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Patient-Derived Organoids in Personalized Medicine
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Patient-Derived Organoids in Personalized Medicine

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 22679

Special Issue Editor

Dr. Zoltán Wiener

E-Mail Website
Guest Editor
Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary
Interests: colorectal cancer; pancreas ductal adenocarcinoma; extracellular vesicles; organoid; stromal cells; intra-tumoral heterogeneity

Special Issue Information

Although classical 2D cell cultures have provided a tremendous amount of data on how cancers and other diseases are established, they do not properly model the intra- and interpatient cellular heterogeneity, characteristic for the in vivo situation. In addition, some diseases are difficult to model with mouse systems. As an example, lung cancer is an extremely heterogenous disease with a wide array of mutations; thus, this variance in genetic differences is difficult to capture with mouse models. The 3D organoid technology is a promising tool to solve many of these problems; it captures much of the cellular heterogeneity of the original tissue, is genetically stable, and it represents the complex architecture of the epithelial tissue of origin well. Not surprisingly, this technology has become an invaluable tool in the study of stem cells and their niche, the effect of mutations for diseases, and in finding novel drug combinations for individual cancer patients. Despite the enormous increase in their application and popularity, their standardization is still ongoing, and in many cases maintaining organoids is quite expensive. In this Special Issue, we welcome original articles and reviews about the application of organoids in disease modelling and drug testing, in understanding the development of tissues and organs, and about methodological advancements in organoid technology.

Dr. Zoltán Wiener
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (7 papers)

