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The Use of Stem Cell-Derived Organoids in Disease Modeling: an Update

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The Use of Stem Cell-Derived Organoids in Disease Modeling: an Update International Journal of Molecular Sciences Review The Use of Stem Cell-Derived Organoids in Disease Modeling: An Update Joseph Azar 1,† , Hisham F. Bahmad 1,2,† , Darine Daher 1,‡, Maya M. Moubarak 1,‡ , Ola Hadadeh 1 , Alissar Monzer 1, Samar Al Bitar 1, Mohamed Jamal 3,* , Mohamed Al-Sayegh 4,* and Wassim Abou-Kheir 1,* 1 Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107 2260, Lebanon; [email protected] (J.A.); [email protected] (H.F.B.); [email protected] (D.D.); [email protected] (M.M.M.); [email protected] (O.H.); [email protected] (A.M.); [email protected] (S.A.B.) 2 Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA 3 Hamdan Bin Mohammed College of Dental Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai 66566, United Arab Emirates 4 Biology Division, New York University Abu Dhabi, Abu Dhabi 2460, United Arab Emirates * Correspondence: [email protected] (M.J.); [email protected] (M.A.-S.); [email protected] (W.A.-K.); Tel.: +971-438-389-27 (M.J.); +971-262-845-60 (M.A.-S.); +961-135-0000 (ext. 4778) (W.A.-K.) † Authors contributed equally to this work as co-first authors. ‡ Authors contributed equally to this work as co-second authors. Abstract: Organoids represent one of the most important advancements in the field of stem cells during the past decade. They are three-dimensional in vitro culturing models that originate from Citation: Azar, J.; Bahmad, H.F.; self-organizing stem cells and can mimic the in vivo structural and functional specificities of body Daher, D.; Moubarak, M.M.; organs. Organoids have been established from multiple adult tissues as well as pluripotent stem Hadadeh, O.; Monzer, A.; Al Bitar, S.; cells and have recently become a powerful tool for studying development and diseases in vitro, drug Jamal, M.; Al-Sayegh, M.; Abou-Kheir, screening, and host–microbe interaction. The use of stem cells—that have self-renewal capacity to W. The Use of Stem Cell-Derived proliferate and differentiate into specialized cell types—for organoids culturing represents a major Organoids in Disease Modeling: An Update. Int. J. Mol. Sci. 2021, 22, 7667. advancement in biomedical research. Indeed, this new technology has a great potential to be used in https://doi.org/10.3390/ a multitude of fields, including cancer research, hereditary and infectious diseases. Nevertheless, ijms22147667 organoid culturing is still rife with many challenges, not limited to being costly and time consuming, having variable rates of efficiency in generation and maintenance, genetic stability, and clinical Academic Editor: Sally Martin applications. In this review, we aim to provide a synopsis of pluripotent stem cell-derived organoids and their use for disease modeling and other clinical applications. Received: 29 April 2021 Accepted: 18 June 2021 Keywords: pluripotent stem cells; embryonic stem cells; organoids; disease modeling; 3D culturing Published: 17 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in 1. Introduction published maps and institutional affil- Organoids represent one of the most important advancements in the field of stem iations. cells during the past decade. The earliest usage of the term goes back to 1946 when Smith and Cochrane described a cystic teratoma case by referring to it as “cystic organoid teratoma” [1]. Organoids, or as the term literally signifies “resembling an organ”, are three- dimensional (3D) in vitro culturing systems that originate from self-organizing stem cells, Copyright: © 2021 by the authors. capable of mimicking the in vivo structural and functional specificities of an organ [2]. They Licensee MDPI, Basel, Switzerland. can be derived from either pluripotent stem cells (PSCs) or organ-specific adult stem cells This article is an open access article (ASCs) [3]. PSCs, for instance, are capable of generating in vitro tissue models recapitulat- distributed under the terms and ing what happens in in vivo organogenesis, where tissues are derived from embryonic stem conditions of the Creative Commons Attribution (CC BY) license (https:// cells (ESCs) [4]. Figure1 summarizes the potential sources for organoids development. creativecommons.org/licenses/by/ 4.0/). Int. J. Mol. Sci. 2021, 22, 7667. https://doi.org/10.3390/ijms22147667 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 40 Int. J. Mol. Sci. 2021, 22, 7667 2 of 39 Figure 1. Organoids generation from differentdifferent types of stem cells. Organoids can be generated from induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs) and patient-derivedpatient-derived adult stem cells from normal and cancerous tissues (ASCs).