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Cells
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Cellular Microenvironment, Cell Fate Determination and Organoid Modeling-from Somatic and...
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Cellular Microenvironment, Cell Fate Determination and Organoid Modeling-from Somatic and Pluripotent Stem Cells

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

Deadline for manuscript submissions: closed (25 November 2022) | Viewed by 27436

Special Issue Editors

Prof. Dr. Yun-Wen Zheng

E-Mail Website
Guest Editor
1. Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan
2. Department of Regenerative Medicine, School of Medicine, Yokohama City University, Yokohama, Kanagawa 234-0006, Japan
Interests: patient iPSCs; hepatic organoids; humanized liver model
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Yuyou Duan

E-Mail Website
Co-Guest Editor
School of Medicine, South China University of Technology, Guangzhou, China
Interests: stem cell; translational medicine
Dr. Li-Ping Liu

E-Mail Website
Co-Guest Editor
Institute for Regenerative Medicine, Jiangsu University, Zhenjiang 212001, Jiangsu, China
Interests: iPS cells of patients; melanocyte regeneration; amniotic epithelial cells; regenerative medicine

Special Issue Information

Dear Colleagues,

Stem cells, especially pluripotent stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have the capability of self-renewal and potential to differentiation into various types of cells. The cellular microenvironment such as soluble factors, cell-cell interactions, extracellular matrix proteins, and physical forces provides support and stimuli necessary to sustain their self-renewal, and it also influences the development of stem cells from quiescence through stages of differentiation. Meanwhile, there are involved different signaling pathways and various factors that regulate stem cell fate determination. Whether to sustain self-renew or to differentiate? What specific types of cells to generate? However, these questions are not clearly answered yet. In addition, stem cells-based organoid or/and disease modeling possess the self-organizing properties to create diverse multicellular structures. However, it is difficult to control the cell fate, and cell-cell/cell-matrix interactions within these systems. Furthermore, there are still issues unaddressed about the placiticity of differentiated cells into expandable ones using small molecules.

To improve the current knowledge in these fields, this special issue aims to mainly calls for papers about stem cells-based researches on multicellular microenvironment, cell fate determination, organoid formation, scalable and suspension cultural system and expandable induction as well as disease modeling involved in all types of tissue or organs such as liver, pancreas, gut, cardiac, brain and skin as well blood system.

We look forward to your contributions.

Prof. Dr. Yun-Wen Zheng
Guest Editor
Prof. Dr. Yuyou Duan
Dr. Li-Ping Liu
Co-Guest Editors

Manuscript Submission Information

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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.

Keywords

  • Embryonic stem cells (ESCs)
  • induced pluripotent stem cells (iPSCs)
  • Somatic stem cells
  • Organoids
  • Multicellular microenvironment
  • Small molecules
  • Cellular interaction
  • Plasticity
  • Expandable
  • Disease modeling

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Published Papers (7 papers)