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Research

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16 pages, 3720 KiB  
Article
Developing 3D Organoid Raft Cultures from Patient-Derived Xenografts as Rapid Models to Screen Efficacy of Experimental Therapeutics
by Prachi Bajpai, Nilam Sanjib Banerjee, Dianne W. Moore, Hyung-Gyoon Kim, Farrukh Afaq, Carlo M. Contreras, Martin J. Heslin, Vishnu B. Reddy, Shajan Peter, Sooryanarayana Varambally, Sameer Al Diffalha and Upender Manne
Int. J. Mol. Sci. 2022, 23(22), 14392; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214392 - 19 Nov 2022
Cited by 1 | Viewed by 1603
Abstract
Reliable preclinical models are needed for screening new cancer drugs. Thus, we developed an improved 3D tumor organoid model termed “organoid raft cultures” (ORCs). Development of ORCs involved culturing tumors ex vivo on collagen beds (boats) with grid supports to maintain their morphological [...] Read more.
Reliable preclinical models are needed for screening new cancer drugs. Thus, we developed an improved 3D tumor organoid model termed “organoid raft cultures” (ORCs). Development of ORCs involved culturing tumors ex vivo on collagen beds (boats) with grid supports to maintain their morphological structure. The ORCs were developed from patient-derived xenografts (PDXs) of colon cancers excised from immune-deficient mice (NOD/SCID/IL2Rgammanull). We utilized these new models to evaluate the efficacy of an investigational drug, Navitoclax (ABT-263). We tested the efficacy of ABT-263, an inhibitor of BCL-2 family proteins, in these ORCs derived from a PDX that showed high expression of antiapoptotic BCL2 family proteins (BCL-2, BCL-XL, and BCL-W). Hematoxylin and eosin staining evaluation of PDXs and corresponding ORCs indicated the retention of morphological and other histological integrity of ORCs. ORCs treated with ABT-263 showed decreased expression of antiapoptotic proteins (BCL2, BCL-XL and BCL-W) and increased proapoptotic proteins (BAX and PUMA), with concomitant activation of caspase 3. These studies support the usefulness of the ORCs, developed from PDXs, as an alternative to PDXs and as faster screening models. Full article
(This article belongs to the Special Issue Patient-Derived Organoids in Personalized Medicine)
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13 pages, 1920 KiB  
Article
Retinoic Acid Promotes the In Vitro Growth, Patterning and Improves the Cellular Composition of Human Pluripotent Stem-Cell-Derived Intestinal Organoids
by Na Qu, Braxton Jeffcoat, Pritiprasanna Maity, Rachael K. Christensen and Jorge O. Múnera
Int. J. Mol. Sci. 2022, 23(15), 8624; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158624 - 03 Aug 2022
Cited by 2 | Viewed by 2046
Abstract
Human intestinal organoids (HIOs) generated from human pluripotent stem cells hold great promise for modeling human development and as a possible source of tissue for transplantation. HIOs generate all of the main epithelial and mesenchymal cell types found in the developing human intestine [...] Read more.
Human intestinal organoids (HIOs) generated from human pluripotent stem cells hold great promise for modeling human development and as a possible source of tissue for transplantation. HIOs generate all of the main epithelial and mesenchymal cell types found in the developing human intestine and mature into intestinal tissue with crypts and villi following transplantation into immunocompromised mice. However, incomplete in vitro patterning and the presence of contaminating neurons could hinder their use for regenerative medicine in humans. Based on studies in model organisms, we hypothesized that the treatment of HIOs with all trans retinoic acid (ATRA) would improve their in vitro growth and patterning. We found that ATRA not only improved the patterning of HIOs, ATRA also increased organoid forming efficiency, improved epithelial growth, enriched intestinal subepithelial myofibroblasts (ISEMFs) and reduced neuronal contamination in HIOs. Taken together, our studies demonstrate how the manipulation of a single developmental signaling pathway can be used to improve the survival, patterning and cellular composition of HIOs. Full article
(This article belongs to the Special Issue Patient-Derived Organoids in Personalized Medicine)
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13 pages, 3292 KiB  
Article
Assessment of Normal Tissue Radiosensitivity by Evaluating DNA Damage and Repair Kinetics in Human Brain Organoids
by Jovana Bojcevski, Changwen Wang, Haikun Liu, Amir Abdollahi and Ivana Dokic
Int. J. Mol. Sci. 2021, 22(24), 13195; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413195 - 07 Dec 2021
Cited by 4 | Viewed by 3311
Abstract
DNA-double strand break (DSB), detected by immunostaining of key proteins orchestrating repair, like γH2AX and 53BP1, is well established as a surrogate for tissue radiosensitivity. We hypothesized that the generation of normal brain 3D organoids (“mini-brains”) from human induced pluripotent stem cells (hiPSC) [...] Read more.
DNA-double strand break (DSB), detected by immunostaining of key proteins orchestrating repair, like γH2AX and 53BP1, is well established as a surrogate for tissue radiosensitivity. We hypothesized that the generation of normal brain 3D organoids (“mini-brains”) from human induced pluripotent stem cells (hiPSC) combined with detection of DNA damage repair (DDR) may hold the promise towards developing personalized models for the determination of normal tissue radiosensitivity. In this study, cerebral organoids, an in vitro model that stands in its complexity between 2D cellular system and an organ, have been used. To quantify radiation-induced response, immunofluorescent staining with γH2AX and 53BP1 were applied at early (30 min, initial damage), and late time points (18 and 72 h, residual damage), following clinical standard 2 Gy irradiation. Based on our findings, assessment of DDR kinetics as a surrogate for radiosensitivity in hiPSC derived cerebral organoids is feasible. Further development of mini-brains recapitulating mature adult neuronal tissue and implementation of additional signaling and toxicity surrogates may pave the way towards development of next-generation personalized assessment of radiosensitivity in healthy neuronal tissue. Full article