(ASCs). CellsCells areare usuallyusually grown grown in in three three dimensional dimensional systems systems under under specific specific conditions conditions to stimulateto stimulate the the growth growth of organoids. of organ- Shapesoids. Shapes and images and images are imported are imported from Servierfrom Servier Medical Medical Art by Art Servier by Servier (http://smart.servier.com/ (http://smart.servier.com/)), accessed, accessed on 24 on May 24 2021.May Licensed2021. Licensed under aunder Creative a CommonsCreative AttributionCommons 3.0Attribution Unported License3.0 Unported (https://creativecommons.org/licenses/by/3.0/ License (https://creativecommons.org/li-). censes/by/3.0/). Organoids have a great potential to be used in a multitude of fields [5,6]. One such avenue is cancer research, particularly through the development of tumor organoids. For example, glioblastoma organoids were established with the hopes of creating a satisfac- tory in vitro model that reflects the in vivo hypoxic gradients and heterogeneity of this greatly heterogenous cancer. This glioblastoma model can be used for both diagnosis and therapeutic purposes [7]. Furthermore, our group succeeded in generating and char- acterizing patient-derived prostate organoids from fresh primary tissue specimens. We confirmed the validity of those organoids as a relevant in vitro model to assess personalized treatment responses wherein we observed a differential drug response between different patient samples, at the protein and gene levels [8]. Moreover, we were able to isolate novel patient-derived prostate epithelial cells from the generated organoids [8]. Organoid models were also used in cancer immunotherapy research. In fact, Jenkins et al. used patient and murine derived organoids to establish an ex vivo profiling of PD-1 blockade. This would significantly help in dissecting the tumor microenvironment, enhancing precision immune-oncologic therapies, and ultimately deciphering the mechanisms behind immune checkpoint blockade resistance [9]. Furthermore, Dijkstra et al. co-cultured epithelial tumor organoids with peripheral blood lymphocytes to expand the population of tumor-reactive T-cells. This co-culture model can be also employed to characterize the sensitivity of neo- plastic cells to the T cell-mediated killing at a personalized patient level [10]. Another potential avenue for the usage of organoids is hereditary diseases such as cystic fibrosis (CF), which maintain the tissue of origin’s genetic fingerprint. Beekman’s group was able to elucidate a quantifying assay of the CF transmembrane conductance regulator (CFTR) function, the malfunctioning chloride channel in CF, using an intestinal model that closely mimics the core aspects of the disease’s in vivo characteristics. This can aid in diagnosis and potentially provides novel therapeutic approaches to enhance drug development strategies for the disease [11]. After the COVID-19 pandemic has swept the world, organoids are Int. J. Mol. Sci. 2021, 22, 7667 3 of 39 proving to be of increasing value as viral replication platforms that can help expand our understanding of this virus [12]. Even though it has significant potential, organoid culturing is still rife with many challenges. Despite these systems’ heterogeneity, the tumor microenvironment is often not properly reconstituted since most of the patient-derived organoids (PDOs) do not have the supporting stroma [13]. Other challenges observed with glioblastoma patient-derived xenotransplantation (PDX) models include cost, time consumption, and variable rates of transplantation [14]. Another limitation with the PDX system is that the immune response Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEWcannot be assessed properly since the host strains used are immunodeficient. Therefore,4 of 40 there is a poor assessment on how the immune system would have responded [15]. In this review, organoid culture will be thoroughly discussed along with its various applications in disease modeling (Figure2). Figure 2. Schematic illustrating the use of stem cell-derived organoids for various biomedical and Figureclinical 2. Schematic applications illustrating including drug the use screening of stem and cell-derived discovery, disease organoids modeling, for geneticvarious manipulation, biomedical and clinicalomics applications analysis, and including regenerative drug medicine screening among and many discovery, others. disease modeling, genetic manipula- tion, omics analysis, and regenerative medicine among many others. 2. Modeling Diseases Using Induced Pluripotent Stem Cells (Ipscs)-Derived Organ- oids Over the years, major advances and discoveries in stem cell research have been made in PSCs.
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