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Current Progress in Organ Regeneration: Cells, Organoids and Organs
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Current Progress in Organ Regeneration: Cells, Organoids and Organs

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 26941

Special Issue Editor

Dr. Hiroshi Yagi

E-Mail Website
Guest Editor
Department of Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan
Interests: decellularization; liver; regeneration; stem cells; transplantation

Special Issue Information

Dear Colleagues,

Recent progress in the field of tissue regeneration has been accelerating since the emergence of ESC/iPSC technology and improved management of the extracellular environment. A promising combined approach that is attracting worldwide attention in developing regenerative therapy in humans is by progressing “from cells to organoids and from organoids to organs”. Although most types of somatic cells can be generated from pluripotent stem cells, it remains a major challenge to construct organs with clinically relevant functionality. The inclusion of the extracellular environment is thought to be the key to overcoming this difficulty, because cellular functions are not only regulated by cell–cell or cell–matrix contacts. Another key aspect is the dynamic behavior of cells, in terms of their lineage conversion or de-differentiation, in the developing tissue/organ. Therefore, further progress in novel biomaterials, organoid technologies, and humanized animals is vital for the development of organ regeneration as a viable therapeutic option. Very recently, it has also become apparent that rather than focusing on single organs in isolation, understanding the interactions between different organs is also important for appropriate organ development. To this end, promising approaches are currently being developed to understand cell fate and behavior in multiple organs using models such as lab-on-a-chip designs, microfluidics, and organoid–organoid interface studies.

This Special Issue offers an open-access forum that aims to bring together a collection of original research and review articles addressing the expanding field of organ regeneration. We hope to provide a stimulating resource for this fascinating subject. We invite the submission of manuscripts on topics that include but are not limited to stem cell differentiation techniques, cell transplantation, novel biomaterials for the extracellular environment, lab-on-a-chip approaches, tissue/organ preservation, novel approaches for organ development using organoids, chimeric animals, and new models to study organ regeneration.

Dr. Hiroshi Yagi
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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 (6 papers)

