Monique Maria Andrea Verstegen
@erasmusmc.nl
Department of Surgery
Erasmus MC
RESEARCH, TEACHING, or OTHER INTERESTS
Cell Biology, Cancer Research, Biomaterials, Transplantation
Scopus Publications
Scopus Publications
Zhenguo Wang, Chen Xing, Luc J. W. van der Laan, Monique M. A. Verstegen, Bart Spee, and Rosalinde Masereeuw
Springer Science and Business Media LLC
Abstract Background Drug induced bile duct injury is a frequently observed clinical problem leading to a wide range of pathological features. During the past decades, several agents have been identified with various postulated mechanisms of bile duct damage, however, mostly still poorly understood. Methods Here, we investigated the mechanisms of chlorpromazine (CPZ) induced bile duct injury using advanced in vitro cholangiocyte cultures. Intrahepatic cholangiocyte organoids (ICOs) were driven into mature cholangiocyte like cells (CLCs), which were exposed to CPZ under cholestatic or non-cholestatic conditions through the addition of a bile acid cocktail. Results CPZ caused loss of monolayer integrity by reducing expression levels of tight junction protein 1 (TJP1), E-cadherin 1 (CDH1) and lysyl oxidase homolog 2 (LOXL2). Loss of zonula occuludens-1 (ZO-1) and E-cadherin was confirmed by immunostaining after exposure to CPZ and rhodamine-123 leakage further confirmed disruption of the cholangiocyte barrier function. Furthermore, oxidative stress seemed to play a major role in the early damage response by CPZ. The drug also decreased expression of three main basolateral bile acid transporters, ABCC3 (ATP binding cassette subfamily C member 3), SLC51A/B (solute carrier family 51 subunit alpha/beta) and multidrug resistance transporter ABCB1 (ATP binding cassette subfamily B member 1), thereby contributing to bile acid accumulation. CPZ did not induce an inflammatory response by itself, but addition of TNFα revealed a synergistic effect. Conclusion These results show that ICOs present a model to identify toxic drugs affecting the bile ducts while providing mechanistic insights into hepatotoxicity.
Hongbo Guo, Dan Liu, Kuan Liu, Yao Hou, Chunyang Li, Qiudi Li, Xiaohui Ding, Monique M.A. Verstegen, Jikai Zhang, Lingli Wang,et al.
Elsevier BV
Hector Tejeda-Mora, Yvette den Hartog, Ivo J. Schurink, Monique M.A. Verstegen, Jeroen de Jonge, Martijn W.F. van den Hoogen, Carla C. Baan, Robert C. Minnee, Martin J. Hoogduijn, Luc J.W. van der Laan,et al.
Mary Ann Liebert Inc
Allogeneic transplant organs are potentially highly immunogeneic. The endothelial cells (EC) located within the vascular system serve as the primary interface between the recipient's immune system and the donor organ, playing a key role in the allo-immune response. In this study, we investigated the potential use of recipient-derived ECs in a vein recellularization model. Here, human iliac veins underwent complete decellularization using a triton X-100 protocol. We demonstrated the feasibility of re-endothelializing acellular blood vessels using either HUVEC or human venous-derived ECs, with this re-endothelization being sustainable for up to 28 days in vitro. The re-endothelialized veins exhibited the restoration of vascular barrier function, along with the restoration of innate immune regulatory capabilities, evident through the facilitation of monocytic cell transmigration and their polarization towards a macrophage phenotype following trans-endothelial extravasation. Finally, we explored whether recellularization with EC of a different donor could prevent antibody-mediated rejection. We demonstrated that in chimeric vessels, allogeneic EC became a target of the humoral anti-donor response after activation of the classical immune complement pathway whereas autologous EC were spared, emphasizing their potential utility prior to transplantation. In conclusion, our study demonstrates that replacement of EC in transplants could reduce the immunological challenges associated with allogeneic grafts.
