The potential of small chemical functional groups for directing the differentiation of kidney stem cells

2010 ◽  
Vol 38 (4) ◽  
pp. 1062-1066 ◽  
Author(s):  
Patricia Murray ◽  
Krasimir Vasilev ◽  
Cristina Fuente Mora ◽  
Egon Ranghini ◽  
Hayeit Tensaout ◽  
...  
Keyword(s):  
Stem Cells ◽  
Kidney Disease ◽  
Functional Groups ◽  
Renal Cell ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Kidney Stem Cells ◽  
Small Chemical

In the future, stem-cell-based therapies could offer new approaches to treat kidney disease and reduce the incidence of ESRD (end-stage renal disease), but, as yet, research in this area is only being conducted in rodents and it is not clear whether or when it could be applied to human patients. Drug therapies, on the other hand, have been very effective at delaying the progression of kidney disease, but, for various reasons, current drug regimes are not suitable for all patients. A greater understanding of the molecular mechanisms that underlie disease progression in chronic kidney disease could help to identify novel drug targets. However, progress in this area is currently hindered due to the lack of appropriate in vitro culture systems for important renal cell types, such as proximal tubule cells and podocytes. This problem could be overcome if it were possible to direct the differentiation of kidney stem cells to renal cell types in vitro. In the present review, we highlight the potential of surface gradients of small chemical functional groups to direct the differentiation of kidney stem cells.

scholarly journals Aldehyde Dehydrogenases: Not Just Markers, but Functional Regulators of Stem Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Giuseppe Vassalli
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cellular Function ◽  
Stem Cell Marker ◽  
Cell Populations ◽  
Aldh Activity ◽  
Cellular Functions ◽  
Stem And Progenitor Cells

Aldehyde dehydrogenase (ALDH) is a superfamily of enzymes that detoxify a variety of endogenous and exogenous aldehydes and are required for the biosynthesis of retinoic acid (RA) and other molecular regulators of cellular function. Over the past decade, high ALDH activity has been increasingly used as a selectable marker for normal cell populations enriched in stem and progenitor cells, as well as for cell populations from cancer tissues enriched in tumor-initiating stem-like cells. Mounting evidence suggests that ALDH not only may be used as a marker for stem cells but also may well regulate cellular functions related to self-renewal, expansion, differentiation, and resistance to drugs and radiation. ALDH exerts its functional actions partly through RA biosynthesis, as all-trans RA reverses the functional effects of pharmacological inhibition or genetic suppression of ALDH activity in many cell types in vitro. There is substantial evidence to suggest that the role of ALDH as a stem cell marker comes down to the specific isoform(s) expressed in a particular tissue. Much emphasis has been placed on the ALDH1A1 and ALDH1A3 members of the ALDH1 family of cytosolic enzymes required for RA biosynthesis. ALDH1A1 and ALDH1A3 regulate cellular function in both normal stem cells and tumor-initiating stem-like cells, promoting tumor growth and resistance to drugs and radiation. An improved understanding of the molecular mechanisms by which ALDH regulates cellular function will likely open new avenues in many fields, especially in tissue regeneration and oncology.

scholarly journals Human pluripotent stem cells for the modelling and treatment of respiratory diseases

2021 ◽  
Vol 30 (161) ◽  
pp. 210042
Author(s):  
Pien A. Goldsteen ◽  
Christina Yoseif ◽  
Amalia M. Dolga ◽  
Reinoud Gosens
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
High Throughput Screening ◽  
Respiratory Diseases ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Human Pluripotent Stem Cells ◽  
Medical Need ◽  
New Chemical Entities

Respiratory diseases are among the leading causes of morbidity and mortality worldwide, representing a major unmet medical need. New chemical entities rarely make it into the clinic to treat respiratory diseases, which is partially due to a lack of adequate predictive disease models and the limited availability of human lung tissues to model respiratory disease. Human pluripotent stem cells (hPSCs) may help fill this gap by serving as a scalable human in vitro model. In addition, human in vitro models of rare genetic mutations can be generated using hPSCs. hPSC-derived epithelial cells and organoids have already shown great potential for the understanding of disease mechanisms, for finding new potential targets by using high-throughput screening platforms, and for personalised treatments. These potentials can also be applied to other hPSC-derived lung cell types in the future. In this review, we will discuss how hPSCs have brought, and may continue to bring, major changes to the field of respiratory diseases by understanding the molecular mechanisms of the pathology and by finding efficient therapeutics.

