Small Molecule-Mediated Stage-Specific Reprogramming of MSCs to Hepatocyte-Like Cells and Hepatic Tissue for Liver Injury Treatment.
Decellularization
Hepatic tissue
Hepatocyte-like cells (dHep)
Mesenchymal stem cells
Small molecules
Journal
Stem cell reviews and reports
ISSN: 2629-3277
Titre abrégé: Stem Cell Rev Rep
Pays: United States
ID NLM: 101752767
Informations de publication
Date de publication:
11 Sep 2024
11 Sep 2024
Historique:
accepted:
04
08
2024
medline:
11
9
2024
pubmed:
11
9
2024
entrez:
11
9
2024
Statut:
aheadofprint
Résumé
Derivation of hepatocytes from stem cells has been established through various protocols involving growth factor (GF) and small molecule (SM) agents, among others. However, mesenchymal stem cell-based derivation of hepatocytes still remains expensive due to the use of a cocktail of growth factors, and a long duration of differentiation is needed, thus limiting its potential clinical application. In this study, we developed a chemically defined differentiation strategy that is exclusively based on SM and takes 14 days, while the GF-based protocol requires 23-28 days. We optimized a stage-specific differentiation protocol for the differentiation of rat bone marrow-derived mesenchymal stem cells (MSCs) into functional hepatocyte-like cells (dHeps) that involved four stages, i.e., definitive endoderm (DE), hepatic competence (HC), hepatic specification (HS) and hepatic differentiation and growth. We further generated hepatic tissue using human decellularized liver extracellular matrix and compared it with hepatic tissue derived from the growth factor-based protocol at the transcriptional level. dHep, upon transplantation in a rat model of acute liver injury (ALI), was capable of ameliorating liver injury in rats and improving liver function and tissue damage compared to those in the ALI model. In summary, this is the first study in which hepatocytes and hepatic tissue were derived from MSCs utilizing a stage-specific strategy by exclusively using SM as a differentiation factor.
Sections du résumé
BACKGROUND
BACKGROUND
Derivation of hepatocytes from stem cells has been established through various protocols involving growth factor (GF) and small molecule (SM) agents, among others. However, mesenchymal stem cell-based derivation of hepatocytes still remains expensive due to the use of a cocktail of growth factors, and a long duration of differentiation is needed, thus limiting its potential clinical application.
METHODS
METHODS
In this study, we developed a chemically defined differentiation strategy that is exclusively based on SM and takes 14 days, while the GF-based protocol requires 23-28 days.
RESULTS
RESULTS
We optimized a stage-specific differentiation protocol for the differentiation of rat bone marrow-derived mesenchymal stem cells (MSCs) into functional hepatocyte-like cells (dHeps) that involved four stages, i.e., definitive endoderm (DE), hepatic competence (HC), hepatic specification (HS) and hepatic differentiation and growth. We further generated hepatic tissue using human decellularized liver extracellular matrix and compared it with hepatic tissue derived from the growth factor-based protocol at the transcriptional level. dHep, upon transplantation in a rat model of acute liver injury (ALI), was capable of ameliorating liver injury in rats and improving liver function and tissue damage compared to those in the ALI model.
CONCLUSIONS
CONCLUSIONS
In summary, this is the first study in which hepatocytes and hepatic tissue were derived from MSCs utilizing a stage-specific strategy by exclusively using SM as a differentiation factor.