Jelle J. F. Sleeboom, Gilles S. van Tienderen, Katja Schenke-Layland, Luc J. W. van der Laan, Antoine A. Khalil, and Monique M. A. Verstegen
American Association for the Advancement of Science (AAAS)
The extracellular matrix (ECM) is essential for cell support during homeostasis and plays a critical role in cancer. Although research often concentrates on the tumor’s cellular aspect, attention is growing for the importance of the cancer-associated ECM. Biochemical and physical ECM signals affect tumor formation, invasion, metastasis, and therapy resistance. Examining the tumor microenvironment uncovers intricate ECM dysregulation and interactions with cancer and stromal cells. Anticancer therapies targeting ECM sensors and remodelers, including integrins and matrix metalloproteinases, and ECM-remodeling cells, have seen limited success. This review explores the ECM’s role in cancer and discusses potential therapeutic strategies for cell-ECM interactions.
Kimberley Ober, Floris J.M. Roos, Gilles S. van Tienderen, Kübra Köten, Annelot Klaassen, Wunan Mi, Luc J.W. van der Laan, and Monique M.A. Verstegen
Elsevier BV
Diego F. Calvisi, Luke Boulter, Javier Vaquero, Anna Saborowski, Luca Fabris, Pedro M. Rodrigues, Cédric Coulouarn, Rui E. Castro, Oreste Segatto, Chiara Raggi,et al.
Springer Science and Business Media LLC
Ruby Lieshout, Eline J. C. A. Kamp, Monique M. A. Verstegen, Michail Doukas, Winand N. M. Dinjens, Kübra Köten, Jan N. M. IJzermans, Marco J. Bruno, Maikel P. Peppelenbosch, Luc J. W. van der Laan,et al.
Wiley
AbstractPrimary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the biliary tree and a risk factor for development of cholangiocarcinoma (CCA). The pathogenesis of PSC‐related CCA is largely unclear, although it is assumed that chronic inflammatory environment plays a pivotal role. We aimed to investigate the effect of inflammation‐related cytokines in PSC on the proliferation rate of cancer cells. For this, the proliferation index in PSC‐CCA and sporadic CCA was determined by Ki‐67 immunohistochemistry. The percentage of Ki‐67 positivity in cancer cells was significantly higher in PSC‐CCA than in sporadic CCA (41.3% ± 5.7% vs 25.8% ± 4.1%; P = .038). To assess which cytokines in the inflammatory environment have the potential to stimulate cancer cell proliferation, patient‐derived CCA organoids (CCAOs) were exposed to five cytokines related to PSC (Interleukin (IL)‐1β, IL‐6, IL‐17A, interferon gamma and tumor necrosis factor alpha). Only IL‐17A showed a significant stimulatory effect on cell proliferation in CCAOs, increasing organoid size by 45.9% ± 16.4% (P < .01) and proliferation rate by 38% ± 16% (P < .05). IL‐17A immunohistochemistry demonstrated that PSC‐CCA might express more IL‐17A than sporadic CCA. Moreover, correlation analysis in sporadic CCA and PSC‐CCA found a significant correlation between IL‐17A expression and proliferation. In conclusion, tumor cell proliferation is increased in PSC‐CCA cells compared with sporadic CCA cells. IL‐17A increases CCA cell proliferation in vitro and may contribute to the high proliferation rate in PSC‐CCA in situ. Therefore, IL‐17A represents a new potential therapeutic target in (PSC‐)CCA, to be tested in future trials.
