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      The reprotoxic adverse side effects of neurogenic and neuroprotective drugs: current use of human organoid modeling as a potential alternative to preclinical models

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          Abstract

          The management of neurological disorders heavily relies on neurotherapeutic drugs, but notable concerns exist regarding their possible negative effects on reproductive health. Traditional preclinical models often fail to accurately predict reprotoxicity, highlighting the need for more physiologically relevant systems. Organoid models represent a promising approach for concurrently studying neurotoxicity and reprotoxicity, providing insights into the complex interplay between neurotherapeutic drugs and reproductive systems. Herein, we have examined the molecular mechanisms underlying neurotherapeutic drug-induced reprotoxicity and discussed experimental findings from case studies. Additionally, we explore the utility of organoid models in elucidating the reproductive complications of neurodrug exposure. Have discussed the principles of organoid models, highlighting their ability to recapitulate neurodevelopmental processes and simulate drug-induced toxicity in a controlled environment. Challenges and future perspectives in the field have been addressed with a focus on advancing organoid technologies to improve reprotoxicity assessment and enhance drug safety screening. This review underscores the importance of organoid models in unraveling the complex relationship between neurotherapeutic drugs and reproductive health.

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          Most cited references277

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          Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

          Differentiated cells can be reprogrammed to an embryonic-like state by transfer of nuclear contents into oocytes or by fusion with embryonic stem (ES) cells. Little is known about factors that induce this reprogramming. Here, we demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Unexpectedly, Nanog was dispensable. These cells, which we designated iPS (induced pluripotent stem) cells, exhibit the morphology and growth properties of ES cells and express ES cell marker genes. Subcutaneous transplantation of iPS cells into nude mice resulted in tumors containing a variety of tissues from all three germ layers. Following injection into blastocysts, iPS cells contributed to mouse embryonic development. These data demonstrate that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors.
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            Induction of pluripotent stem cells from adult human fibroblasts by defined factors.

            Successful reprogramming of differentiated human somatic cells into a pluripotent state would allow creation of patient- and disease-specific stem cells. We previously reported generation of induced pluripotent stem (iPS) cells, capable of germline transmission, from mouse somatic cells by transduction of four defined transcription factors. Here, we demonstrate the generation of iPS cells from adult human dermal fibroblasts with the same four factors: Oct3/4, Sox2, Klf4, and c-Myc. Human iPS cells were similar to human embryonic stem (ES) cells in morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity. Furthermore, these cells could differentiate into cell types of the three germ layers in vitro and in teratomas. These findings demonstrate that iPS cells can be generated from adult human fibroblasts.
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              Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.

              The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of about six cycling Lgr5(+) stem cells at the bottoms of small-intestinal crypts. Here we describe the establishment of long-term culture conditions under which single crypts undergo multiple crypt fission events, while simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5(+) stem cells can also initiate these cryptvillus organoids. Tracing experiments indicate that the Lgr5(+) stem-cell hierarchy is maintained in organoids. We conclude that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.
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                Author and article information

                Contributors
                Role: Role:
                Role: Role:
                Role: Role:
                URI : https://loop.frontiersin.org/people/1893675/overviewRole: Role:
                URI : https://loop.frontiersin.org/people/935705/overviewRole: Role:
                URI : https://loop.frontiersin.org/people/490080/overviewRole: Role:
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                14 June 2024
                2024
                : 15
                : 1412188
                Affiliations
                [1] 1 Organic Metrology Group , Division of Chemical and Material Metrology , Korea Research Institute of Standards and Science , Daejeon, Republic of Korea
                [2] 2 Department of Bio-Analytical Science , University of Science and Technology , Daejeon, Republic of Korea
                [3] 3 Department of Nutrition and Food Science , National Research Centre , Cairo, Egypt
                [4] 4 Deperament of Comparative Medicine , King Faisal Specialist Hospital and Research Centre , Riyadh, Saudi Arabia
                [5] 5 College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University , Seoul, Republic of Korea
                Author notes

                Edited by: Chongyang Shen, Chengdu University of Traditional Chinese Medicine, China

                Reviewed by: Åsa Fex-Svenningsen, University of Southern Denmark, Denmark

                Alan Marc Hoberman, Charles River Laboratories, United States

                *Correspondence: Islam M. Saadeldin, imohamed@ 123456kfshrc.edu.sa
                Article
                1412188
                10.3389/fphar.2024.1412188
                11211546
                38948466
                5e820287-7133-42a8-9fa0-1d7c5949a7eb
                Copyright © 2024 Abady, Jeong, Kwon, Assiri, Cho and Saadeldin.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 April 2024
                : 29 May 2024
                Funding
                The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
                Categories
                Pharmacology
                Review
                Custom metadata
                Experimental Pharmacology and Drug Discovery

                Pharmacology & Pharmaceutical medicine
                drug-induced reprotoxicity,organoid model,neurotherapeutic drug,side effect,toxicicity

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