Pluripotent-Stem-Cell-Derived Hepatic Cells: Hepatocytes and Organoids for Liver Therapy and Regeneration
Abstract
:1. Introduction
2. Liver Therapy and Regeneration Approaches: Pros and Cons
2.1. Orthotopic Liver Transplantation (OLT)
2.2. Artificial Liver Devices
2.3. Cell Therapy: Transplantation of Isolated Cell
2.4. Cell Therapy: Bioengineering Approaches
2.4.1. Liver Organoids
2.4.2. Bio Artificial Liver (BAL) Devices
2.4.3. Decellularized/Cellularized Liver Scaffolds
2.4.4. Liver Biofabrication and Bioprinting
3. Cell Sources for Hepatocyte Transplantation and Liver Repair
3.1. Primary Human Hepatocytes (PHHs)
3.2. Fetal Liver Progenitors (FLPs)
3.3. Adult Human Liver Stem Cells (AdHLSCs)
3.4. Hematopoietic Stem Cells (HSCs) and Mesenchymal Stem Cells (MSCs)
3.5. Human Pluripotent Stem Cells (hPSCs)
3.6. Overview on Embryogenesis and Published Differentiation Protocols for hiPSC Differentiation into HLCs
3.7. Genetic Integrity
3.8. Epigenetics in hPSCs
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Methods for Organoid Generation | |
---|---|
Scaffold-Based Methods |
|
Scaffold-Free Methods |
|
Advantages | Disadvantages | |
---|---|---|
Orthotopic Liver Transplantation (OLT) | 88% patient survival Clinically defined | Shortage of donors Post-surgery complications Life-long immunosuppressive treatment Organ rejection |
Artificial Liver (AL) Device | Detoxification ability Bridge patients to OLT | Selective removal/detoxification of toxins Ineffective against encephalopathy Temporary support device |
Cell Transplantation | Surgical procedure safer and less invasive than OLT Partial correction of liver metabolic disorders | Shortage of cells Transitory improvement of patients’ conditions |
Bio Artificial Liver (BAL) Device | Improved detoxification ability due to biological components Bridge patients to OLT | Shortage of cells Clinical trials suspended or incomplete Complex set-up and scale-up |
Decellularized/CellularizedLiver Scaffolds (Pre-Clinical Development) | Improvement of hepatic cells functions with respect to classic scaffold-based culture approaches Liver-like tissue bio-construction transplantable | Shortage of cells Partial cell repopulation of the scaffolds Slow maturation of the construct Poor viability in pre-clinical studies |
Liver Biofabrication and Bioprinting (Pre-Clinical Development) | Easy scale-up of the 3D liver constructs Improvement of hepatic cell maturations with respect to 3D classic culture approaches | Shortage of cells Slow maturation of the construct Contradictory published data on construct viability |
Cell | Source | Advantages | Disadvantages | Ref. |
---|---|---|---|---|
PHHs | Cadaveric liver Partial hepatectomy | No ethical/political concerns Mature functional cells No risk of teratoma formation Clinically established cells | Immunogenicity Not proliferative in vitro Rapid loss of functionality Not available at large scale Cell aging DNA damage | [23,134] |
FLPs | Aborted fetus | Highly proliferative Lower immunogenicity than PHHs Transdifferentiation into mature hepatocytes | Ethical concern Low number of cells per fetal liver leading to multiple donors Difficult supply | [135] |
AdLSCs | Adult liver | Proliferative Bi-potent | Immunogenicity Not available at large scale Cell aging DNA damage | [90,91,92] |
HSCs | Bone marrow Blood | No ethical concern Highly proliferative Non-invasive collection procedures Abundant supplies (bone marrow) Low viral contamination No risk of teratoma formation Contribution to liver regeneration | Poorly effective: cell fusion with resident hepatocytes/trophic effects Limited number per single cord blood unit (multiple donors) Cell aging DNA damage | [136] |
MSCs | Bone marrow Umbilical cord Adipose tissue Blood | Highly proliferative Multipotency Immunomodulatory effects Antifibrotic effects | Downregulation of apoptotic genes Downregulation of DNA repair genes Heteroplasmic point mutations Viral transmission Cell aging DNA damage | [137] |
ESCs | Embryos | Self-renewal Pluripotency | Ethical concern Tumorigenicity Safety concerns (genetic stability) Immunogenicity | [126] |
iPSCs | Reprogramming of somatic cells | Self-renewal Pluripotency Possibly autologous | Safety concerns Tumorigenicity | [126,138] |
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Messina, A.; Luce, E.; Hussein, M.; Dubart-Kupperschmitt, A. Pluripotent-Stem-Cell-Derived Hepatic Cells: Hepatocytes and Organoids for Liver Therapy and Regeneration. Cells 2020, 9, 420. https://doi.org/10.3390/cells9020420
Messina A, Luce E, Hussein M, Dubart-Kupperschmitt A. Pluripotent-Stem-Cell-Derived Hepatic Cells: Hepatocytes and Organoids for Liver Therapy and Regeneration. Cells. 2020; 9(2):420. https://doi.org/10.3390/cells9020420
Chicago/Turabian StyleMessina, Antonietta, Eléanor Luce, Marwa Hussein, and Anne Dubart-Kupperschmitt. 2020. "Pluripotent-Stem-Cell-Derived Hepatic Cells: Hepatocytes and Organoids for Liver Therapy and Regeneration" Cells 9, no. 2: 420. https://doi.org/10.3390/cells9020420
APA StyleMessina, A., Luce, E., Hussein, M., & Dubart-Kupperschmitt, A. (2020). Pluripotent-Stem-Cell-Derived Hepatic Cells: Hepatocytes and Organoids for Liver Therapy and Regeneration. Cells, 9(2), 420. https://doi.org/10.3390/cells9020420