Hepatocytes: cells that help the liver live
Compared to an industrial plant/factory that releases harmful gases and chemicals in the process of making useful goods from raw materials, the human body, which is also a factory that works 24x7, produces tons of toxins on a daily basis. These toxins are released as a byproduct of the body’s normal chemical reactions such as nutrient absorption, metabolic functions, protein production etc., that should be removed in a timely manner to maintain the normal functions of the human body (1).
The triangular-shaped liver is one of the largest and most complex organs, located in the upper right abdomen, below the lung. Besides removing harmful substances from the body, the liver performs numerous other physiological processes including protein and amino acid metabolism, blood volume regulation, immune system support, the breakdown of xenobiotic compounds, and many more (2). The liver alone works tirelessly round the clock to fulfil 500 different vital body functions. These unique functions are achieved by the cooperation of various cell types that comprise the liver. They are: hepatocytes, cholangiocytes, stellate cells, Kupffer cells and liver sinusoidal endothelial cells (SECs). 80% of the total liver volume is made up of hepatocytes which are responsible for carrying out most of the functions attributed to it.
The polygonal shaped (typically six-sided) hepatocytes measure about 25–40 um in size with a distinct nucleus located in the center of the cell. Hepatocytes are arranged as hepatic plates, partly facing the sinusoids distributing outwards from the central vein to form a bile canaliculi (3). Compared to other cell types, hepatocytes are long-lived cells, having an average life span of five to six months.
The regenerative capability of hepatocytes is highly dependent on the ploidy (number of sets of chromosomes) level. It has been reported that diploid (2n) hepatocytes have a 7-fold higher birth rate than the polyploid (for e.g., 4n) hepatocytes. Polyploid hepatocytes are mostly observed in adults (>75 years of age) suggesting that aging can significantly affect the ploidy state of the human liver and hence its renewal capacity (4).
Hepatocytes: the regenerative marvels
Science has witnessed the regenerative capabilities of reptiles like lizards and amphibians such as axolotl larvae. It has also inspired the creation of fictional characters like Deadpool and Wolverine. Similarly, regeneration of the liver is one of the most fascinating phenomena beheld by clinicians and surgeons in the field of medicine. Tissue regeneration is a complex process by which an injured organ can restore its normal morphology and functionality (5). Hepatocytes, along with cholangiocytes, harbor the capacity to drive the liver regeneration process. The regeneration process is largely dependent on the volume of liver withdrawn during partial hepatectomy (PH) (surgical resection of the liver). If one-third PH is performed on the liver, hepatocytes compensate for the original mass by hypertrophy (increase in cell size). When two-thirds of the liver is removed due to an injury, hepatocytes recover the loss with hypertrophy followed by hyperplasia (increase in cell number). Very interestingly, when 80–90% of the liver is damaged due to a chronic illness/injury, the regenerative capacity of the hepatocytes reaches a threshold and they repopulate the damaged liver with the help of biliary epithelial cells (BECs). BECs differentiate into liver progenitor cells (LPCs) which further proliferate into hepatocytes to restore the normal cell population of the liver (6). It has been proven through transplantation and repopulation experiments that hepatocytes are highly differentiated cells with a remarkable capacity for multiple replications (7).
Hepatocytes in hepatic tissue engineering
Hepatic failure due to severe and life-threatening diseases such as cancer, cirrhosis, hepatitis C virus (HCV), non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), or drug-induced liver injury (DILI), leaves the patient with one common therapeutic option, liver transplant (8). With a continuous decline in the number of organ donors, hepatic tissue engineering alleviates the situation by serving as an alternative method to traditional transplantation. Hepatocytes isolated from patients or deceased donors play a pivotal role in the development of in vitro liver disease models using the cutting-edge technologies of organ-on-a-chip (9), 3D bioprinting (10), organoids (11) etc. Although a crucial entity in the development and advancement of physiological liver tissue models, hepatocytes come with their own set of challenges. Since the first successful in vitro culture of primary rat hepatocytes in 1989, scientists have struggled to maintain long-term cultures because hepatocytes tend to lose their phenotype when cultured in vitro in an artificial environment. Maintaining their phenotype/morphology is the key to achieving liver functions similar to the physiological scale (12). To overcome this challenge, scientists have started developing trust and confidence in the use of stem-cell-derived hepatocyte-like cells to build a promising future towards hepatic tissue engineering. Constituting the majority population of one of the most complex and unique organs of the human body, further studies on the performance and longevity of hepatocyte cultures are imperative.