Identifiants
pubmed: 39259445
doi: 10.1007/s12015-024-10771-x
pii: 10.1007/s12015-024-10771-x
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Dwyer, B. J., Macmillan, M. T., Brennan, P. N., & Forbes, S. J. (2021). Cell therapy for advanced liver diseases: Repair or rebuild. Journal of Hepatology, 74(1), 185–199. https://doi.org/10.1016/j.jhep.2020.09.014
doi: 10.1016/j.jhep.2020.09.014
pubmed: 32976865
Yu, Y., Fisher, J. E., Lillegard, J. B., Rodysill, B., Amiot, B., & Nyberg, S. L. (2012). Cell therapies for liver diseases. Liver Transplantation, 18(1), 9–21. https://doi.org/10.1002/lt.22467
doi: 10.1002/lt.22467
pubmed: 22140063
pmcid: 3245367
Yamaguchi, T., Matsuzaki, J., Katsuda, T., Saito, Y., Saito, H., & Ochiya, T. (2019). Generation of functional human hepatocytes in vitro: Current status and future prospects. Inflammation and Regeneration, 39(1), 13. https://doi.org/10.1186/s41232-019-0102-4
doi: 10.1186/s41232-019-0102-4
pubmed: 31308858
pmcid: 6604181
Maepa, S. W., & Ndlovu, H. (2020). Advances in generating liver cells from pluripotent stem cells as a tool for modeling liver diseases. Stem Cells, 38(5), 606–612. https://doi.org/10.1002/stem.3154
doi: 10.1002/stem.3154
pubmed: 32012379
Mitani, S., et al. (2017). Human ESC/iPSC-derived hepatocyte-like cells achieve zone-specific hepatic properties by modulation of WNT signaling. Molecular Therapy, 25(6), 1420–1433. https://doi.org/10.1016/j.ymthe.2017.04.006
doi: 10.1016/j.ymthe.2017.04.006
pubmed: 28462819
pmcid: 5475257
Afshari, A., Shamdani, S., Uzan, G., Naserian, S., & Azarpira, N. (2020). Different approaches for transformation of mesenchymal stem cells into hepatocyte-like cells. Stem Cell Research & Therapy, 11(1), 54. https://doi.org/10.1186/s13287-020-1555-8
doi: 10.1186/s13287-020-1555-8
Bishi, D. K., et al. (2016). A patient-inspired ex vivo liver tissue engineering approach with autologous mesenchymal stem cells and hepatogenic serum. Advanced Healthcare Materials, 5(9), 1058–1070. https://doi.org/10.1002/adhm.201500897
doi: 10.1002/adhm.201500897
pubmed: 26890619
Alwahsh, S. M., Rashidi, H., & Hay, D. C. (2018). Liver cell therapy: Is this the end of the beginning? Cellular and Molecular Life Sciences, 75(8), 1307–1324. https://doi.org/10.1007/s00018-017-2713-8
doi: 10.1007/s00018-017-2713-8
pubmed: 29181772
Hu, C., & Li, L. (2015). In vitro and in vivo hepatic differentiation of adult somatic stem cells and extraembryonic stem cells for treating end stage liver diseases. Stem Cells International, 2015, 871972. https://doi.org/10.1155/2015/871972
Siller, R., Greenhough, S., Naumovska, E., & Sullivan, G. J. (2015). Small-Molecule-Driven Hepatocyte Differentiation of Human Pluripotent Stem Cells. Stem Cell Reports, 4(5), 939–952. https://doi.org/10.1016/j.stemcr.2015.04.001
doi: 10.1016/j.stemcr.2015.04.001
pubmed: 25937370
pmcid: 4437467
Varghese, D. S., Alawathugoda, T. T., & Ansari, S. A. (2019). Fine tuning of hepatocyte differentiation from human embryonic stem cells: growth factor vs. small molecule-based approaches. Stem Cells International, 2019, 5968236. https://doi.org/10.1155/2019/5968236
doi: 10.1155/2019/5968236
pubmed: 30805010
pmcid: 6362496
Itaba, N., et al. (2015). Identification of the small molecule compound which induces hepatic differentiation of human mesenchymal stem cells. Regenerative Therapy, 2, 32–41. https://doi.org/10.1016/j.reth.2015.10.001
doi: 10.1016/j.reth.2015.10.001
pubmed: 31245457
pmcid: 6581787
Zhang, Y., Li, W., Laurent, T., & Ding, S. (2012). Small molecules, big roles – the chemical manipulation of stem cell fate and somatic cell reprogramming. Journal of Cell Science, 125(23), 5609–5620. https://doi.org/10.1242/jcs.096032
