Role of Tumor Associated Fibroblasts in Human Liver Regeneration, Cirrhosis, and Cancer

Tumor associated fibroblasts (TAFs) are considered a microenvironmental element critical for tumor growth and progression. Experimental studies suggest that their origin could be from mesenchymal stem cells (MSCs) derived from the bone marrow. However, the role played by TAFs in cirrhosis, hepatocellular carcinoma development, and progression is largely unknown, andin vitrohuman models are missing. This paper for the first time demonstrates that (1) human neoplastic livers possess a population of multipotent adult stem cells (MASCs) with properties of TAFs; (2) a population of MASC-derived TAFs is already present in cirrhotic, not yet neoplastic, livers; (3) MASCs isolated from nonneoplastic and noncirrhotic liver scan acquire a TAF phenotype when grown in a medium conditioned by tumor cell lines, supporting the notion that TAF could originate from resident primitive cells (MASCs), possibly through a paracrine mechanism.

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YAP regulates porcine skin-derived stem cells self-renewal partly by repressing Wnt/β-catenin signaling pathway

10.21203/rs.3.rs-414853/v1 ◽

2021 ◽

Author(s):

Hong-Chen Yan ◽

Yu Sun ◽

Ming-Yu Zhang ◽

Shu-Er Zhang ◽

Jia-Dong Sun ◽

...

Keyword(s):

Stem Cells ◽

Signaling Pathway ◽

Adult Stem Cells ◽

Self Renewal ◽

Human Ascs ◽

Regulation Mechanisms ◽

Interfering Rna ◽

Pluripotency Genes

Abstract Background Skin-derived stem cells (SDSCs) are a class of adult stem cells (ASCs) that have the ability to self-renew and differentiate. The regulation mechanisms involved in the differentiation of ASCs is a hot topic. Porcine models have close similarities to humans and porcine SDSCs (pSDSCs) offer an ideal in vitro model to investigate human ASCs. To date, studies concerning the role of yes-associated protein (YAP) in ASCs are limited, and the mechanism of its influence on self-renewal and differentiation of ASCs remain unclear. In this paper, we explore the link between the transcriptional regulator YAP and the fate of pSDSCs. Results We found that YAP promotes the pluripotent state of pSDSCs by maintaining the high expression of the pluripotency genes Sox2, Oct4. The overexpression of YAP prevented the differentiation of pSDSCs and the depletion of YAP by small interfering RNA (siRNAs) suppressed the self-renewal of pSDSCs. In addition, we found that YAP regulates the fate of pSDSCs through a mechanism related to the Wnt/β-catenin signaling pathway. When an activator of the Wnt/β-catenin signaling pathway, CHIR99021, was added to pSDSCs overexpressing YAP the ability of pSDSCs to differentiate was partially restored. Conversely, when XAV939 an inhibitor of Wnt/β-catenin signaling pathway, was added to YAP knockdown pSDSCs a higher self-renewal ability resulted. Conclusions our results suggested that, YAP and the Wnt/β-catenin signaling pathway interact to regulate the fate of pSDSCs.

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Transcriptomic Analysis of mRNA-lncRNA-miRNA Interactions in Hepatocellular Carcinoma

Scientific Reports ◽

10.1038/s41598-019-52559-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 14

Author(s):

Xia Tang ◽

Delong Feng ◽

Min Li ◽

Jinxue Zhou ◽

Xiaoyuan Li ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Rna Seq ◽

Pairwise Interactions ◽

Micro Rnas ◽

Non Coding Rnas ◽

First Time

Abstract Fully elucidating the molecular mechanisms of non-coding RNAs (ncRNAs), including micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs), underlying hepatocarcinogenesis is challenging. We characterized the expression profiles of ncRNAs and constructed a regulatory mRNA-lncRNA-miRNA (MLMI) network based on transcriptome sequencing (RNA-seq) of hepatocellular carcinoma (HCC, n = 9) patients. Of the identified miRNAs (n = 203) and lncRNAs (n = 1,090), we found 16 significantly differentially expressed (DE) miRNAs and three DE lncRNAs. The DE RNAs were highly enriched in 21 functional pathways implicated in HCC (p < 0.05), including p53, MAPK, and NAFLD signaling. Potential pairwise interactions between DE ncRNAs and mRNAs were fully characterized using in silico prediction and experimentally-validated evidence. We for the first time constructed a MLMI network of reciprocal interactions for 16 miRNAs, three lncRNAs, and 253 mRNAs in HCC. The predominant role of MEG3 in the MLMI network was validated by its overexpression in vitro that the expression levels of a proportion of MEG3-targeted miRNAs and mRNAs was changed significantly. Our results suggested that the comprehensive MLMI network synergistically modulated carcinogenesis, and the crosstalk of the network provides a new avenue to accurately describe the molecular mechanisms of hepatocarcinogenesis.