Luc Magré, Monique M A Verstegen, Sonja Buschow, Luc J W van der Laan, Maikel Peppelenbosch, and Jyaysi Desai
BMJ
In the past decade, treatments targeting the immune system have revolutionized the cancer treatment field. Therapies such as immune checkpoint inhibitors have been approved as first-line treatment in a variety of solid tumors such as melanoma and non-small cell lung cancer while other therapies, for instance, chimeric antigen receptor (CAR) lymphocyte transfer therapies, are still in development. Although promising results are obtained in a small subset of patients, overall clinical efficacy of most immunotherapeutics is limited due to intertumoral heterogeneity and therapy resistance. Therefore, prediction of patient-specific responses would be of great value for efficient use of costly immunotherapeutic drugs as well as better outcomes. Because many immunotherapeutics operate by enhancing the interaction and/or recognition of malignant target cells by T cells, in vitro cultures using the combination of these cells derived from the same patient hold great promise to predict drug efficacy in a personalized fashion. The use of two-dimensional cancer cell lines for such cultures is unreliable due to altered phenotypical behavior of cells when compared with the in vivo situation. Three-dimensional tumor-derived organoids, better mimic in vivo tissue and are deemed a more realistic approach to study the complex tumor–immune interactions. In this review, we present an overview of the development of patient-specific tumor organoid-immune co-culture models to study the tumor-specific immune interactions and their possible therapeutic infringement. We also discuss applications of these models which advance personalized therapy efficacy and understanding the tumor microenvironment such as: (1) Screening for efficacy of immune checkpoint inhibition and CAR therapy screening in a personalized manner. (2) Generation of tumor reactive lymphocytes for adoptive cell transfer therapies. (3) Studying tumor–immune interactions to detect cell-specific roles in tumor progression and remission. Overall, these onco-immune co-cultures might hold a promising future toward developing patient-specific therapeutic approaches as well as increase our understanding of tumor–immune interactions.
Gilles S. van Tienderen, James Conboy, Iain Muntz, Jorke Willemse, Jantine Tieleman, Kathryn Monfils, Ivo J. Schurink, Jeroen A.A. Demmers, Michail Doukas, Gijsje H. Koenderink,et al.
Elsevier BV
Gilles S van Tienderen, Oskar Rosmark, Ruby Lieshout, Jorke Willemse, Floor de Weijer, Linda Elowsson Rendin, Gunilla Westergren-Thorsson, Michail Doukas, Bas Groot Koerkamp, Martin E van Royen,et al.
Elsevier BV
Shaojun Shi, Henk P. Roest, Thierry P.P. van den Bosch, Marcel J.C. Bijvelds, Markus U. Boehnert, Jeroen de Jonge, Sven O. Dekker, Antoine A.F. de Vries, Hugo R. de Jonge, Monique M.A. Verstegen,et al.
Elsevier BV
Gilles S. van Tienderen, Marije E. A. van Beek, Ivo J. Schurink, Oskar Rosmark, Henk P. Roest, Jantine Tieleman, Jeroen Demmers, Iain Muntz, James Conboy, Gunilla Westergren-Thorsson,et al.
Frontiers Media SA
Cholangiocarcinoma (CCA) is a type of liver cancer with an aggressive phenotype and dismal outcome in patients. The metastasis of CCA cancer cells to distant organs, commonly lung and lymph nodes, drastically reduces overall survival. However, mechanistic insight how CCA invades these metastatic sites is still lacking. This is partly because currently available models fail to mimic the complexity of tissue-specific environments for metastatic CCA. To create an in vitro model in which interactions between epithelial tumor cells and their surrounding extracellular matrix (ECM) can be studied in a metastatic setting, we combined patient-derived CCA organoids (CCAOs) (n=3) with decellularized human lung (n=3) and decellularized human lymph node (n=13). Decellularization resulted in removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin. Proteomic analyses showed a tissue-specific ECM protein signature reflecting tissue functioning aspects. The macro and micro-scale mechanical properties, as determined by rheology and micro-indentation, revealed the local heterogeneity of the ECM. When growing CCAOs in decellularized lung and lymph nodes genes related to metastatic processes, including epithelial-to-mesenchymal transition and cancer stem cell plasticity, were significantly influenced by the ECM in an organ-specific manner. Furthermore, CCAOs exhibit significant differences in migration and proliferation dynamics dependent on the original patient tumor and donor of the target organ. In conclusion, CCA metastatic outgrowth is dictated both by the tumor itself as well as by the ECM of the target organ. Convergence of CCAOs with the ECM of its metastatic organs provide a new platform for mechanistic study of cancer metastasis.