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Research

18 pages, 3211 KiB  
Article
Decellularized Organ-Derived Scaffold Is a Promising Carrier for Human Induced Pluripotent Stem Cells-Derived Hepatocytes
by Hideaki Kojima, Hiroshi Yagi, Hiroko Kushige, Yukiko Toda, Kazuo Takayama, Shinako Masuda, Toshinori Morisaku, Tomonori Tsuchida, Kohei Kuroda, Kazuya Hirukawa, Jumpei Inui, Kotaro Nishi, Yutaka Nakano, Masayuki Tanaka, Shutaro Hori, Yasushi Hasegawa, Yuta Abe, Minoru Kitago, Shungo Adachi, Masatoshi Tomi, Katsuhisa Matsuura, Hiroyuki Mizuguchi and Yuko Kitagawaadd Show full author list remove Hide full author list
Cells 2022, 11(8), 1258; https://doi.org/10.3390/cells11081258 - 07 Apr 2022
Cited by 7 | Viewed by 2695
Abstract
Human induced pluripotent stem cells (hiPSCs) are a promising cell source for elucidating disease pathology and therapy. The mass supply of hiPSC-derived cells is technically feasible. Carriers that can contain a large number of hiPSC-derived cells and evaluate their functions in vivo-like environments [...] Read more.
Human induced pluripotent stem cells (hiPSCs) are a promising cell source for elucidating disease pathology and therapy. The mass supply of hiPSC-derived cells is technically feasible. Carriers that can contain a large number of hiPSC-derived cells and evaluate their functions in vivo-like environments will become increasingly important for understanding disease pathogenesis or treating end-stage organ failure. hiPSC-derived hepatocyte-like cells (hiPSC-HLCs; 5 × 108) were seeded into decellularized organ-derived scaffolds under circumfusion culture. The scaffolds were implanted into immunodeficient microminiature pigs to examine their applicability in vivo. The seeded hiPSC-HLCs demonstrated increased albumin secretion and up-regulated cytochrome P450 activities compared with those in standard two-dimensional culture conditions. Moreover, they showed long-term survival accompanied by neovascularization in vivo. The decellularized organ-derived scaffold is a promising carrier for hiPSC-derived cells for ex vivo and in vivo use and is an essential platform for regenerative medicine and research. Full article
(This article belongs to the Special Issue Current Progress in Organ Regeneration: Cells, Organoids and Organs)
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25 pages, 6833 KiB  
Article
Functional Recellularization of Acellular Rat Liver Scaffold by Induced Pluripotent Stem Cells: Molecular Evidence for Wnt/B-Catenin Upregulation
by Nesrine Ebrahim, Omnia A. M. Badr, Mohamed M. Yousef, Amira Hassouna, Dina Sabry, Ayman Samir Farid, Ola Mostafa, Hajir A. Al Saihati, Yasmin Seleem, Eman Abd El Aziz, Ahmed Hassan Khalil, Ahmed Nawar, Ahmed A. Shoulah, Mohammad Aljasir, Amira Zaki Mohamed, Mohamed El-Sherbiny, Nehal M. Elsherbiny, Mohamed Ahmed Eladl, Nicholas Robert Forsyth and Rabab F. Salim
Cells 2021, 10(11), 2819; https://doi.org/10.3390/cells10112819 - 20 Oct 2021
Cited by 8 | Viewed by 3045
Abstract
Background. Liver transplantation remains the only viable therapy for liver failure but has a severely restricted utility. Here, we aimed to decellularize rat livers to form acellular 3D bio-scaffolds suitable for seeding with induced pluripotent cells (iPSCs) as a tool to investigate the [...] Read more.
Background. Liver transplantation remains the only viable therapy for liver failure but has a severely restricted utility. Here, we aimed to decellularize rat livers to form acellular 3D bio-scaffolds suitable for seeding with induced pluripotent cells (iPSCs) as a tool to investigate the role of Wnt/β-catenin signaling in liver development and generation. Methods. Dissected rat livers were randomly divided into three groups: I (control); II (decellularized scaffolds) and III (recellularized scaffolds). Liver decellularization was established via an adapted perfusion procedure and assessed through the measurement of extracellular matrix (ECM) proteins and DNA content. Liver recellularization was assessed through histological examination and measurement of transcript levels of Wnt/β-catenin pathway, hepatogenesis, liver-specific microRNAs and growth factors essential for liver development. Adult rat liver decellularization was confirmed by the maintenance of ECM proteins and persistence of growth factors essential for liver regeneration. Results. iPSCs seeded rat decellularized livers displayed upregulated transcript expression of Wnt/β-catenin pathway-related, growth factors, and liver specification genes. Further, recellularized livers displayed restored liver-specific functions including albumin secretion and urea synthesis. Conclusion. This establishes proof-of-principle for the generation of three-dimensional liver organ scaffolds as grafts and functional re-establishment. Full article