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Characterization of the secretory profile and exosomes of limbal stem cells in the canine species

PLoS ONE ◽

10.1371/journal.pone.0244327 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0244327

Author(s):

Antonio J. Villatoro ◽

Cristina Alcoholado ◽

María del Carmen Martín-Astorga ◽

Gustavo Rico ◽

Viviana Fernández ◽

...

Keyword(s):

Stem Cells ◽

Ocular Surface ◽

Inhibitory Effect ◽

Proteomic Profile ◽

Limbal Stem Cells ◽

High Concentrations ◽

First Time

Limbal stem cells (LSCs) are a quiescent cell population responsible for the renewal of the corneal epithelium. Their deficiency is responsible for the conjunctivization of the cornea that is seen in different ocular pathologies, both in humans and in the canine species. The canine species represents an interesting preclinical animal model in ocular surface pathologies. However, the role of LSCs in physiological and pathological conditions in canine species is not well understood. Our objective was to characterize for the first time the soluble factors and the proteomic profile of the secretome and exosomes of canine LSCs (cLSCs). In addition, given the important role that fibroblasts play in the repair of the ocular surface, we evaluated the influence of the secretome and exosomes of cLSCs on their proliferation in vitro. Our results demonstrated a secretory profile of cLSCs with high concentrations of MCP-1, IL-8, VEGF-A, and IL-10, as well as significant production of exosomes. Regarding the proteomic profile, 646 total proteins in the secretome and 356 in exosomes were involved in different biological processes. Functionally, the cLSC secretome showed an inhibitory effect on the proliferation of fibroblasts in vitro, which the exosomes did not. These results open the door to new studies on the possible use of the cLSC secretome or some of its components to treat certain pathologies of the ocular surface in canine species.

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LIVER-SPECIFIC STEM CELLS AND HEPATOCELLULAR CARCINOMA: AN IN VITRO COMPARISON BETWEEN STEM CELLS ISOLATED FROM MALIGNANT AND NON- MALIGNANT HUMAN LIVER TISSUE.

Journal of the Medical Research Institute ◽

10.21608/jmalexu.2016.109028 ◽

2016 ◽

Vol 37 (2) ◽

pp. 50-57

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cells ◽

Liver Tissue ◽

Human Liver ◽

Human Liver Tissue ◽

In Vitro Comparison

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Activation of Tyrosine Metabolism in CD13+ Cancer Stem Cells Drives Relapse in Hepatocellular Carcinoma

Cancer Research and Treatment ◽

10.4143/crt.2019.444 ◽

2020 ◽

Vol 52 (2) ◽

pp. 604-621 ◽

Cited By ~ 4

Author(s):

Li Sun ◽

Lin Zhang ◽

Jun Chen ◽

Chaoqun Li ◽

Hongqin Sun ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cells ◽

Metabolic Pathways ◽

Isotope Labeling ◽

Chemotherapeutic Agents ◽

Protein Levels ◽

Huh7 Cells ◽

Tyrosine Metabolism

PurposeCancer stem cells (CSCs) are naturally resistant to chemotherapy, explaining why tumor relapse frequently occurs after initial regression upon administration of chemotherapeutic agents in most cases. A CSC population characterized by CD13 expression has been identified in hepatocellular carcinoma (HCC). In the current study, we aimed to clarify the molecular mechanism by which it escapes conventional therapies. Materials and MethodsHere, we used flow cytometry to examine the percentage of CD13+ CSCs in HepG2 and HuH7 cells after chemotherapy. Using in vitro isotope labeling technique, we compared metabolic pathways between CD13+ and CD13– subpopulations. Using co-immunoprecipitation and western blotting, we determined the target expressions in protein levels under different conditions. We also performed immunohistochemistry to detect the target proteins under different conditions. Animal models were constructed to verify the potential role of tyrosine metabolism in post-chemotherapeutic relapse in vivo.ResultsWe observed that quiescent CD13+ CSCs are enriched after chemotherapy in HCCs, and serve as a reservoir for recurrence. Mechanistically, CD13+ CSCs were dependent on aerobic metabolism of tyrosine rather than glucose as energy source. Tyrosine metabolism also generated nuclear acetyl-CoA to acetylate and stabilize Foxd3, thereby allowing CD13+ CSCs cells to sustain quiescence and resistance to chemotherapeutic agents.ConclusionThese findings encourage further exploration of eliminating CD13+ cells by targeting specific metabolic pathways to prevent recurrence in HCCs.