Recognizing and appreciating the labs working in this space
- Dr. Sangeeta Bhatia, Laboratory for Multiscale Regenerative Technologies, MIT. Cambridge, Massachusetts, USA. https://www.lmrt.mit.edu/ , Twitter: @snbhatia
- Dr. Bin Gao, Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism. Bethesda, Maryland, USA. https://www.niaaa.nih.gov/research/division-intramural-clinical-and-biological-research/laboratory-liver-diseases , Twitter: @NIAAAnews
- The Bouchard Lab, Drexel University, College of Medicine. Philadelphia, USA. https://drexel.edu/medicine/about/departments/biochemistry-molecular-biology/research/bouchard-lab/
- Dr. Anja Lode, Centre for Translational Bone, Joint and Soft Tissue Research, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany. https://tu-dresden.de/med/mf/tfo/das-institut/beschaeftigte/anja-lode-1
- Willenbring Lab, Department of Surgery, University of California. San Francisco, California, USA. https://willenbringlab.ucsf.edu/ , Twitter: @UCSFTransplant
- Dr. Salman Khetani, Microfabricated Tissue Models Laboratory, University of Illinois. Chicago, USA. https://www.mtmlaboratory.com/
- CN Bio, Organ-on-a-chip company. Cambridge, UK. https://cn-bio.com/ , Twitter: @CN_Bio
- Dhawan Lab, Institute of Liver Studies, King’s College London. London, UK. https://dhawanlab.org/
- Laboratory of Hepatocyte Regulation, National institute of Biomedical Health and Nutrition. Osaka, Japan. https://www.nibiohn.go.jp/en/activities/hepatocyte-regulation.html
- Liver Cell Laboratory, Department of Clinical Science, Intervention and Technology, CLINTEC. Karolinska Institute, Stockholm, Sweden. https://ki.se/en/clintec/liver-cells-laboratory
- Liver Tissue Chip, Javelin Biotech. Woburn, Massachusetts, USA. https://javelinbiotech.com/
References
- Hansel, Marc C et al. “The history and use of human hepatocytes for the treatment of liver diseases: the first 100 patients.” Current protocols in toxicology vol. 62 14.12.1–23. 6 Nov. 2014, doi:10.1002/0471140856.tx1412s62
- Trefts, Elijah et al. “The liver.” Current biology : CB vol. 27,21 (2017): R1147-R1151. doi:10.1016/j.cub.2017.09.019
- Krishna, Murli. “Microscopic anatomy of the liver.” Clinical liver disease vol. 2,Suppl 1 S4-S7. 29 Mar. 2013, doi:10.1002/cld.147
- Heinke, Paula et al. “Diploid hepatocytes drive physiological liver renewal in adult humans.” Cell systems vol. 13,6 (2022): 499–507.e12. doi:10.1016/j.cels.2022.05.001
- Cao, Binrui et al. “Bacteriophage-based biomaterials for tissue regeneration.” Advanced drug delivery reviews vol. 145 (2019): 73–95. doi:10.1016/j.addr.2018.11.004
- Gilgenkrantz, Hélène, and Alexandra Collin de l’Hortet. “Understanding Liver Regeneration: From Mechanisms to Regenerative Medicine.” The American journal of pathology vol. 188,6 (2018): 1316–1327. doi:10.1016/j.ajpath.2018.03.008
- Fausto, Nelson, and Jean S Campbell. “The role of hepatocytes and oval cells in liver regeneration and repopulation.” Mechanisms of development vol. 120,1 (2003): 117–30. doi:10.1016/s0925–4773(02)00338–6
- Nair, Dileep G, and Ralf Weiskirchen. “Recent Advances in Liver Tissue Engineering as an Alternative and Complementary Approach for Liver Transplantation.” Current issues in molecular biology vol. 46,1 262–278. 29 Dec. 2023, doi:10.3390/cimb46010018
- Liu, Jie et al. “Construction of in vitro liver-on-a-chip models and application progress.” Biomedical engineering online vol. 23,1 33. 15 Mar. 2024, doi:10.1186/s12938–024–01226-y
- Li, Wenhui et al. “Application of 3D Bioprinting in Liver Diseases.” Micromachines vol. 14,8 1648. 21 Aug. 2023, doi:10.3390/mi14081648
- Hu, Yang et al. “Research progress and application of liver organoids for disease modeling and regenerative therapy.” Journal of molecular medicine (Berlin, Germany), 10.1007/s00109–024–02455–3. 28 May. 2024, doi:10.1007/s00109–024–02455–3
- Kazemnejad, Somaieh. “Hepatic tissue engineering using scaffolds: state of the art.” Avicenna journal of medical biotechnology vol. 1,3 (2009): 135–45.
About the author:
DR. SURUCHI PODDAR
Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Poddar received a PhD in Biomedical Engineering from Indian Institute of Technology-Banaras Hindu University (IIT-BHU), Varanasi, India. She started her career as a postdoctoral researcher in 2020 with the Nanoscience Technology Center at the University of Central Florida, Orlando where she worked on a multi-organ human-on-a-chip system. Currently she is working on solid-state nanopore technology at Wake Forest University, North Carolina. When not working, she enjoys watching movies, cooking food and exploring new places, restaurants, attractions.
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NELLY AGHEKYAN
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Nelli Aghekyan did a bachelor’s and master’s in Architecture in Armenia, after studying architecture and interior design for 6 years, she concentrated on her drawing skills and continued her path in the illustration world. She works mainly on children’s book illustrations, some of her books are now being published. Currently living in Italy, she works as a full-time freelance artist, collaborating with different companies and clients.
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Animator The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Petretto received his Ph.D. in Biochemistry at the University of Fribourg, Switzerland, focusing on the behavior of matter at nanoscopic scales and the stability of colloidal systems. Using molecular dynamics simulations, he explored the delicate interaction among particles, interfaces, and solvents.
Currently, he is fully pursuing another delicate interaction: the intricate interplay between art and science. Through data visualization, motion design, and games, he wants to show the wonders of the complexity surrounding us.
About the series:
The League of Extraordinary Cell types
The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.