doi: 10.1242/jcs.096032
pubmed: 23420199
pmcid: 4067267
Luo, Q., et al. (2023). Pluripotent stem cell-derived hepatocyte-like cells: induction methods and applications. International Journal of Molecular Sciences, 24(14). https://doi.org/10.3390/ijms241411592
Graffmann, N., Scherer, B., & Adjaye, J. (2022). In vitro differentiation of pluripotent stem cells into hepatocyte like cells – Basic principles and current progress. Stem Cell Research, 61, 102763. https://doi.org/10.1016/j.scr.2022.102763
doi: 10.1016/j.scr.2022.102763
pubmed: 35395623
Szkolnicka, D., & Hay, D. C. (2016). Concise review: advances in generating hepatocytes from pluripotent stem cells for translational medicine. Stem Cells, 34(6), 1421–1426. https://doi.org/10.1002/stem.2368
doi: 10.1002/stem.2368
pubmed: 27015786
Pareja, E., Gómez-Lechón, M. J., & Tolosa, L. (April 2020). Induced pluripotent stem cells for the treatment of liver diseases: challenges and perspectives from a clinical viewpoint. The Annals of Translational Medicine, 8(8), [Online]. Available: https://atm.amegroups.com/article/view/37729
Liu, G., David, B. T., Trawczynski, M., & Fessler, R. G. (2020). Advances in pluripotent stem cells: history, mechanisms, technologies, and applications. Stem Cell Reviews and Reports, 16(1), 3–32. https://doi.org/10.1007/s12015-019-09935-x
doi: 10.1007/s12015-019-09935-x
pubmed: 31760627
Hosseini, V., et al. (2019). Current progress in hepatic tissue regeneration by tissue engineering. Journal of Translational Medicine, 17(1), 383. https://doi.org/10.1186/s12967-019-02137-6
doi: 10.1186/s12967-019-02137-6
pubmed: 31752920
pmcid: 6873477
Mazza, G., Al-Akkad, W., Rombouts, K., & Pinzani, M. (2018). Liver tissue engineering: From implantable tissue to whole organ engineering. Hepatology Communications, 2(2), 131–141. https://doi.org/10.1002/hep4.1136
doi: 10.1002/hep4.1136
pubmed: 29404520
Rossi, E. A., Quintanilha, L. F., Nonaka, C. K. V., & de F. Souza, B. S. (2019). Advances in hepatic tissue bioengineering with decellularized liver bioscaffold. Stem Cells International, 2019, 2693189. https://doi.org/10.1155/2019/2693189
Jiang, W. C., Cheng, Y. H., Yen, M. H., Chang, Y., Yang, V. W., & Lee, O. K. (2014). Cryo-chemical decellularization of the whole liver for mesenchymal stem cells-based functional hepatic tissue engineering. Biomaterials, 35(11), 3607–3617. https://doi.org/10.1016/j.biomaterials.2014.01.024
doi: 10.1016/j.biomaterials.2014.01.024
pubmed: 24462361
pmcid: 4678102
Hussein, K. H., et al. (2024). Liver tissue engineering using decellularized scaffolds: Current progress, challenges, and opportunities. Bioactive Materials, 40, 280–305. https://doi.org/10.1016/j.bioactmat.2024.06.001
doi: 10.1016/j.bioactmat.2024.06.001
pubmed: 38973992
pmcid: 11226731
Schuurman, H.-J., & Hoogendoorn, K. (2020). Solid organ xenotransplantation at the interface between research and clinical development: Regulatory aspects. Xenotransplantation, 27(3), e12608. https://doi.org/10.1111/xen.12608
doi: 10.1111/xen.12608
pubmed: 32500587
Czysz, K., Minger, S., & Thomas, N. (Feb. 2015). DMSO efficiently down regulates pluripotency genes in human embryonic stem cells during definitive endoderm derivation and increases the proficiency of hepatic differentiation,. PLoS One, 10(2), e0117689, [Online]. Available: https://doi.org/10.1371/journal.pone.0117689
Gao, X., Li, R., Cahan, P., Zhao, Y., Yourick, J. J., & Sprando, R. L. (2020). Hepatocyte-like cells derived from human induced pluripotent stem cells using small molecules: Implications of a transcriptomic study. Stem Cell Research & Therapy, 11(1), 393. https://doi.org/10.1186/s13287-020-01914-1