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Research

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21 pages, 7455 KiB  
Article
C/EBPβ Coupled with E2F2 Promoted the Proliferation of hESC-Derived Hepatocytes through Direct Binding to the Promoter Regions of Cell-Cycle-Related Genes
by Shoupei Liu, Jue Wang, Sen Chen, Zonglin Han, Haibin Wu, Honglin Chen and Yuyou Duan
Cells 2023, 12(3), 497; https://doi.org/10.3390/cells12030497 - 2 Feb 2023
Viewed by 2271
Abstract
Human embryonic stem cells (hESCs) hold the potential to solve the problem of the shortage of functional hepatocytes in clinical applications and drug development. However, a large number of usable hepatocytes derived from hESCs cannot be effectively obtained due to the limited proliferation [...] Read more.
Human embryonic stem cells (hESCs) hold the potential to solve the problem of the shortage of functional hepatocytes in clinical applications and drug development. However, a large number of usable hepatocytes derived from hESCs cannot be effectively obtained due to the limited proliferation capacity. In this study, we found that enhancement of liver transcription factor C/EBPβ during hepatic differentiation could not only significantly promote the expression of hepatic genes, such as albumin, alpha fetoprotein, and alpha-1 antitrypsin, but also dramatically reinforce proliferation-related phenotypes, including increasing the expression of proliferative genes, such as CDC25C, CDC45L, and PCNA, and the activation of cell cycle and DNA replication pathways. In addition, the analysis of CUT&Tag sequencing further revealed that C/EBPβ is directly bound to the promoter region of proliferating genes to promote cell proliferation; this interaction between C/EBPβ and DNA sequences of the promoters was verified by luciferase assay. On the contrary, the knockdown of C/EBPβ could significantly inhibit the expression of the aforementioned proliferative genes. RNA transcriptome analysis and GSEA enrichment indicated that the E2F family was enriched, and the expression of E2F2 was changed with the overexpression or knockdown of C/EBPβ. Moreover, the results of CUT&Tag sequencing showed that C/EBPβ also directly bound the promoter of E2F2, regulating E2F2 expression. Interestingly, Co-IP analysis exhibited a direct binding between C/EBPβ and E2F2 proteins, and this interaction between these two proteins was also verified in the LO2 cell line, a hepatic progenitor cell line. Thus, our results demonstrated that C/EBPβ first initiated E2F2 expression and then coupled with E2F2 to regulate the expression of proliferative genes in hepatocytes during the differentiation of hESCs. Therefore, our findings open a new avenue to provide an in vitro efficient approach to generate proliferative hepatocytes to potentially meet the demands for use in cell-based therapeutics as well as for pharmaceutical and toxicological studies. Full article
(This article belongs to the Special Issue Cellular Microenvironment, Cell Fate Determination and Organoid Modeling-from Somatic and Pluripotent Stem Cells)
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17 pages, 4449 KiB  
Article
Multiomics Analysis of a DNAH5-Mutated PCD Organoid Model Revealed the Key Role of the TGF-β/BMP and Notch Pathways in Epithelial Differentiation and the Immune Response in DNAH5-Mutated Patients
by Wenhao Yang, Lina Chen, Juncen Guo, Fang Shi, Qingxin Yang, Liang Xie, Danli Lu, Yingna Li, Jiaxin Luo, Li Wang, Li Qiu, Ting Chen, Yan Li, Rui Zhang, Lu Chen, Wenming Xu and Hanmin Liu
Cells 2022, 11(24), 4013; https://doi.org/10.3390/cells11244013 - 12 Dec 2022
Cited by 5 | Viewed by 3005
Abstract
Dynein axonemal heavy chain 5 (DNAH5) is the most mutated gene in primary ciliary dyskinesia (PCD), leading to abnormal cilia ultrastructure and function. Few studies have revealed the genetic characteristics and pathogenetic mechanisms of PCD caused by DNAH5 mutation. Here, we established a [...] Read more.
Dynein axonemal heavy chain 5 (DNAH5) is the most mutated gene in primary ciliary dyskinesia (PCD), leading to abnormal cilia ultrastructure and function. Few studies have revealed the genetic characteristics and pathogenetic mechanisms of PCD caused by DNAH5 mutation. Here, we established a child PCD airway organoid directly from the bronchoscopic biopsy of a patient with the DNAH5 mutation. The motile cilia in the organoid were observed and could be stably maintained for an extended time. We further found abnormal ciliary function and a decreased immune response caused by the DNAH5 mutation through single-cell RNA sequencing (scRNA-Seq) and proteomic analyses. Additionally, the directed induction of the ciliated cells, regulated by TGF-β/BMP and the Notch pathway, also increased the expression of inflammatory cytokines. Taken together, these results demonstrated that the combination of multiomics analysis and organoid modelling could reveal the close connection between the immune response and the DNAH5 gene. Full article
(This article belongs to the Special Issue Cellular Microenvironment, Cell Fate Determination and Organoid Modeling-from Somatic and Pluripotent Stem Cells)
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17 pages, 6945 KiB  
Article
Polymerized Laminin-521: A Feasible Substrate for Expanding Induced Pluripotent Stem Cells at a Low Protein Concentration
by Fernanda C. P. Mesquita, Eliel S. Leite, Jacquelynn Morrissey, Catarina Freitas, Tatiana Coelho-Sampaio and Camila Hochman-Mendez
Cells 2022, 11(24), 3955; https://doi.org/10.3390/cells11243955 - 7 Dec 2022
Cited by 2 | Viewed by 2745
Abstract
Laminins (LNs) play a central role in the self-assembly and maintenance of basement membranes and are involved in critical interactions between cells and other extracellular matrix (ECM) proteins. Among the defined, xeno-free ECM culture matrices, LNs—namely LN521—have emerged as promising coating systems for [...] Read more.