Stefan H. Luijmes, Monique M.A. Verstegen, Martin J. Hoogduijn, Leonard Seghers, Robert C. Minnee, Edris A.F. Mahtab, Yannick J.H.J. Taverne, Marlies E.J. Reinders, Luc J.W. van der Laan, and Jeroen de Jonge
Elsevier BV
The use of extended criteria donor grafts is a promising strategy to increase the number of organ transplantations and reduce waitlist mortality. However, these organs are often compromised and/or damaged, are more susceptible to preservation injury, and are at risk for developing post‐transplant complications. Ex vivo organ perfusion is a novel technology to preserve donor organs while providing oxygen and nutrients at distinct perfusion temperatures. This preservation method allows to resuscitate grafts and optimize function with therapeutic interventions prior to solid organ transplantation. Stem cell‐based therapies are increasingly explored for their ability to promote regeneration and reduce the inflammatory response associated with in vivo reperfusion. The aim of this review is to describe the current state of stem cell‐based therapies during ex vivo organ perfusion for the kidney, liver, lung, and heart. We discuss different strategies, including type of cells, route of administration, mechanisms of action, efficacy, and safety. The progress made within lung transplantation justifies the initiation of clinical trials, whereas more research is likely required for the kidney, liver, and heart to progress into clinical application. We emphasize the need for standardization of methodology to increase comparability between future (clinical) studies.
Ruby Lieshout, Alessandra V. S. Faria, Maikel P. Peppelenbosch, Luc J. W. van der Laan, Monique M. A. Verstegen, and Gwenny M. Fuhler
Springer Science and Business Media LLC
Abstract Background Cholangiocarcinoma is a rare but lethal cancer of the biliary tract. Its first-line treatment is currently restricted to chemotherapy, which provides limited clinical benefit. Kinase inhibitors targeting oncogenic intracellular signaling have changed the treatment paradigm of cancer over the last decades. However, they are yet to be widely applied in cholangiocarcinoma therapy. Cholangiocarcinoma has marked molecular heterogeneity, which complicates the discovery of new treatments and requires patient stratification. Therefore, we investigated whether a commercial kinome profiling platform could predict druggable targets in cholangiocarcinoma. Methods Kinase activity in patient-derived cholangiocarcinoma organoids, non-tumorous adjacent tissue-derived and healthy donor-derived intrahepatic cholangiocyte organoids was determined using the PamChip® phosphotyrosine kinase microarray platform. Kinome profiles were compared and correlated with RNA sequencing and (multi-)kinase inhibitor screening of the cholangiocarcinoma organoids. Results Kinase activity profiles of individual cholangiocarcinoma organoids are different and do not cluster together. However, growth factor signaling (EGFR, PDGFRβ) and downstream effectors (MAPK pathway) are more active in cholangiocarcinoma organoids and could provide potential druggable targets. Screening of 31 kinase inhibitors revealed several promising pan-effective inhibitors and compounds that show patient-specific efficacy. Kinase inhibitor sensitivity correlated to the activity of its target kinases for several inhibitors, signifying them as potential predictors of response. Moreover, we identified correlations between drug response and kinases not directly targeted by those drugs. Conclusions In conclusion, kinome profiling is a feasible method to identify druggable targets for cholangiocarcinoma. Future studies should confirm the potential of kinase activity profiles as biomarkers for patient stratification and precision medicine.