doi: 10.1186/s13287-020-01914-1
Geerts, S., Ozer, S., Jaramillo, M., Yarmush, M. L., & Uygun, B. E. (2016). Nondestructive methods for monitoring cell removal during rat liver decellularization. Tissue Engineering. Part C, Methods, 22(7), 671–678. https://doi.org/10.1089/ten.tec.2015.0571
doi: 10.1089/ten.tec.2015.0571
pubmed: 27169332
pmcid: 4943465
Bishi, D. K., et al. (2013). Trans-differentiation of human mesenchymal stem cells generates functional hepatospheres on poly(l-lactic acid)-co-poly(ε-caprolactone)/collagen nanofibrous scaffolds. J. Mater. Chem. B, 1(32), 3972–3984. https://doi.org/10.1039/C3TB20241K
doi: 10.1039/C3TB20241K
pubmed: 32261223
Bishi, D. K., Mathapati, S., Cherian, K. M., Guhathakurta, S., & Verma, R. S. (Mar. 2014). In vitro hepatic trans-differentiation of human mesenchymal stem cells using sera from congestive/ischemic liver during cardiac failure. PLoS One, 9(3), e92397, [Online]. Available: https://doi.org/10.1371/journal.pone.0092397
Babicki, S., et al. (2016). Heatmapper: Web-enabled heat mapping for all. Nucleic Acids Research, 44(W1), W147–W153. https://doi.org/10.1093/nar/gkw419
doi: 10.1093/nar/gkw419
pubmed: 27190236
pmcid: 4987948
Forbes, S. J., Gupta, S. & Dhawan, A. (2015). Cell therapy for liver disease: From liver transplantation to cell factory. Journal of Hepatology, 62(1, Supplement), S157–S169. https://doi.org/10.1016/j.jhep.2015.02.040
Gordillo, M., Evans, T., & Gouon-Evans, V. (2015). Orchestrating liver development. Development, 142(12), 2094–2108. https://doi.org/10.1242/dev.114215
doi: 10.1242/dev.114215
pubmed: 26081571
pmcid: 4483763
Si-Tayeb, K., Lemaigre, F. P., & Duncan, S. A. (2010). Organogenesis and Development of the Liver. Developmental Cell, 18(2), 175–189. https://doi.org/10.1016/j.devcel.2010.01.011
doi: 10.1016/j.devcel.2010.01.011
pubmed: 20159590
Corbett, J. L. & Duncan, S. A. (2019). iPSC-derived hepatocytes as a platform for disease modeling and drug discovery. Frontiers in Medicine, 6, 265, [Online]. Available: https://doi.org/10.3389/fmed.2019.00265
Hay, D. C., et al. (2008). Efficient differentiation of hepatocytes from human embryonic stem cells exhibiting markers recapitulating liver development in vivo. Stem Cells, 26(4), 894–902. https://doi.org/10.1634/stemcells.2007-0718
doi: 10.1634/stemcells.2007-0718
pubmed: 18238852
Snykers, S., De Kock, J., Tamara, V., & Rogiers, V. (2011). Hepatic differentiation of mesenchymal stem cells. In M. Vemuri, L. G. Chase, & M. S. Rao (Eds.), Vitro strategies BT - Mesenchymal stem cell assays and applications (pp. 305–314). Humana Press.
doi: 10.1007/978-1-60761-999-4_23
Zhang, Y., et al. (2023). Definitive endodermal cells supply an in vitro source of mesenchymal stem/stromal cells. Communications Biology, 6(1), 476. https://doi.org/10.1038/s42003-023-04810-5
doi: 10.1038/s42003-023-04810-5
pubmed: 37127734
pmcid: 10151361
Ma, Y., et al. (Jul. 2019,). CHIR-99021 regulates mitochondrial remodelling via β-catenin signalling and miRNA expression during endodermal differentiation. Journal of Cell Science, 132(15), jcs229948. https://doi.org/10.1242/jcs.229948
Teo, A. K. K., Valdez, I. A., Dirice, E., & Kulkarni, R. N. (2014). Comparable generation of activin-induced definitive endoderm via additive Wnt or BMP signaling in absence of serum. Stem Cell Reports, 3(1), 5–14. https://doi.org/10.1016/j.stemcr.2014.05.007
doi: 10.1016/j.stemcr.2014.05.007
pubmed: 25068117
pmcid: 4110751