Neural Development by Transplanted Human Embryonal Carcinoma Stem Cells Expressing Green Fluorescent Protein

2005 ◽  
Vol 14 (6) ◽  
pp. 339-351 ◽  
Author(s):  
R. Stewart ◽  
M. Lako ◽  
G. M. Horrocks ◽  
S. A. Przyborski
Keyword(s):  
Stem Cells ◽  
Green Fluorescent Protein ◽  
Neural Development ◽  
Molecular Mechanisms ◽  
Embryonal Carcinoma ◽  
Fluorescent Protein ◽  
Cell Types ◽  
Green Fluorescent

For many years, researchers have investigated the fate and potential of neuroectodermal cells during the development of the central nervous system. Although several key factors that regulate neural differentiation have been identified, much remains unknown about the molecular mechanisms that control the fate and specification of neural subtypes, especially in humans. Human embryonal carcinoma (EC) stem cells are valuable research tools for the study of neural development; however, existing in vitro experiments are limited to inducing the differentiation of EC cells into only a handful of cell types. In this study, we developed and characterized a novel EC cell line (termed TERA2.cl.SP12-GFP) that carries the reporter molecule, green fluorescent protein (GFP). We demonstrate that TERA2.cl.SP12-GFP stem cells and their differentiated neural derivatives constitutively express GFP in cells grown both in vitro and in vivo. Cellular differentiation does not appear to be affected by insertion of the transgene. We propose that TERA2.cl.SP12-GFP cells provide a valuable research tool to track the fate of cells subsequent to transplantation into alternative environments and that this approach may be particularly useful to investigate the differentiation of human neural tissues in response to local environmental signals.

scholarly journals Kinases of the Focal Adhesion Complex Contribute to Cardiomyocyte Specification

2021 ◽  
Vol 22 (19) ◽  
pp. 10430
Author(s):  
Sacha Robert ◽  
Marcus Flowers ◽  
Brenda M. Ogle
Keyword(s):  
Stem Cells ◽  
Focal Adhesion ◽  
Pluripotent Stem Cells ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Culture Conditions ◽  
Model Systems ◽  
Critical Components

Differentiation of pluripotent stem cells to cardiomyocytes is influenced by culture conditions including the extracellular matrices or similar synthetic scaffolds on which they are grown. However, the molecular mechanisms that link the scaffold with differentiation outcomes are not fully known. Here, we determined by immunofluorescence staining and mass spectrometry approaches that extracellular matrix (ECM) engagement by mouse pluripotent stem cells activates critical components of canonical wingless/integrated (Wnt) signaling pathways via kinases of the focal adhesion to drive cardiomyogenesis. These kinases were found to be differentially activated depending on type of ECM engaged. These outcomes begin to explain how varied ECM composition of in vivo tissues with development and in vitro model systems gives rise to different mature cell types, having broad practical applicability for the design of engineered tissues.

scholarly journals Pathogenesis Study of Down Syndrome Prone to Leukemia Using iPSCs from Trisomy 21 Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5085-5085
Author(s):  
Hui Jin ◽  
Zijuan Wu ◽  
Handong Sun ◽  
Jianyong Li
Keyword(s):  
Stem Cells ◽  
Down Syndrome ◽  
Drug Targets ◽  
Erythroid Differentiation ◽  
Cell Types ◽  
Patient Specific ◽  
Potential Drug ◽  
Induced Pluripotent ◽  
Potential Drug Targets

Abstract Aims Down syndrome (DS) is the most frequent single cause of human birth defects and intellectual disability (ID). Its etiology has been known for over 50 years, DS is caused by trisomy of chromosome 21 (Ts21). In addition, there are more evidences in clinical show that patients of DS are also have high incidence of leukemia, but its underlying mechanisms have yet to be discovered. Elucidation of these mechanisms has been hindered by the difficulties in isolating and expanding enough hematopoietic stem cells (HSCs) from the patients. Circular RNAs (CircRNAs) are a novel type of endogenous noncoding RNAs that reported to play important roles in biological and pathological processes. Our present study aims to investigate the pathogenesis of Down Syndrome prone to leukemia using iPSCs from DS patients and the modulation mechansim of key target gene and circRNAs. Methods To overcome the limitation of clinical sample resources, we developed Ts21-induced pluripotent stem cells (iPSCs) from mononuclear cells using Episomal vectors which highly express Oct4,Sox2 and Klf4. Under certain conditions, these Ts-21 specific iPSCs could be further induced into any cell types, including HSCs. Next, we induced the patient-specific iPSCs differentiate into HSCs under serum free and feeder-free condition in vitro. By using flow cytometry, qRT-PCR and CFU assays, we have made well comparisons between HSCs derived from TS-21 iPSCs and control iPSCs, and expolre the pathological feature and mechanisms. By performing circRNA-seq analysis, we identified key circRNA and its host gene regulatory networks in DS with hematopoietic disorder. On the basis of that, we can further search for the potential drug targets that effective against leukemia of DS patients. Results We show here by gene sequencing, karyotyping and immunohistochemistry staining, the initial characterization of the patient-specific induced pluripotent stem are confirmed to be fully reprogrammed and they still carry the original mutation. These cells can be used for screening approaches and can be modified for loss- and gain-of-function strategies to identify pathways and test candidate mechanisms. We have observed that myeloid differentiation potential of HSCs derived from DS patients was significantly higher than normal patinets. DS-iPSCs exhibited a 2-4 fold increase in a population of CD43+/GPA+ hematopoietic cells, accompanied by increased multilineage colony-forming potential in CFU assays.During this process, has_circ_0082802 was significantly up-regulated. After knockdown of has_circ_0082802 using shRNAs, the erythroid differentiation level as well as cell proliferation were decreased. The potential modulation mechansim of them will be further explored. Conclusion We established the cellular models of DS patients and derived differentiation into different cell types in vitro, which has the similar function with patient HSCs. On the basis of that, we found has_circ_0082802 may play important role in erythroid differentiation. We can further search for the potential drug targets that effective against leukemia of DS patients. This approach would provide a powerful cell resource for clinical research and a useful model for the study of the mechanisms of DS-AML Disclosures No relevant conflicts of interest to declare.

