Immunoprofiling of Adult-Derived Human Liver Stem/Progenitor Cells: Impact of Hepatogenic Differentiation and Inflammation

El-Kehdy, Hoda; Sargiacomo, Camillo; Fayyad‐Kazan, Mohammad; Fayyad‐Kazan, Hussein; Lombard, Catherine; Lagneaux, Laurence; Sokal, Étienne; Najar, Mehdi; Najimi, Mustapha

doi:10.1155/2017/2679518

Cited by 18 publications

(22 citation statements)

References 54 publications

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“…Transplanted cells are sensitive to the environment and have to conjugate with resident or infiltrating immune cells to ensure safe therapeutic application (25,36,37). Indeed, cell engraftment was shown to critically depend on the inflammatory environment, which implies that progenitor cells such as ADHLSCs have to finely balance their immunological profile according to the context (28). It is thus crucial to evaluate the cytokines and growth factors implicated in liver function (38).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, the immunological and inflammatory features of ADHLSCs are not clear. Both HD and stimulation with a mixture of inflammatory cytokines in vitro (I) influence the immunophenotype of ADHLSCs, with CD200 being the most altered immune marker (28). In parallel, inflammation was shown to significantly modulate several immunological cytokines within HSCs (29).…”

Section: Original Articlementioning

confidence: 99%

See 1 more Smart Citation

Cytokinome of adult-derived human liver stem/progenitor cells: immunological and inflammatory features

Najar¹,

Crompot²,

Raicevic³

et al. 2018

Hepatobiliary Surg. Nutr

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Background: Being non-immunogenic and capable of achieving major metabolic liver functions, adultderived human liver stem/progenitor cells (ADHLSCs) are of special interest in the field of liver cell therapy. The cytokine repertoire of engrafted cells may have critical impacts on the immune response balance, particularly during cell transplantation. Methods: In this work, we analyzed the cytokinome of ADHLSCs during hepatogenic differentiation (HD) following stimulation with a mixture of inflammatory cytokines (I) in vitro and compared it to that of mature hepatocytes. Results: Independent of their hepatic state, ADHLSCs showed no constitutive expression of proinflammatory cytokines, which were significantly induced by inflammation (IL-1β, IL-6, IL-8, TNFα, CCL5, IL-12a, IL-12b, IL-23p19, IL-27p28 and EBI-3). IL1-RA and IDO-1, as immunoregulatory cytokines, were highly induced in undifferentiated ADHLSCs, whereas TGF-β was downregulated by both hepatic and inflammatory events. Interestingly, TDO-1 was exclusively expressed in ADHLSCs after hepatic differentiation and enhanced by inflammatory cytokines. Compared to mature hepatocytes, hepaticdifferentiated ADHLSCs showed significantly different cytokine expression patterns. Conclusions: By establishing the cytokinome of ADHLSCs and highlighting their immunological and inflammatory features, we can enhance our knowledge about the safety and efficiency of the transplantation strategy.

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Section: Discussionmentioning

confidence: 99%

Section: Original Articlementioning

confidence: 99%

Cytokinome of adult-derived human liver stem/progenitor cells: immunological and inflammatory features

Najar¹,

Crompot²,

Raicevic³

et al. 2018

Hepatobiliary Surg. Nutr

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“…Thereafter, cells were seeded at density of 1 × 10 5 cells/well, on 96-well plates. CYP3A4 activity was analyzed using P450-Glo TM assay according to the manufacturer’s instructions (Promega, Madison, WI, USA) and as previously adapted [ 13 ].…”

Section: Methodsmentioning

confidence: 99%

Inflammation Differentially Modulates the Biological Features of Adult Derived Human Liver Stem/Progenitor Cells