Li, Z., et al. (2019). Generation of qualified clinical-grade functional hepatocytes from human embryonic stem cells in chemically defined conditions. Cell Death & Disease, 10(10), 763. https://doi.org/10.1038/s41419-019-1967-5
doi: 10.1038/s41419-019-1967-5
Russell, J. O., & Monga, S. P. (2018). Wnt/β-catenin signaling in liver development, homeostasis, and pathobiology. Annual Review of Pathology: Mechanisms of Disease, 13(1), 351–378. https://doi.org/10.1146/annurev-pathol-020117-044010
doi: 10.1146/annurev-pathol-020117-044010
Pour, M. et al. (2022). Emergence and patterning dynamics of mouse-definitive endoderm. iScience, 25(1), 103556. https://doi.org/10.1016/j.isci.2021.103556
van den Brink, S. C., et al. (2014). Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse embryonic stem cells. Development, 141(22), 4231–4242. https://doi.org/10.1242/dev.113001
doi: 10.1242/dev.113001
pubmed: 25371360
pmcid: 4302915
Turner, D. A., et al. (2017). Anteroposterior polarity and elongation in the absence of extra-embryonic tissues and of spatially localised signalling in gastruloids: Mammalian embryonic organoids. Development, 144(21), 3894–3906. https://doi.org/10.1242/dev.150391
doi: 10.1242/dev.150391
pubmed: 28951435
pmcid: 5702072
Malik, R., Selden, C., & Hodgson, H. (2002). The role of non-parenchymal cells in liver growth. Seminars in Cell & Developmental Biology, 13(6), 425–431. https://doi.org/10.1016/S1084952102001301
doi: 10.1016/S1084952102001301
Tremblay, K. D., & Zaret, K. S. (2005). Distinct populations of endoderm cells converge to generate the embryonic liver bud and ventral foregut tissues. Developmental Biology, 280(1), 87–99. https://doi.org/10.1016/j.ydbio.2005.01.003
doi: 10.1016/j.ydbio.2005.01.003
pubmed: 15766750
Clerbaux, L.-A., Manco, R., & Leclercq, I. (2016). Upstream regulators of hepatic Wnt/β-catenin activity control liver metabolic zonation, development, and regeneration. Hepatology, 64(4), 1361–1363. https://doi.org/10.1002/hep.28763
doi: 10.1002/hep.28763
pubmed: 27515485
Thompson, M. D., & Monga, S. P. S. (2007). WNT/β-catenin signaling in liver health and disease. Hepatology, 45(5), 1298–1305. https://doi.org/10.1002/hep.21651
doi: 10.1002/hep.21651
pubmed: 17464972
McLin, V. A., Rankin, S. A., & Zorn, A. M. (2007). Repression of Wnt/β-catenin signaling in the anterior endoderm is essential for liver and pancreas development. Development, 134(12), 2207–2217. https://doi.org/10.1242/dev.001230
doi: 10.1242/dev.001230
pubmed: 17507400
DeLaForest, A., et al. (2019). HNF4A regulates the formation of hepatic progenitor cells from human iPSC-derived endoderm by facilitating efficient recruitment of RNA Pol II. Genes, 10(1). https://doi.org/10.3390/genes10010021
Chien, C.-C., et al. (2006). In vitro differentiation of human placenta-derived multipotent cells into hepatocyte-like cells. Stem Cells, 24(7), 1759–1768. https://doi.org/10.1634/stemcells.2005-0521
doi: 10.1634/stemcells.2005-0521
pubmed: 16822884
Cipriano, M., et al. (2017). The role of epigenetic modifiers in extended cultures of functional hepatocyte-like cells derived from human neonatal mesenchymal stem cells. Archives of Toxicology, 91(6), 2469–2489. https://doi.org/10.1007/s00204-016-1901-x
doi: 10.1007/s00204-016-1901-x
pubmed: 27909741
Zhao, X., Zhu, Y., Laslett, A. L., & Chan, H. F. (2020). Hepatic differentiation of stem cells in 2D and 3D biomaterial systems. Bioengineering, 7(2). https://doi.org/10.3390/bioengineering7020047
Khan, A. A., Vishwakarma, S. K., Bhavani, G., WilayathHussain, S., & Habeeb, M. A. (2014). Decellularized liver scaffold as a potential resource for the development of functional humanized liver. Cytotherapy, 16(4), S89.
