Abstract
Although liver transplantation is a potential effective cure for patients with end-stage liver diseases, this strategy has several drawbacks including high cost, long waiting list, and limited availability of liver organs. Therefore, stem cell-based therapy is presented as an alternative option, which showed promising results in animal models of acute and chronic liver injuries. ABCB5+ cells isolated from skin dermis represent an easy accessible and expandable source of homogenous stem cell populations. In addition, ABCB5+ cells showed already promising results in the treatment of corneal and skin injury. To date, the effect of these cells on liver injury is still unknown. In the current study, sixteen weeks old Mdr2KO mice were i.v. injected with 500,000 ABCB5+ cells using different experimental setups. The effects of cellular therapy on inflammation, fibrosis, apoptosis, and proliferation were analyzed in the collected liver tissues. Toxicity of ABCB5+ cells was additionally investigated in mice with partial liver resection. In vitro, the fibrosis- and inflammatory-modulating effects of supernatant from ABCB5+ cells were examined in the human hepatic stellate cell line (LX-2). Cell injections into fibrotic Mdr2KO mice as well as into mice upon partial liver resection have no signs of toxicity with regard to cell transformation, cellular damage, fibrosis or inflammation as compared to controls. We next investigated the effects of ABCB5+ cells on established biliary liver fibrosis in the Mdr2KO mice. ABCB5+ cells to some extent influenced the shape of the liver inflammatory response and significantly reduced the amount of collagen deposition, as estimated from quantification of sirius red staining. Furthermore, reduced apoptosis and enhanced death compensatory proliferation resulted from ABCB5+ cell transformation. The stem cells secreted several trophic factors that activated TGF-β family signaling in cultured LX-2 hepatic stellate cells (HSCs), therewith shaping cell fate to an αSMAhigh, Vimentinlow phenotype. Taken together, ABCB5+ cells can represent a safe and feasible strategy to support liver regeneration and to reduce liver fibrosis in chronic liver diseases.
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29 October 2019
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Abbreviations
- ABCB5:
-
ATP-binding cassette sub-family B, member 5 (ABCB5) P-glycoprotein
- ACLF:
-
Acute-on-chronic liver failure
- ALT:
-
Alanine aminotransferase
- AP:
-
Alkaline phosphatase
- AST:
-
Aspartate aminotransferase
- BDL:
-
Bile duct ligation
- CCl4 :
-
Carbon tetrachloride
- EVs:
-
Extracellular vesicles
- GLDH:
-
Glutamate dehydrogenase
- HCC:
-
Hepatocellular carcinoma
- HCV:
-
Hepatitis C virus
- HSCs:
-
Hepatic stellate cells
- IL-1RA:
-
Interleukin-1 receptor antagonist
- INF:
-
Interferon
- LPS:
-
Lipopolysaccharide
- LSC:
-
Limbal stem cells
- MACS:
-
Magnetic activated cell sorting
- Mdr2:
-
Multidrug resistance gene 2
- MHC:
-
Major histocompatibility complex
- MSCs:
-
Mesenchymal stromal cells
- PD-1:
-
Programmed death1
- PHH:
-
Primary hepatocytes
- PMA:
-
Phorbol 12-myristate 13-acetate
- PSC:
-
Primary sclerosing cholangitis
- RDEB:
-
Recessive dystrophic epidermolysis bullosa
- TG:
-
Triglycerides
- TIMP1:
-
Tissue inhibitor of metalloproteinases 1
- TGF:
-
Tumor growth factor
- VEGF:
-
Vascular endothelial growth factor
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Financial support for this study was provided by RHEACELL GmbH and Co. KG.
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Conception and design: SD, RV, AK. ABCB5+ cell isolation and preservation: TICEBA GmbH. Collecting animal model data performing experiments and analysis and interpretation of data: VH, BD, TL, AD, NT, LT, BC, SD. Collecting in vitro data, performing experiments and analyses and interpretation of data: VH, TL, BD, SD. Drafting the article: VH, BD, SD. Manuscript editing: VH, BD, NT, SD, BC. All authors read and approved the final manuscript.
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Vanessa Hartwig, Steven Dooley, Lysann Tietze, and Bruno Christ participate in corporate-sponsored research collaborations with RHEACELL GmbH and Co. KG. The remaining authors have no conflicting interests. Data and data presentation is uninfluenced by RHEACELL.