Michael Koch, Sandra Nickel, Ruby Lieshout, Susanna M. Lissek, Martina Leskova, Luc J. W. van der Laan, Monique M. A. Verstegen, Bruno Christ, and Francesco Pampaloni
MDPI AG
Monitoring tumor growth dynamics is crucial for understanding cancer. To establish an in vitro method for the continuous assessment of patient-specific tumor growth, tumor organoids were generated from patients with intrahepatic CCA (iCCA). Organoid growth was monitored for 48 h by label-free live brightfield imaging. Growth kinetics were calculated and validated by MTS assay as well as immunohistochemistry of Ki67 to determine proliferation rates. We exposed iCCA organoids (iCCAOs) and non-tumor intrahepatic cholangiocyte organoids (ICOs) to sub-therapeutic concentrations of sorafenib. Monitoring the expansion rate of iCCAOs and ICOs revealed that iCCAO growth was inhibited by sorafenib in a time- and dose-dependent fashion, while ICOs were unaffected. Quantification of the proliferation marker Ki67 confirmed inhibition of iCCAO growth by roughly 50% after 48 h of treatment with 4 µM sorafenib. We established a robust analysis pipeline combining brightfield microscopy and a straightforward image processing approach for the label-free growth monitoring of patient-derived iCCAOs. Combined with bioanalytical validation, this approach is suitable for a fast and efficient high-throughput drug screening in tumor organoids to develop patient-specific systemic treatment options.
Gilles S. van Tienderen, Jorke Willemse, Bas van Loo, Eline V. A. van Hengel, Jeroen de Jonge, Luc J. W. van der Laan, Jeroen Leijten, and Monique M. A. Verstegen
MDPI AG
Advances in biomaterials, particularly in combination with encapsulation strategies, have provided excellent opportunities to increase reproducibility and standardization for cell culture applications. Herein, hybrid microcapsules are produced in a flow-focusing microfluidic droplet generator combined with enzymatic outside-in crosslinking of dextran-tyramine, enriched with human liver extracellular matrix (ECM). The microcapsules provide a physiologically relevant microenvironment for the culture of intrahepatic cholangiocyte organoids (ICO) and patient-derived cholangiocarcinoma organoids (CCAO). Micro-encapsulation allowed for the scalable and size-standardized production of organoids with sustained proliferation for at least 21 days in vitro. Healthy ICO (n = 5) expressed cholangiocyte markers, including KRT7 and KRT19, similar to standard basement membrane extract cultures. The CCAO microcapsules (n = 3) showed retention of stem cell phenotype and expressed LGR5 and PROM1. Furthermore, ITGB1 was upregulated, indicative of increased cell adhesion to ECM in microcapsules. Encapsulated CCAO were amendable to drug screening assays, showing a dose-response response to the clinically relevant anti-cancer drugs gemcitabine and cisplatin. High-throughput drug testing identified both pan-effective drugs as well as patient-specific resistance patterns. The results described herein show the feasibility of this one-step encapsulation approach to create size-standardized organoids for scalable production. The liver extracellular matrix-containing microcapsules can provide a powerful platform to build mini healthy and tumor tissues for potential future transplantation or personalized medicine applications.
Guoying Zhou, Ruby Lieshout, Gilles S. van Tienderen, Valeska de Ruiter, Martin E. van Royen, Patrick P. C. Boor, Luc Magré, Jyaysi Desai, Kübra Köten, Yik Yang Kan,et al.
Springer Science and Business Media LLC
Abstract Background Immunotherapy with immune checkpoint inhibitors (ICIs) is being explored to improve cholangiocarcinoma (CCA) therapy. However, it remains difficult to predict which ICI will be effective for individual patients. Therefore, the aim of this study is to develop a co-culture method with patient-derived CCA organoids and immune cells, which could represent anti-cancer immunity in vitro. Methods CCA organoids were co-cultured with peripheral blood mononuclear cells or T cells. Flow cytometry, time-lapse confocal imaging for apoptosis, and quantification of cytokeratin 19 fragment (CYFRA) release were applied to analyse organoid and immune cell behaviour. CCA organoids were also cultured in immune cell-conditioned media to analyse the effect of soluble factors. Results The co-culture system demonstrated an effective anti-tumour organoid immune response by a decrease in live organoid cells and an increase in apoptosis and CYFRA release. Interpatient heterogeneity was observed. The cytotoxic effects could be mediated by direct cell–cell contact and by release of soluble factors, although soluble factors only decreased viability in one organoid line. Conclusions In this proof-of-concept study, a novel CCA organoid and immune cell co-culture method was established. This can be the first step towards personalised immunotherapy for CCA by predicting which ICIs are most effective for individual patients.