(This article belongs to the Special Issue Patient-Derived Organoids in Personalized Medicine)
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16 pages, 4267 KiB  
Article
Fabrication of Hydroxyapatite with Bioglass Nanocomposite for Human Wharton’s-Jelly-Derived Mesenchymal Stem Cell Growing Substrate
by Shamsi Ebrahimi, Yusoff Umul Hanim, Coswald Stephen Sipaut, Norsazlina binti Ahmad Jan, Sazmal E. Arshad and Siew Eng How
Int. J. Mol. Sci. 2021, 22(17), 9637; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179637 - 06 Sep 2021
Cited by 8 | Viewed by 2054
Abstract
Recently, composite scaffolding has found many applications in hard tissue engineering due to a number of desirable features. In this present study, hydroxyapatite/bioglass (HAp/BG) nanocomposite scaffolds were prepared in different ratios using a hydrothermal approach. The aim of this research was to evaluate [...] Read more.
Recently, composite scaffolding has found many applications in hard tissue engineering due to a number of desirable features. In this present study, hydroxyapatite/bioglass (HAp/BG) nanocomposite scaffolds were prepared in different ratios using a hydrothermal approach. The aim of this research was to evaluate the adhesion, growth, viability, and osteoblast differentiation behavior of human Wharton’s-jelly-derived mesenchymal stem cells (hWJMSCs) on HAp/BG in vitro as a scaffold for application in bone tissue engineering. Particle size and morphology were investigated by TEM and bioactivity was assessed and proven using SEM analysis with hWJMSCs in contact with the HAp/BG nanocomposite. Viability was evaluated using PrestoBlueTM assay and early osteoblast differentiation and mineralization behaviors were investigated by ALP activity and EDX analysis simultaneously. TEM results showed that the prepared HAp/BG nanocomposite had dimensions of less than 40 nm. The morphology of hWJMSCs showed a fibroblast-like shape, with a clear filopodia structure. The viability of hWJMSCs was highest for the HAp/BG nanocomposite with a 70:30 ratio of HAp to BG (HAp70/BG30). The in vitro biological results confirmed that HAp/BG composite was not cytotoxic. It was also observed that the biological performance of HAp70/BG30 was higher than HAp scaffold alone. In summary, HAp/BG scaffold combined with mesenchymal stem cells showed significant potential for bone repair applications in tissue engineering. Full article
(This article belongs to the Special Issue Patient-Derived Organoids in Personalized Medicine)
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15 pages, 10000 KiB  
Article
Multicellular Human Cardiac Organoids Transcriptomically Model Distinct Tissue-Level Features of Adult Myocardium
by Charles M. Kerr, Dylan Richards, Donald R. Menick, Kristine Y. Deleon-Pennell and Ying Mei
Int. J. Mol. Sci. 2021, 22(16), 8482; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168482 - 06 Aug 2021
Cited by 19 | Viewed by 3299
Abstract
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used for disease modeling and drug cardiotoxicity screening. To this end, we recently developed human cardiac organoids (hCOs) for modeling human myocardium. Here, we perform a transcriptomic analysis of various in vitro hiPSC-CM platforms [...] Read more.
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used for disease modeling and drug cardiotoxicity screening. To this end, we recently developed human cardiac organoids (hCOs) for modeling human myocardium. Here, we perform a transcriptomic analysis of various in vitro hiPSC-CM platforms (2D iPSC-CM, 3D iPSC-CM and hCOs) to deduce the strengths and limitations of these in vitro models. We further compared iPSC-CM models to human myocardium samples. Our data show that the 3D in vitro environment of 3D hiPSC-CMs and hCOs stimulates the expression of genes associated with tissue formation. The hCOs demonstrated diverse physiologically relevant cellular functions compared to the hiPSC-CM only models. Including other cardiac cell types within hCOs led to more transcriptomic similarities to adult myocardium. hCOs lack matured cardiomyocytes and immune cells, which limits a complete replication of human adult myocardium. In conclusion, 3D hCOs are transcriptomically similar to myocardium, and future developments of engineered 3D cardiac models would benefit from diversifying cell populations, especially immune cells. Full article
(This article belongs to the Special Issue Patient-Derived Organoids in Personalized Medicine)
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13 pages, 3714 KiB  
Article
Establishment and Long-Term Expansion of Small Cell Lung Cancer Patient-Derived Tumor Organoids
by Seon Young Choi, Yong-Hee Cho, Da-Som Kim, Wonjun Ji, Chang-Min Choi, Jae Cheol Lee, Jin Kyung Rho and Gi Seok Jeong
Int. J. Mol. Sci. 2021, 22(3), 1349; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031349 - 29 Jan 2021
Cited by 21 | Viewed by 3136
Abstract
Differential chemo-sensitivity of cancer cells, which is attributed to the cellular heterogeneity and phenotypic variation of cancer cells, is considered to be the main reason for tumor recurrence after chemotherapy. Here, we generated small cell lung cancer patient-derived tumor organoids and subjected them [...] Read more.
Differential chemo-sensitivity of cancer cells, which is attributed to the cellular heterogeneity and phenotypic variation of cancer cells, is considered to be the main reason for tumor recurrence after chemotherapy. Here, we generated small cell lung cancer patient-derived tumor organoids and subjected them to long-term expansion with the addition of WNT3A or R-spondin1. We confirmed that the organoids have similar genetic profiles, molecular characteristics, and morphological architectures to the corresponding patient tumor tissue during and after long-term expansion. Interestingly, the cellular heterogeneity of organoids is reflected in their differential response to cisplatin or etoposide. We propose to utilize the organoids as small cell lung cancer patient avatar models that would be ideal for investigating the mechanisms underlying tumor recurrence after chemotherapy, and would ultimately help to develop personalized medicine. Full article
(This article belongs to the Special Issue Patient-Derived Organoids in Personalized Medicine)
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Review