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TICEBA is holder of a manufacturing license according § 13 AMG (allogeneic mesenchymal ABCB5-positive cells, obtained from human skin) since 22.06.2017. Written informed consent was obtained from all donors before collecting skin samples. Animal experimental protocols were approved by the local council of animal care of Baden-Wuerttemberg, Germany (Permit number G254-15).
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Assessment of adverse effects of ABCB5+ cell transplantation in the PHx mouse model. Collagen fibers were visualized with the Sirius red stain (a) 2 days and 7 weeks after transplantation of ABCB5+ cells into livers of Pfp/Rag2KO mice. HRG was used as carrier control. Pictures show representative images of slices from 2 animals in each group. Scale bar – 100 µm. Using semiquantitative RT-PCR (b), the relative expression of mRNAs of TIMP1 and VEGF was determined 2 days (white columns) and 7 weeks (grey columns) after transplantation of ABCB5+ cells. (c, d) Relative expression of inflammation (c) and apoptosis (d) markers in livers of Pfp/Rag2KO mice 2 days (white columns) and 7 weeks (grey columns) after transplantation of ABCB5+cells. Values shown are means ± SD of n=4 animals in each group (* p < 0.05). Housekeeping genes β2-microglobulin and TATA-box binding protein were used for normalization of expression levels.
Comparison of male and female Mdr2KO mice. Quantification of Sirius red staining (a) in control mice at different ages, as indicated, and (b) after ABCB5+ cells treatment for the indicated time points; positive staining is presented as scatter plots, discriminating periportal, pericentral and mid-zonal areas, as indicated for n=4-8 for 4 weeks, n=4 for 6 days and 2 weeks time points. Black color represents saline-treated Mdr2KO mice, red color indicates ABCB5+ cell-treated Mdr2KO mice. Triangles represent nis and squares represent ABCB5+ mice with double cell treatment. Pink color represents female mice; ut, untreated; t, treated with ABCB5+ cells.
Effects of ABCB5+cells treatment on biliary fibrosis in Mdr2KO mice. Quantification of (a) αSMA and (b) SMA22α positive staining is presented as scatter plots, discriminating periportal, pericentral and mid-zonal areas, as indicated for n=4-8 for 4 weeks, n=4 for 6 days and 2 weeks time points. Representative IHC staining for SMA22α is shown in 10 and 40 fold magnification. (c) Real-time RT-PCR data for selected fibrogenesis-related gene expression, as indicated, and biochemical determination of hydroxyproline levels (HYP). Black color represents saline-treated Mdr2KO mice, red color indicates ABCB5+ cell-treated Mdr2KO mice. Triangles represent nis and squares represent ABCB5+ mice with double cell treatment.
Effects of ABCB5+cell treatment on liver inflammation in Mdr2KO mice. IHC staining of CD45 (a) is presented in 10 and 40 fold magnification. Quantification of CD45 (a) and CD163 (b) positive staining is presented as scatter plots, discriminating periportal, pericentral and mid-zonal areas, as indicated for n=4 for 6 days and 2 weeks time points. (c) Real-time RT-PCR data for selected inflammation related gene expression, as indicated. Black color represents saline-treated Mdr2KO mice, red color indicates ABCB5+ cells-treated Mdr2KO mice. Triangles represent nis and squares represent ABCB5+ mice with double cell treatment.
Effects of ABCB5+cells treatment on apoptosis and proliferation in Mdr2KO mice. (a) Representative documentation of apoptotic cells based on TUNEL assays and immunofluorescent staining (n=4) 2 and 6 days after cell treatment. (b) Quantification of Ki-67 immunostaining is presented as scatter plots, discriminating periportal, pericentral and mid-zonal areas, as indicated of n=8 for 4 weeks and n=4 for 6 days and 2 weeks time points. Black color represents saline-treated Mdr2KO mice, red color indicates ABCB5+ cell-treated Mdr2KO mice. Triangles represent nis and squares represent ABCB5+ mice with double cell treatment.
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Hartwig, V., Dewidar, B., Lin, T. et al. Human skin-derived ABCB5+ stem cell injection improves liver disease parameters in Mdr2KO mice. Arch Toxicol 93, 2645–2660 (2019). https://doi.org/10.1007/s00204-019-02533-3
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DOI: https://doi.org/10.1007/s00204-019-02533-3