Gautam Kok, Monique M. A. Verstegen, Roderick H. J. Houwen, Edward E. S. Nieuwenhuis, Herold J. Metselaar, Wojciech G. Polak, Luc J. W. van der Laan, Eric Spierings, Caroline M. den Hoed, and Sabine A. Fuchs
Ovid Technologies (Wolters Kluwer Health)
For liver transplantations, human leukocyte antigen (HLA) matching is not routinely performed because observed effects have been inconsistent. Nevertheless, long‐term liver transplantation outcomes remain suboptimal. The availability of a more precise HLA‐matching algorithm, Predicted Indirectly Recognizable HLA Epitopes II (PIRCHE‐II), now enables robust assessment of the association between HLA matching and liver transplantation outcomes. We performed a single‐center retrospective cohort study of 736 liver transplantation patients. Associations between PIRCHE‐II and HLAMatchmaker scores and mortality, graft loss, acute and chronic rejection, ischemic cholangiopathy, and disease recurrence were evaluated with Cox proportional hazards models. Associations between PIRCHE‐II with 1‐year, 2‐year, and 5‐year outcomes and severity of acute rejection were assessed with logistic and linear regression analyses, respectively. Subgroup analyses were performed for autoimmune and nonautoimmune indications, and patients aged 30 years and younger, and older than 30 years. PIRCHE‐II and HLAMatchmaker scores were not associated with any of the outcomes. However, patients who received transplants for autoimmune disease showed more acute rejection and graft loss, and these risks negatively associated with age. Rhesus mismatch more than doubled the risk of disease recurrence. Moreover, PIRCHE‐II was inversely associated with graft loss in the subgroup of patients aged 30 years and younger with autoimmune indications. The absence of associations between PIRCHE‐II and HLAMatchmaker scores and the studied outcomes refutes the need for HLA matching for liver (stem cell) transplantations for nonautoimmune disease. For autoimmune disease, the activated immune system seems to increase risks of acute rejection and graft loss. Our results may suggest the benefits of transplantations with rhesus matched but PIRCHE‐II mismatched donor livers.
Shaojun Shi, Eliano Bonaccorsi-Riani, Ivo Schurink, Thierry van den Bosch, Michael Doukas, Karishma A. Lila, Henk P. Roest, Daela Xhema, Pierre Gianello, Jeroen de Jonge,et al.
Frontiers Media SA
BackgroundEarly allograft dysfunction (EAD) following liver transplantation (LT) remains a major threat to the survival of liver grafts and recipients. In animal models, it is shown that hepatic ischemia-reperfusion injury (IRI) triggers phosphorylation of Mixed Lineage Kinase domain-like protein (pMLKL) inducing necroptotic cell death. However, the clinical implication of pMLKL-mediated cell death in human hepatic IRI remains largely unexplored. In this study, we aimed to investigate the expression of pMLKL in human liver grafts and its association with EAD after LT.MethodsThe expression of pMLKL was determined by immunohistochemistry in liver biopsies obtained from both human and rat LT. Human liver biopsies were obtained at the end of preservation (T0) and ~1 hour after reperfusion (T1). The positivity of pMLKL was quantified electronically and compared in rat and human livers and post-LT outcomes. Multiplex immunofluorescence staining was performed to characterize the pMLKL-expressing cells.ResultsIn the rat LT model, significant pMLKL expression was observed in livers after IRI as compared to livers of sham-operation animals. Similarly, the pMLKL score was highest after IRI in human liver grafts (in T1 biopsies). Both in rats and humans, the pMLKL expression is mostly observed in the portal triads. In grafts who developed EAD after LT (n=24), the pMLKL score at T1 was significantly higher as compared to non-EAD grafts (n=40). ROC curve revealed a high predictive value of pMLKL score at T1 (AUC 0.70) and the ratio of pMLKL score at T1 and T0 (pMLKL-index, AUC 0.82) for EAD. Liver grafts with a high pMLKL index (&gt;1.64) had significantly higher levels of serum ALT, AST, and LDH 24 hours after LT compared to grafts with a low pMLKL index. Multivariate logistical regression analysis identified the pMLKL-index (Odds ratio=1.3, 95% CI 1.1-1.7) as a predictor of EAD development. Immunohistochemistry on serial sections and multiplex staining identified the periportal pMLKL-positive cells as portal fibroblasts, fibrocytes, and a minority of cholangiocytes.ConclusionPeriportal pMLKL expression increased significantly after IRI in both rat and human LT. The histological score of pMLKL is predictive of post-transplant EAD and is associated with early liver injury after LT. Periportal non-parenchymal cells (i.e. fibroblasts) appear most susceptible to pMLKL-mediated cell death during hepatic IRI.