(This article belongs to the Special Issue Current Progress in Organ Regeneration: Cells, Organoids and Organs)
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12 pages, 5055 KiB  
Article
Human Blood Vessel Organoids Penetrate Human Cerebral Organoids and Form a Vessel-Like System
by Yujin Ahn, Ju-Hyun An, Hae-Jun Yang, Dong Gil Lee, Jieun Kim, Hyebin Koh, Young-Ho Park, Bong-Seok Song, Bo-Woong Sim, Hong J. Lee, Jong-Hee Lee and Sun-Uk Kim
Cells 2021, 10(8), 2036; https://doi.org/10.3390/cells10082036 - 09 Aug 2021
Cited by 47 | Viewed by 9839
Abstract
Vascularization of tissues, organoids and organ-on-chip models has been attempted using endothelial cells. However, the cultured endothelial cells lack the capacity to interact with other somatic cell types, which is distinct from developing vascular cells in vivo. Recently, it was demonstrated that blood [...] Read more.
Vascularization of tissues, organoids and organ-on-chip models has been attempted using endothelial cells. However, the cultured endothelial cells lack the capacity to interact with other somatic cell types, which is distinct from developing vascular cells in vivo. Recently, it was demonstrated that blood vessel organoids (BVOs) recreate the structure and functions of developing human blood vessels. However, the tissue-specific adaptability of BVOs had not been assessed in somatic tissues. Herein, we investigated whether BVOs infiltrate human cerebral organoids and form a blood–brain barrier. As a result, vascular cells arising from BVOs penetrated the cerebral organoids and developed a vessel-like architecture composed of CD31+ endothelial tubes coated with SMA+ or PDGFR+ mural cells. Molecular markers of the blood-brain barrier were detected in the vascularized cerebral organoids. We revealed that BVOs can form neural-specific blood-vessel networks that can be maintained for over 50 days. Full article
(This article belongs to the Special Issue Current Progress in Organ Regeneration: Cells, Organoids and Organs)
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14 pages, 6029 KiB  
Article
Organoids Are Limited in Modeling the Colon Adenoma–Carcinoma Sequence
by Yoshihisa Tokumaru, Masanori Oshi, Ankit Patel, Wanqing Tian, Li Yan, Nobuhisa Matsuhashi, Manabu Futamura, Kazuhiro Yoshida and Kazuaki Takabe
Cells 2021, 10(3), 488; https://doi.org/10.3390/cells10030488 - 25 Feb 2021
Cited by 11 | Viewed by 3414
Abstract
The colon adenoma–carcinoma sequence is a multistep genomic-altering process that occurs during colorectal cancer (CRC) carcinogenesis. Organoids are now commonly used to model both non-cancerous and cancerous tissue. This study aims to investigate how well organoids mimic tissues in the adenoma–carcinoma sequence by [...] Read more.
The colon adenoma–carcinoma sequence is a multistep genomic-altering process that occurs during colorectal cancer (CRC) carcinogenesis. Organoids are now commonly used to model both non-cancerous and cancerous tissue. This study aims to investigate how well organoids mimic tissues in the adenoma–carcinoma sequence by comparing their transcriptomes. A total of 234 tissue samples (48 adenomas and 186 CRC) and 60 organoid samples (15 adenomas and 45 CRC) were analyzed. We found that cell-proliferation-related gene sets were consistently enriched in both CRC tissues and organoids compared to adenoma tissues and organoids by gene set enrichment analysis (GSEA). None of the known pathways in the colon adenoma–carcinoma sequence were consistently enriched in CRC organoids. There was no enrichment of the tumor microenvironment-related gene sets in CRC organoids. CRC tissues enriched immune-response-related gene sets, whereas CRC organoids did not. The proportions of infiltrating immune cells were different between tissues and organoids, whereas there was no difference between cancer and adenoma organoids. The amounts of cancer stem cells and progenitor cells were not different between CRC and adenoma organoids, whereas a difference was noted between CRC and adenoma tissues. In conclusion, we demonstrated that organoids model only part of the adenoma–carcinoma sequence and should be used with caution after considering their limitations. Full article
(This article belongs to the Special Issue Current Progress in Organ Regeneration: Cells, Organoids and Organs)
