Regenerative medicine for the hepatobiliary system: A review

Huang, Yufan; Miyamoto, Daisuke; Hidaka, Masaaki; Adachi, Tomohiko; Gu, Weizhong; Eguchi, Susumu

doi:10.1002/jhbp.882

Cited by 10 publications

(7 citation statements)

References 127 publications

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“…Recently, several culture systems for long-term expansion and largescale cultivation of liver cells have been established for liver regenerative medicine. 2 Previously, a cocktail of the molecules Y27632, A-83-01, and CHIR99021 was reportedly able to reprogram mature rat and mouse hepatocytes into chemically induced liver progenitor (CLiP) cells. 3 Besides, a cocktail combining the molecules A-83-01, CHIR99021, and hepatocyte growth factor (HGF) or fetal bovine serum (FBS) has also been reported to reprogram human hepatocytes into bipotent progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

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Chemical conversion of aged hepatocytes into bipotent liver progenitor cells

Huang

Miyamoto

et al. 2021

Hepatology Research

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Aim: In the aging society, understanding the influence of hepatocyte age on hepatocyte donation may inform efforts to expand alternative cell sources to mitigate liver donor shortage. A combination of the molecules Y27632, A-83-01, and CHIR99021 has been used to reprogram rodent young hepatocytes into chemically induced liver progenitor (CLiP) cells; however, whether it could also reprogram aged hepatocytes has not yet been elucidated. Methods: Primary hepatocytes were isolated from aged and young donor rats, respectively. Hepatic histological changes were evaluated. Differences in gene expression in hepatocytes were identified. The in vitro reprogramming plasticity of hepatocytes as evidenced by CLiP conversion and the hepatocyte and cholangiocyte maturation capacity of reprogrammed CLIPs were analyzed. The effect of hepatocyte growth factor (HGF) on cell propagation was also investigated. Results: The histological findings revealed ongoing liver damage with inflammation, fibrosis, senescence, and ductular reaction in aged livers. Microarray analysis showed altered gene expression profiles in hepatocytes from aged donors, especially with regard to metabolic pathways. Aged hepatocytes could be converted into CLiPs (Aged-CLiPs) expressing progenitor cell markers, but with a relatively low proliferative rate compared with young hepatocytes. Aged-CLiPs possessed both hepatocyte and cholangiocyte maturation capacity. HGF facilitated CLiP conversion in aged hepatocytes, which was partly related to the activation of Erk1 and Akt1 signaling. Conclusions: Aged rat hepatocytes have retained reprogramming plasticity as evidenced by CLiP conversion in culture. HGF promoted proliferation and CLiP conversion in aged hepatocytes. Hepatocytes from aged donors may be used as an alternative cell source to mitigate donor shortage.

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Section: Introductionmentioning

confidence: 99%

“…Due to the shortage of donors for liver or hepatocyte transplantation, several strategies have been established to expand hepatocyte cell sources. 2 In the aging society, making use of the livers of elderly donors could help alleviate the shortage of donor livers.…”

Section: Introductionmentioning

confidence: 99%

Chemical conversion of aged hepatocytes into bipotent liver progenitor cells

Huang

Miyamoto

et al. 2021

Hepatology Research

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“…Hepatic organoids were also obtained with a new method from ESCs that can be converted to both hepatocytes and cholangiocytes [ 109 ]. These hepatic organoids can proliferate and replace damaged cells with mature hepatocytes after grafting in FRG mice with liver dysfunction [ 95 , 110 – 112 ]. The creative point is that it is possible to study drug toxicity on the liver using ESC-derived organoids and apply it to screening models [ 109 , 113 ].…”

Section: Stem Cell-derived Organoidsmentioning

confidence: 99%

Advancement of Organoid Technology in Regenerative Medicine

Arjmand

Rabbani

Soveyzi

et al. 2022

Regen. Eng. Transl. Med.