Moniaux, N., & Faivre, J. (2011). A reengineered liver for transplantation. Journal of Hepatology. https://doi.org/10.1016/j.jhep.2010.07.053
doi: 10.1016/j.jhep.2010.07.053
pubmed: 21349303
Kaur, S., Tripathi, D. M., Venugopal, J. R., & Ramakrishna, S. (2020). Advances in biomaterials for hepatic tissue engineering. Current Opinion in Biomedical Engineering, 13, 190–196. https://doi.org/10.1016/j.cobme.2020.05.005
doi: 10.1016/j.cobme.2020.05.005
Gilpin, A., & Yang, Y. (2017). Decellularization strategies for regenerative medicine: from processing techniques to applications. BioMed Research International, 2017(1), 9831534. https://doi.org/10.1155/2017/9831534
doi: 10.1155/2017/9831534
pubmed: 28540307
pmcid: 5429943
Mendibil, U., Ruiz-Hernandez, R., Retegi-Carrion, S., Garcia-Urquia, N., Olalde-Graells, B. & Abarrategi, A. (2020). Tissue-specific decellularization methods: rationale and strategies to achieve regenerative compounds. International Journal of Molecular Sciences, 21(15). https://doi.org/10.3390/ijms21155447
Xu, H., et al. ( Jan. 2014). Comparison of decellularization protocols for preparing a decellularized porcine annulus fibrosus scaffold. PLoS One, 9(1), e86723, [Online]. Available: https://doi.org/10.1371/journal.pone.0086723
Damania, A., et al. (2018). Decellularized Liver Matrix-Modified Cryogel Scaffolds as Potential Hepatocyte Carriers in Bioartificial Liver Support Systems and Implantable Liver Constructs. ACS Applied Materials & Interfaces, 10(1), 114–126. https://doi.org/10.1021/acsami.7b13727
doi: 10.1021/acsami.7b13727
Asumda, F. Z., et al. (2018). Differentiation of hepatocyte-like cells from human pluripotent stem cells using small molecules. Differentiation, 101, 16–24. https://doi.org/10.1016/j.diff.2018.03.002
doi: 10.1016/j.diff.2018.03.002
pubmed: 29626713
pmcid: 6055513
Du, C., et al. (2018). Highly efficient and expedited hepatic differentiation from human pluripotent stem cells by pure small-molecule cocktails. Stem Cell Research & Therapy, 9(1), 58. https://doi.org/10.1186/s13287-018-0794-4
doi: 10.1186/s13287-018-0794-4
Zaret, K. S. (2009). Using Small Molecules to Great Effect in Stem Cell Differentiation. Cell Stem Cell, 4(5), 373–374. https://doi.org/10.1016/j.stem.2009.04.012
doi: 10.1016/j.stem.2009.04.012
pubmed: 19427285
Fujiyoshi, J., et al. (2019). Therapeutic potential of hepatocyte-like-cells converted from stem cells from human exfoliated deciduous teeth in fulminant Wilson’s disease. Science and Reports, 9(1), 1535. https://doi.org/10.1038/s41598-018-38275-y
doi: 10.1038/s41598-018-38275-y
Alfaifi, M., Eom, Y. W., Newsome, P. N., & Baik, S. K. (2018). Mesenchymal stromal cell therapy for liver diseases. Journal of Hepatology, 68(6), 1272–1285. https://doi.org/10.1016/j.jhep.2018.01.030
doi: 10.1016/j.jhep.2018.01.030
pubmed: 29425678
Hu, C., Zhao, L., Wu, Z., & Li, L. (2020). Transplantation of mesenchymal stem cells and their derivatives effectively promotes liver regeneration to attenuate acetaminophen-induced liver injury. Stem Cell Research & Therapy, 11(1), 88. https://doi.org/10.1186/s13287-020-01596-9
doi: 10.1186/s13287-020-01596-9
Hu, C., Wu, Z., & Li, L. (2020). Mesenchymal stromal cells promote liver regeneration through regulation of immune cells. International Journal of Biological Sciences, 16(5), 893–903. https://doi.org/10.7150/ijbs.39725
doi: 10.7150/ijbs.39725
pubmed: 32071558
pmcid: 7019139
van Poll, D., et al. (2008). Mesenchymal stem cell–derived molecules directly modulate hepatocellular death and regeneration in vitro and in vivo. Hepatology, 47(5), 1634–1643. https://doi.org/10.1002/hep.22236
doi: 10.1002/hep.22236
pubmed: 18395843
Lai, L., et al. (2016). Transplantation of MSCs Overexpressing HGF into a Rat Model of Liver Fibrosis. Molecular Imaging and Biology, 18(1), 43–51. https://doi.org/10.1007/s11307-015-0869-x
doi: 10.1007/s11307-015-0869-x
pubmed: 26194009
Toriumi, K., Horikoshi, Y., Yoshiyuki Osamura, R., Yamamoto, Y., Nakamura, N., & Takekoshi, S. (2013). Carbon tetrachloride-induced hepatic injury through formation of oxidized diacylglycerol and activation of the PKC/NF-κB pathway. Laboratory Investigation, 93(2), 218–229. https://doi.org/10.1038/labinvest.2012.145