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12 pages, 1969 KiB  
Article
Establishment of Human Leukocyte Antigen-Mismatched Immune Responses after Transplantation of Human Liver Bud in Humanized Mouse Models
by Akihiro Mori, Soichiro Murata, Nao Tashiro, Tomomi Tadokoro, Satoshi Okamoto, Ryo Otsuka, Haruka Wada, Tomoki Murata, Takeshi Takahashi, Ken-ichiro Seino and Hideki Taniguchi
Cells 2021, 10(2), 476; https://doi.org/10.3390/cells10020476 - 23 Feb 2021
Cited by 7 | Viewed by 3196
Abstract
Humanized mouse models have contributed significantly to human immunology research. In transplant immunity, human immune cell responses to donor grafts have not been reproduced in a humanized animal model. To elicit human T-cell immune responses, we generated immune-compromised nonobese diabetic/Shi-scid, IL-2RγKO Jic (NOG) [...] Read more.
Humanized mouse models have contributed significantly to human immunology research. In transplant immunity, human immune cell responses to donor grafts have not been reproduced in a humanized animal model. To elicit human T-cell immune responses, we generated immune-compromised nonobese diabetic/Shi-scid, IL-2RγKO Jic (NOG) with a homozygous expression of human leukocyte antigen (HLA) class I heavy chain (NOG-HLA-A2Tg) mice. After the transplantation of HLA-A2 human hematopoietic stem cells into NOG-HLA-A2Tg, we succeeded in achieving alloimmune responses after the HLA-mismatched human-induced pluripotent stem cell (hiPSC)-derived liver-like tissue transplantation. This immune response was inhibited by administering tacrolimus. In this model, we reproduced allograft rejection after the human iPSC-derived liver-like tissue transplantation. Human tissue transplantation on the humanized mouse liver surface is a good model that can predict T-cell-mediated cellular rejection that may occur when organ transplantation is performed. Full article
(This article belongs to the Special Issue Current Progress in Organ Regeneration: Cells, Organoids and Organs)
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17 pages, 2973 KiB  
Article
EpCAM (CD326) Regulates Intestinal Epithelial Integrity and Stem Cells via Rho-Associated Kinase
by Takeshi Ouchi, Sohshi Morimura, Lukas E. Dow, Hiroyuki Miyoshi and Mark C. Udey
Cells 2021, 10(2), 256; https://doi.org/10.3390/cells10020256 - 28 Jan 2021
Cited by 9 | Viewed by 3721
Abstract
Humans with biallelic inactivating mutations in Epithelial Cell Adhesion Molecule (EpCAM) develop congenital tufting enteropathy (CTE). To gain mechanistic insights regarding EpCAM function in this disorder, we prepared intestinal epithelial cell (IEC) organoids and spheroids. IEC organoids and spheroids were generated from ROSA-Cre [...] Read more.
Humans with biallelic inactivating mutations in Epithelial Cell Adhesion Molecule (EpCAM) develop congenital tufting enteropathy (CTE). To gain mechanistic insights regarding EpCAM function in this disorder, we prepared intestinal epithelial cell (IEC) organoids and spheroids. IEC organoids and spheroids were generated from ROSA-CreERT2 EpCAMfl/fl mice. Proliferation, tight junctions, cell polarity and epithelial integrity were assessed in tamoxifen-induced EpCAM-deficient organoids via confocal immunofluorescence microscopy and Western blotting. Olfm4-expressing stem cells were assessed in IEC cells in vitro and in vivo via fluorescence in situ hybridization. To determine if existing drugs could ameliorate effects of EpCAM deficiency in IEC cells, a variety of pharmacologic inhibitors were screened. Deletion of EpCAM resulted in increased apoptosis and attenuated growth of organoids and spheroids. Selected claudins were destabilized and epithelial integrity was severely compromised. Epithelial integrity was improved by treatment with Rho-associated coiled-coil kinase (ROCK) inhibitors without restoration of claudin expression. Correspondingly, enhanced phosphorylation of myosin light chain, a serine/threonine ROCK substrate, was observed in EpCAM-deficient organoids. Strikingly, frequencies of Olfm4-expressing stem cells in EpCAM-deficient IEC cells in vitro and in vivo were decreased. Treatment with ROCK inhibitors increased numbers of stem cells in EpCAM-deficient organoids and spheroids. Thus, EpCAM regulates intestinal epithelial homeostasis via a signaling pathway that includes ROCK. Full article
(This article belongs to the Special Issue Current Progress in Organ Regeneration: Cells, Organoids and Organs)
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