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25 pages, 1596 KiB  
Review
From Spheroids to Organoids: The Next Generation of Model Systems of Human Cardiac Regeneration in a Dish
by Mariangela Scalise, Fabiola Marino, Luca Salerno, Eleonora Cianflone, Claudia Molinaro, Nadia Salerno, Antonella De Angelis, Giuseppe Viglietto, Konrad Urbanek and Daniele Torella
Int. J. Mol. Sci. 2021, 22(24), 13180; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413180 - 07 Dec 2021
Cited by 24 | Viewed by 5634
Abstract
Organoids are tiny, self-organized, three-dimensional tissue cultures that are derived from the differentiation of stem cells. The growing interest in the use of organoids arises from their ability to mimic the biology and physiology of specific tissue structures in vitro. Organoids indeed represent [...] Read more.
Organoids are tiny, self-organized, three-dimensional tissue cultures that are derived from the differentiation of stem cells. The growing interest in the use of organoids arises from their ability to mimic the biology and physiology of specific tissue structures in vitro. Organoids indeed represent promising systems for the in vitro modeling of tissue morphogenesis and organogenesis, regenerative medicine and tissue engineering, drug therapy testing, toxicology screening, and disease modeling. Although 2D cell cultures have been used for more than 50 years, even for their simplicity and low-cost maintenance, recent years have witnessed a steep rise in the availability of organoid model systems. Exploiting the ability of cells to re-aggregate and reconstruct the original architecture of an organ makes it possible to overcome many limitations of 2D cell culture systems. In vitro replication of the cellular micro-environment of a specific tissue leads to reproducing the molecular, biochemical, and biomechanical mechanisms that directly influence cell behavior and fate within that specific tissue. Lineage-specific self-organizing organoids have now been generated for many organs. Currently, growing cardiac organoid (cardioids) from pluripotent stem cells and cardiac stem/progenitor cells remains an open challenge due to the complexity of the spreading, differentiation, and migration of cardiac muscle and vascular layers. Here, we summarize the evolution of biological model systems from the generation of 2D spheroids to 3D organoids by focusing on the generation of cardioids based on the currently available laboratory technologies and outline their high potential for cardiovascular research. Full article
(This article belongs to the Special Issue Patient-Derived Organoids in Personalized Medicine)
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