Floris J.M. Roos, Gilles S. van Tienderen, Haoyu Wu, Ignacio Bordeu, Dina Vinke, Laura Muñoz Albarinos, Kathryn Monfils, Sabrah Niesten, Ron Smits, Jorke Willemse,et al.
Elsevier BV
Jorke Willemse, Gilles van Tienderen, Eline van Hengel, Ivo Schurink, Diana van der Ven, Yik Kan, Petra de Ruiter, Oskar Rosmark, Gunilla Westergren-Thorsson G, Kerstin Schneeberger,et al.
Elsevier BV
Marcel J.C. Bijvelds, Floris J.M. Roos, Kelly F. Meijsen, Henk P. Roest, Monique M.A. Verstegen, Hettie M. Janssens, Luc J.W. van der Laan, and Hugo R. de Jonge
Elsevier BV
Gilles S. van Tienderen, Ling Li, Laura Broutier, Yoshimasa Saito, Patricia Inacio, Meritxell Huch, Florin M. Selaru, Luc J.W. van der Laan, and Monique M.A. Verstegen
Elsevier BV
Jorke Willemse, Luc J. W. van der Laan, Jeroen de Jonge, and Monique M. A. Verstegen
MDPI AG
Organoid technology holds great promise for regenerative medicine. Recent studies show feasibility for bile duct tissue repair in humans by successfully transplanting cholangiocyte organoids in liver grafts during perfusion. Large-scale expansion of cholangiocytes is essential for extending these regenerative medicine applications. Human cholangiocyte organoids have a high and stable proliferation capacity, making them an attractive source of cholangiocytes. Commercially available basement membrane extract (BME) is used to expand the organoids. BME allows the cells to self-organize into 3D structures and stimulates cell proliferation. However, the use of BME is limiting the clinical applications of the organoids. There is a need for alternative tissue-specific and clinically relevant culture substrates capable of supporting organoid proliferation. Hydrogels prepared from decellularized and solubilized native livers are an attractive alternative for BME. These hydrogels can be used for the culture and expansion of cholangiocyte organoids in a clinically relevant manner. Moreover, the liver-derived hydrogels retain tissue-specific aspects of the extracellular microenvironment. They are composed of a complex mixture of bioactive and biodegradable extracellular matrix (ECM) components and can support the growth of various hepatobiliary cells. In this review, we provide an overview of the clinical potential of native liver ECM-based hydrogels for applications with human cholangiocyte organoids. We discuss the current limitations of BME for the clinical applications of organoids and how native ECM hydrogels can potentially overcome these problems in an effort to unlock the full regenerative clinical potential of the organoids.
Ling Wang, Meng Li, Bingting Yu, Shaojun Shi, Jiaye Liu, Ruyi Zhang, Ibrahim Ayada, Monique M. A. Verstegen, Luc J. W. van der Laan, Maikel P. Peppelenbosch,et al.
Springer Science and Business Media LLC