for liver engineering paved the way for future development of engineered tissues. ’We developed a strategy to incorporate major aspects of liver tissue engineering, such as cellular complexity, mimicry of the extracellular matrix, fluidic stimuli, and vascularization.’ Ye's thesis condenses his extensive research in liver tissue engineering, providing a roadmap to anyone interested in the field.  

The next step

Shicheng Ye moved to the Netherlands to start his PhD in 2018, after completing a masters in Biochemistry and Molecular Biology in Shanghai. The biggest adjustment for him was the difference in work culture; ‘In China we work from nine in the morning until nine at night, six days a week.’ Even so, he really enjoyed working at the RMCU. ‘It’s a really international environment and people treat each other like equals.’  

When asked about his future plans, Shicheng said: ‘I have always wanted to become a professor, so the next step is finding a suitable post-doc position.’ In the meantime, Ye works at start-up company Orgonex.