El-Kehdy

Najar

Kock

et al. 2020

Cells

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The progression of mesenchymal stem cell-based therapy from concept to cure closely depends on the optimization of conditions that allow a better survival and favor the cells to achieve efficient liver regeneration. We have previously demonstrated that adult-derived human liver stem/progenitor cells (ADHLSC) display significant features that support their clinical development. The current work aims at studying the impact of a sustained pro-inflammatory environment on the principal biological features of ADHLSC in vitro. METHODS: ADHLSC from passages 4–7 were exposed to a cocktail of inflammatory cytokines for 24 h and 9 days and subsequently analyzed for their viability, expression, and secretion profiles by using flow cytometry, RT-qPCR, and antibody array assay. The impact of inflammation on the hepatocytic differentiation potential of ADHLSC was also evaluated. RESULTS: ADHLSC treated with a pro-inflammatory cocktail displayed significant decrease of cell yield at both times of treatment while cell mortality was observed at 9 days post-priming. After 24 h, no significant changes in the immuno-phenotype of ADHLSC expression profile could be noticed while after 9 days, the expression profile of relevant markers has changed both in the basal conditions and after inflammation treatment. Inflammation cocktail enhanced the release of IL-6, IL-8, CCL5, monocyte-chemo-attractant protein-2 and 3, CXCL1/GRO, and CXCL5/ENA78. Furthermore, while IP-10 secretion was increased after 24 h priming, granulocyte macrophage colony-stimulating factor enhanced secretion was noticed after 9 days treatment. Finally, priming of ADHLSC did not affect their potential to differentiate into hepatocyte-like cells. CONCLUSION: These results indicate that ADHLSCs are highly sensitive to inflammation and respond to such signals by adjusting their gene and protein expression. Accordingly, monitoring the inflammatory status of patients at the time of cell transplantation, will certainly help in enhancing ADHLSC safety and efficiency.

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“…Interestingly, in HCC samples, 35% of normal hepatocytes in non-cancerous areas and 55% of cancer cells expressed cytoplasmic CD105 [45]. Various in vitro cell lines, including those of normal hepatocytes [49], HCC cancer cells [16,50], as well as undifferentiated and differentiated adult-derived human liver stem/progenitor cells [49,51], human adipose-derived stem cells [52], and hepatic perivascular mesenchymal stem cells [48,53] are also characterised by endoglin expression of varying levels.…”

Section: From Tumor-angiogenesis Factor (Taf) Through Vascular Endmentioning

confidence: 99%

“…A role of other CD105-positive liver cells in HCC pathogenesis cannot be ruled out. These include the previously mentioned HSCs [13], human liver-derived stem cells [49,51], and human adipose-derived stem cells [52]. The former differentiate into myofibroblasts (fibrotic role), with the two latter types able to be induced into functional hepatocyte-like cells.…”

Section: Endoglin In Pathomechanisms Of Hccmentioning

confidence: 99%

Role of Endoglin (CD105) in the Progression of Hepatocellular Carcinoma and Anti-Angiogenic Therapy

Kasprzak

Adamek

2018

IJMS

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The liver is perfused by both arterial and venous blood, with a resulting abnormal microenvironment selecting for more-aggressive malignancies. Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, the sixth most common cancer globally, and the third leading cause of cancer-related mortality worldwide. HCC is characterized by its hypervascularization. Improving the efficiency of anti-angiogenic treatment and mitigation of anti-angiogenic drug resistance are the top priorities in the development of non-surgical HCC therapies. Endoglin (CD105), a transmembrane glycoprotein, is one of the transforming growth factor β (TGF-β) co-receptors. Involvement of that protein in angiogenesis of solid tumours is well documented. Endoglin is a marker of activated endothelial cells (ECs), and is preferentially expressed in the angiogenic endothelium of solid tumours, including HCC. HCC is associated with changes in CD105-positive ECs within and around the tumour. The large spectrum of endoglin effects in the liver is cell-type- and HCC- stage-specific. High expression of endoglin in non-tumour tissue suggests that this microenvironment might play an especially important role in the progression of HCC. Evaluation of tissue expression, as well as serum concentrations of this glycoprotein in HCC, tends to confirm its role as an important biomarker in HCC diagnosis and prognosis. The role of endoglin in liver fibrosis and HCC progression also makes it an attractive therapeutic target. Despite these facts, the exact molecular mechanisms of endoglin functioning in hepatocarcinogenesis are still poorly understood. This review summarizes the current data concerning the role and signalling pathways of endoglin in hepatocellular carcinoma development and progression, and provides an overview of the strategies available for a specific targeting of CD105 in anti-angiogenic therapy in HCC.

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Immunoprofiling of Adult-Derived Human Liver Stem/Progenitor Cells: Impact of Hepatogenic Differentiation and Inflammation

Cited by 18 publications

References 54 publications

Cytokinome of adult-derived human liver stem/progenitor cells: immunological and inflammatory features

Cytokinome of adult-derived human liver stem/progenitor cells: immunological and inflammatory features

Inflammation Differentially Modulates the Biological Features of Adult Derived Human Liver Stem/Progenitor Cells

Role of Endoglin (CD105) in the Progression of Hepatocellular Carcinoma and Anti-Angiogenic Therapy

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