Laminins (LNs) play a central role in the self-assembly and maintenance of basement membranes and are involved in critical interactions between cells and other extracellular matrix (ECM) proteins. Among the defined, xeno-free ECM culture matrices, LNs—namely LN521—have emerged as promising coating systems for the large-scale expansion of induced pluripotent stem cells (iPSCs). The biologic activity of LNs is enhanced by their acidification-induced self-polymerization into a cell-associated network called polylaminin (polyLN), which can recapitulate the native-like polymeric array in a cell-free system. Here, we show for the first time to our knowledge that polyLN521 displays a native-like hexagonal-like structure and that, at basal and low concentrations, it permits the large-scale expansion of human iPSCs. Human iPSCs expanded with polyLN521 maintained the pluripotent state and showed no impairment of karyotype stability or telomere length. These results suggest that low-concentration polyLN521 is a stable and cost-effective coating for large-scale iPSC expansion. Full article
(This article belongs to the Special Issue Cellular Microenvironment, Cell Fate Determination and Organoid Modeling-from Somatic and Pluripotent Stem Cells)
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16 pages, 4170 KiB  
Article
Modeling MEN1 with Patient-Origin iPSCs Reveals GLP-1R Mediated Hypersecretion of Insulin
by Ziqi Cheng, Dongsheng Guo, Aynisahan Ruzi, Tingcai Pan, Kai You, Yan Chen, Xinping Huang, Jiaye Zhang, Fan Yang, Lizhi Niu, Kecheng Xu and Yin-Xiong Li
Cells 2022, 11(15), 2387; https://doi.org/10.3390/cells11152387 - 3 Aug 2022
Cited by 2 | Viewed by 3482
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is an inherited disease caused by mutations in the MEN1 gene encoding a nuclear protein menin. Among those different endocrine tumors of MEN1, the pancreatic neuroendocrine tumors (PNETs) are life-threatening and frequently implicated. Since there are uncertainties [...] Read more.
Multiple endocrine neoplasia type 1 (MEN1) is an inherited disease caused by mutations in the MEN1 gene encoding a nuclear protein menin. Among those different endocrine tumors of MEN1, the pancreatic neuroendocrine tumors (PNETs) are life-threatening and frequently implicated. Since there are uncertainties in genotype and phenotype relationship and there are species differences between humans and mice, it is worth it to replenish the mice model with human cell resources. Here, we tested whether the patient-origin induced pluripotent stem cell (iPSC) lines could phenocopy some defects of MEN1. In vitro β-cell differentiation revealed that the percentage of insulin-positive cells and insulin secretion were increased by at least two-fold in MEN1-iPSC derived cells, which was mainly resulted from significantly higher proliferative activities in the pancreatic progenitor stage (Day 7–13). This scenario was paralleled with increased expressions of prohormone convertase1/3 (PC1/3), glucagon-like peptide-1 (GLP-1), GLP-1R, and factors in the phosphatidylinositol 3-kinase (PI3K)/AKT signal pathway, and the GLP-1R was mainly expressed in β-like cells. Blockages of either GLP-1R or PI3K significantly reduced the percentages of insulin-positive cells and hypersecretion of insulin in MEN1-derived cells. Furthermore, in transplantation of different stages of MEN1-derived cells into immune-deficient mice, only those β-like cells produced tumors that mimicked the features of the PNETs from the original patient. To the best of our knowledge, this was the first case using patient-origin iPSCs modeling most phenotypes of MEN1, and the results suggested that GLP-1R may be a potential therapeutic target for MEN1-related hyperinsulinemia. Full article
(This article belongs to the Special Issue Cellular Microenvironment, Cell Fate Determination and Organoid Modeling-from Somatic and Pluripotent Stem Cells)
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17 pages, 7108 KiB  
Article
Transcriptomic and Functional Evidence Show Similarities between Human Amniotic Epithelial Stem Cells and Keratinocytes
by Li-Ping Liu, Dong-Xu Zheng, Zheng-Fang Xu, Hu-Cheng Zhou, Yun-Cong Wang, Hang Zhou, Jian-Yun Ge, Daisuke Sako, Mi Li, Kazunori Akimoto, Yu-Mei Li and Yun-Wen Zheng
Cells 2022, 11(1), 70; https://doi.org/10.3390/cells11010070 - 27 Dec 2021
Cited by 3 | Viewed by 5017
Abstract
Amniotic epithelial stem cells (AESCs) are considered as potential alternatives to keratinocytes (KCs) in tissue-engineered skin substitutes used for treating skin damage. However, their clinical application is limited since similarities and distinctions between AESCs and KCs remain unclear. Herein, a transcriptomics analysis and [...] Read more.
Amniotic epithelial stem cells (AESCs) are considered as potential alternatives to keratinocytes (KCs) in tissue-engineered skin substitutes used for treating skin damage. However, their clinical application is limited since similarities and distinctions between AESCs and KCs remain unclear. Herein, a transcriptomics analysis and functional evaluation were used to understand the commonalities and differences between AESCs and KCs. RNA-sequencing revealed that AESCs are involved in multiple epidermis-associated biological processes shared by KCs and show more similarity to early stage immature KCs than to adult KCs. However, AESCs were observed to be heterogeneous, and some possessed hybrid mesenchymal and epithelial features distinct from KCs. A functional evaluation revealed that AESCs can phagocytose melanosomes transported by melanocytes in both 2D and 3D co-culture systems similar to KCs, which may help reconstitute pigmented skin. The overexpression of TP63 and activation of NOTCH signaling could promote AESC stemness and improve their differentiation features, respectively, bridging the gap between AESCs and KCs. These changes induced the convergence of AESC cell fate with KCs. In future, modified reprogramming strategies, such as the use of small molecules, may facilitate the further modulation human AESCs for use in skin regeneration. Full article
(This article belongs to the Special Issue Cellular Microenvironment, Cell Fate Determination and Organoid Modeling-from Somatic and Pluripotent Stem Cells)
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Review