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MAPK p38alpha Kinase Influences Haematopoiesis in Embryonic Stem Cells

Stem Cells International ◽

10.1155/2019/5128135 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Kateřina Štefková ◽

Markéta Hanáčková ◽

Jan Kučera ◽

Katarzyna Anna Radaszkiewicz ◽

Barbora Ambrůžová ◽

...

Keyword(s):

Stem Cells ◽

Embryonic Stem Cells ◽

Embryonic Stem ◽

Wild Type ◽

Colony Forming Unit ◽

Haematopoietic Cells ◽

Colony Forming Units ◽

First Time

The activation of p38alpha kinase mediates cell response to various extracellular factors including many interleukins and growth factors important for haematopoiesis. The role of p38alpha kinase was previously analysed in particular haematopoietic cells. In this study and for the first time, the role of p38alpha kinase in haematopoiesis was studied using a model of continuous haematopoietic development in pluripotent embryonic stem cellsin vitro. The expression of transcripts associated with haematopoiesis and the potential for the formation of specific haematopoietic cell colonies were compared between wild-type and mutant p38alpha gene-depleted cells. The absence of p38alpha kinase led to the inhibition of hemangioblast formation during the first step of haematopoiesis. Later, during differentiation, due to the lack of p38alpha kinase, erythrocyte maturation was impaired. Mutant p38α−/−cells also exhibited decreased potential with respect to the expansion of granulocyte colony-forming units. This effect was reversed in the absence of erythropoietin as shown by colony-forming unit assay in media for colony-forming unit granulocytes/macrophages. p38alpha kinase thus plays an important role in the differentiation of common myeloid precursor cells into granulocyte lineages.

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Stem-cell treatment in disc degeneration: What is the evidence?

Coluna/Columna ◽

10.1590/s1808-18512013000100013 ◽

2013 ◽

Vol 12 (1) ◽

pp. 61-63

Author(s):

Manuela Peletti-Figueiró ◽

Pedro Guarise da Silva ◽

Olívia Egger de Souza ◽

Ana Paula Lambert ◽

Denise Cantarelli Machado ◽

...

Keyword(s):

Stem Cells ◽

Degenerative Disc Disease ◽

Clinical Studies ◽

Potential Role ◽

Experimental Studies ◽

Disc Disease ◽

Degenerative Disc ◽

Stem Cell Treatment

To review the potential role of stem cells in treating degenerative disc disease of the intervertebral disc (IVD). A review was performed of articles from the Medline database concerning stem cells and degenerative disc disease (DDD). To discuss the data, the papers were classified as: review, in vitro, experimental, and clinical. The currently available treatments were basically for symptom reduction, not to revert the IVD degenerative process. The use of mesenchymal stem cells (MSC) is being proposed as an option of treatment for DDD. In vitro studies have shown that the MSC are able to differentiate into NP cells and that the MSC also reduce the inflammatory levels of the degenerated IVD. Besides, experimental studies demonstrated that the MSC remained viable when injected into the IVD, and that they were able to regenerate partially from the degenerated IVD and its structure. The few clinical studies found in the literature presented diverging results. The use of MSC is being widely studied and shows promising results for the treatment of DDD. Although many advances are being achieved in studies in vitro and experimental, there is a lack of clinical studies to prove the role of MSC in DDD management.

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The role of physical cues in the development of stem cell-derived organoids

European Biophysics Journal ◽

10.1007/s00249-021-01551-3 ◽

2021 ◽

Author(s):

Ilaria Tortorella ◽

Chiara Argentati ◽

Carla Emiliani ◽

Sabata Martino ◽

Francesco Morena

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Adult Stem Cells ◽

Three Dimensional ◽

Bioactive Molecules ◽

Cell Specification ◽

Cell Niche ◽

Structure Complexity

AbstractOrganoids are a novel three-dimensional stem cells’ culture system that allows the in vitro recapitulation of organs/tissues structure complexity. Pluripotent and adult stem cells are included in a peculiar microenvironment consisting of a supporting structure (an extracellular matrix (ECM)-like component) and a cocktail of soluble bioactive molecules that, together, mimic the stem cell niche organization. It is noteworthy that the balance of all microenvironmental components is the most critical step for obtaining the successful development of an accurate organoid instead of an organoid with heterogeneous morphology, size, and cellular composition. Within this system, mechanical forces exerted on stem cells are collected by cellular proteins and transduced via mechanosensing—mechanotransduction mechanisms in biochemical signaling that dictate the stem cell specification process toward the formation of organoids. This review discusses the role of the environment in organoids formation and focuses on the effect of physical components on the developmental system. The work starts with a biological description of organoids and continues with the relevance of physical forces in the organoid environment formation. In this context, the methods used to generate organoids and some relevant published reports are discussed as examples showing the key role of mechanosensing–mechanotransduction mechanisms in stem cell-derived organoids.

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