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Purpose Organoids are three-dimensional cultures of stem cells in an environment similar to the body’s extracellular matrix. This is also a novel development in the realm of regenerative medicine. Stem cells can begin to develop into 3D structures by modifying signaling pathways. To form organoids, stem cells are transplanted into the extracellular matrix. Organoids have provided the required technologies to reproduce human tissues. As a result, it might be used in place of animal models in scientific study. The key goals of these investigations are research into viral and genetic illnesses, malignancies, and extracellular vesicles, pharmaceutical discovery, and organ transplantation. Organoids can help pave the road for precision medicine through genetic editing, pharmaceutical development, and cell therapy. Methods PubMed, Google Scholar, and Scopus were used to search for all relevant papers written in English (1907–2021). The study abstracts were scrutinized. Studies on the use of stem-cell-derived organoids in regenerative medicine, organoids as 3D culture models for EVs analysis, and organoids for precision medicine were included. Articles with other irrelevant aims, meetings, letters, commentaries, congress and conference abstracts, and articles with no available full texts were excluded. Results According to the included studies, organoids have various origins, types, and applications in regenerative and precision medicine, as well as an important role in studying extracellular vesicles. Conclusion Organoids are considered a bridge that connects preclinical studies to clinical ones. However, the lack of a standardized protocol and other barriers addressed in this review, hinder the vast use of this technology. Lay Summary Organoids are 3D stem cell propagations in biological or synthetic scaffolds that mimic ECM to allow intercellular or matrix-cellular crosstalk. Because these structures are similar to organs in the body, they can be used as research models. Organoids are medicine’s future hope for organ transplantation, tumor biobank formation, and the development of precision medicine. Organoid models can be used to study cell-to-cell interactions as well as effective factors like inflammation and aging. Bioengineering technologies are also used to define the size, shape, and composition of organoids before transforming them into precise structures. Finally, the importance of organoid applications in regenerative medicine has opened a new window for a better understanding of biological research, as discussed in this study.

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“…Cell transplantation makes it possible to overcome the acute shortage of donor organs, reduce the risk of complications associated with surgical methods of treatment, neutralize toxic effects after the use of drugs, and also prevent inhibition of the regenerative recovery of the affected organ. − The cost of cell technologies is lower compared to organ transplantation; they are safer and allow repeated transplantation several times, making a “bridge” while waiting for an organ for transplantation. They allow for providing medical care to a larger number of patients and, in some cases, allow for avoiding the use of immunosuppressive drugs.…”

Section: Introductionmentioning

confidence: 99%

Engineered Fibrous NiTi Scaffolds with Cultured Hepatocytes for Liver Regeneration in Rats

Kokorev

Марченко

Хлусов

et al. 2023

ACS Biomater. Sci. Eng.

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At present, the use of alternative systems to replenish the lost functions of hepatic metabolism and partial replacement of liver organ failure is relevant, due to an increase in the incidence of various liver disorders, insufficiency, and cost of organs for transplantation, as well as the high cost of using the artificial liver systems. The development of low-cost intracorporeal systems for maintaining hepatic metabolism using tissue engineering, as a bridge before liver transplantation or completely replacing liver function, deserves special attention. In vivo applications of intracorporeal fibrous nickel–titanium scaffolds (FNTSs) with cultured hepatocytes are described. Hepatocytes cultured in FNTSs are superior to their injections in terms of liver function, survival time, and recovery in a CCl4-induced cirrhosis rats’ model. 232 animals were divided into 5 groups: control, CCl4-induced cirrhosis, CCl4-induced cirrhosis followed by implantation of cell-free FNTSs (sham surgery), CCl4-induced cirrhosis followed by infusion of hepatocytes (2 mL, 107 cells/mL), and CCl4-induced cirrhosis followed by FNTS implantation with hepatocytes. Restoration of hepatocyte function in the FNTS implantation with the hepatocytes group was accompanied by a significant decrease in the level of aspartate aminotransferase (AsAT) in blood serum compared to the cirrhosis group. A significant decrease in the level of AsAT was noted after 15 days in the infused hepatocytes group. However, on the 30th day, the AsAT level increased and was close to the cirrhosis group due to the short-term effect after the introduction of hepatocytes without a scaffold. The changes in alanine aminotransferase (AlAT), alkaline phosphatase (AlP), total and direct bilirubin, serum protein, triacylglycerol, lactate, albumin, and lipoproteins were similar to those in AsAT. The survival time of animals was significantly longer in the FNTS implantation with hepatocytes group. The obtained results showed the scaffolds’ ability to support hepatocellular metabolism. The development of hepatocytes in FNTS was studied in vivo using 12 animals using scanning electron microscopy. Hepatocytes demonstrated good adhesion to the scaffold wireframe and survival in allogeneic conditions. Mature tissue, including cellular and fibrous, filled the scaffold space by 98% in 28 days. The study shows the extent to which an implantable “auxiliary liver” compensates for the lack of liver function without replacement in rats.

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Regenerative medicine for the hepatobiliary system: A review

Cited by 10 publications

References 127 publications

Chemical conversion of aged hepatocytes into bipotent liver progenitor cells

Chemical conversion of aged hepatocytes into bipotent liver progenitor cells

Advancement of Organoid Technology in Regenerative Medicine

Engineered Fibrous NiTi Scaffolds with Cultured Hepatocytes for Liver Regeneration in Rats

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