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27 pages, 1164 KiB  
Review
Recognition of Melanocytes in Immuno-Neuroendocrinology and Circadian Rhythms: Beyond the Conventional Melanin Synthesis
by Yan-Yan Chen, Li-Ping Liu, Hang Zhou, Yun-Wen Zheng and Yu-Mei Li
Cells 2022, 11(13), 2082; https://doi.org/10.3390/cells11132082 - 30 Jun 2022
Cited by 12 | Viewed by 5846
Abstract
Melanocytes produce melanin to protect the skin from UV-B radiation. Notwithstanding, the spectrum of their functions extends far beyond their well-known role as melanin production factories. Melanocytes have been considered as sensory and computational cells. The neurotransmitters, neuropeptides, and other hormones produced by [...] Read more.
Melanocytes produce melanin to protect the skin from UV-B radiation. Notwithstanding, the spectrum of their functions extends far beyond their well-known role as melanin production factories. Melanocytes have been considered as sensory and computational cells. The neurotransmitters, neuropeptides, and other hormones produced by melanocytes make them part of the skin’s well-orchestrated and complex neuroendocrine network, counteracting environmental stressors. Melanocytes can also actively mediate the epidermal immune response. Melanocytes are equipped with ectopic sensory systems similar to the eye and nose and can sense light and odor. The ubiquitous inner circadian rhythm controls the body’s basic physiological processes. Light not only affects skin photoaging, but also regulates inner circadian rhythms and communicates with the local neuroendocrine system. Do melanocytes “see” light and play a unique role in photoentrainment of the local circadian clock system? Why, then, are melanocytes responsible for so many mysterious functions? Do these complex functional devices work to maintain homeostasis locally and throughout the body? In addition, melanocytes have also been shown to be localized in internal sites such as the inner ear, brain, and heart, locations not stimulated by sunlight. Thus, what can the observation of extracutaneous melanocytes tell us about the “secret identity” of melanocytes? While the answers to some of these intriguing questions remain to be discovered, here we summarize and weave a thread around available data to explore the established and potential roles of melanocytes in the biological communication of skin and systemic homeostasis, and elaborate on important open issues and propose ways forward. Full article
(This article belongs to the Special Issue Cellular Microenvironment, Cell Fate Determination and Organoid Modeling-from Somatic and Pluripotent Stem Cells)
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12 pages, 284 KiB  
Review
Improving Cardiac Reprogramming for Heart Regeneration in Translational Medicine
by Liu Liu, Yijing Guo, Zhaokai Li and Zhong Wang
Cells 2021, 10(12), 3297; https://doi.org/10.3390/cells10123297 - 25 Nov 2021
Cited by 3 | Viewed by 3675
Abstract
Direct reprogramming of fibroblasts into CM-like cells has emerged as an attractive strategy to generate induced CMs (iCMs) in heart regeneration. However, low conversion rate, poor purity, and the lack of precise conversion of iCMs are still present as significant challenges. In this [...] Read more.
Direct reprogramming of fibroblasts into CM-like cells has emerged as an attractive strategy to generate induced CMs (iCMs) in heart regeneration. However, low conversion rate, poor purity, and the lack of precise conversion of iCMs are still present as significant challenges. In this review, we summarize the recent development in understanding the molecular mechanisms of cardiac reprogramming with various strategies to achieve more efficient iCMs. reprogramming. Specifically, we focus on the identified critical roles of transcriptional regulation, epigenetic modification, signaling pathways from the cellular microenvironment, and cell cycling regulation in cardiac reprogramming. We also discuss the progress in delivery system optimization and cardiac reprogramming in human cells related to preclinical applications. We anticipate that this will translate cardiac reprogramming-based heart therapy into clinical applications. In addition to optimizing the cardiogenesis related transcriptional regulation and signaling pathways, an important strategy is to modulate the pathological microenvironment associated with heart injury, including inflammation, pro-fibrotic signaling pathways, and the mechanical properties of the damaged myocardium. We are optimistic that cardiac reprogramming will provide a powerful therapy in heart regenerative medicine. Full article
(This article belongs to the Special Issue Cellular Microenvironment, Cell Fate Determination and Organoid Modeling-from Somatic and Pluripotent Stem Cells)
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