scholarly journals MicroRNAs and Stem-like Properties: The Complex Regulation Underlying Stemness Maintenance and Cancer Development

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1074
Author(s):  
Giuseppina Divisato ◽  
Silvia Piscitelli ◽  
Mariantonietta Elia ◽  
Emanuela Cascone ◽  
Silvia Parisi
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Embryonic Stem ◽  
Cell Types ◽  
Cancer Development ◽  
Special Focus ◽  
Self Renewal ◽  
Mesenchymal Transition ◽  
Different Cell Types

Embryonic stem cells (ESCs) have the extraordinary properties to indefinitely proliferate and self-renew in culture to produce different cell progeny through differentiation. This latter process recapitulates embryonic development and requires rounds of the epithelial–mesenchymal transition (EMT). EMT is characterized by the loss of the epithelial features and the acquisition of the typical phenotype of the mesenchymal cells. In pathological conditions, EMT can confer stemness or stem-like phenotypes, playing a role in the tumorigenic process. Cancer stem cells (CSCs) represent a subpopulation, found in the tumor tissues, with stem-like properties such as uncontrolled proliferation, self-renewal, and ability to differentiate into different cell types. ESCs and CSCs share numerous features (pluripotency, self-renewal, expression of stemness genes, and acquisition of epithelial–mesenchymal features), and most of them are under the control of microRNAs (miRNAs). These small molecules have relevant roles during both embryogenesis and cancer development. The aim of this review was to recapitulate molecular mechanisms shared by ESCs and CSCs, with a special focus on the recently identified classes of microRNAs (noncanonical miRNAs, mirtrons, isomiRs, and competitive endogenous miRNAs) and their complex functions during embryogenesis and cancer development.

scholarly journals Stability of Imprinting and Differentiation Capacity in Naïve Human Cells Induced by Chemical Inhibition of CDK8 and CDK19

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 876
Author(s):  
Raquel Bernad ◽  
Cian J. Lynch ◽  
Rocio G. Urdinguio ◽  
Camille Stephan-Otto Attolini ◽  
Mario F. Fraga ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Primordial Germ Cell ◽  
Normal Karyotype ◽  
Cell Types ◽  
Dna Demethylation ◽  
Starting State ◽  
Teratoma Formation

Pluripotent stem cells can be stabilized in vitro at different developmental states by the use of specific chemicals and soluble factors. The naïve and primed states are the best characterized pluripotency states. Naïve pluripotent stem cells (PSCs) correspond to the early pre-implantation blastocyst and, in mice, constitute the optimal starting state for subsequent developmental applications. However, the stabilization of human naïve PSCs remains challenging because, after short-term culture, most current methods result in karyotypic abnormalities, aberrant DNA methylation patterns, loss of imprinting and severely compromised developmental potency. We have recently developed a novel method to induce and stabilize naïve human PSCs that consists in the simple addition of a chemical inhibitor for the closely related CDK8 and CDK19 kinases (CDK8/19i). Long-term cultured CDK8/19i-naïve human PSCs preserve their normal karyotype and do not show widespread DNA demethylation. Here, we investigate the long-term stability of allele-specific methylation at imprinted loci and the differentiation potency of CDK8/19i-naïve human PSCs. We report that long-term cultured CDK8/19i-naïve human PSCs retain the imprinting profile of their parental primed cells, and imprints are further retained upon differentiation in the context of teratoma formation. We have also tested the capacity of long-term cultured CDK8/19i-naïve human PSCs to differentiate into primordial germ cell (PGC)-like cells (PGCLCs) and trophoblast stem cells (TSCs), two cell types that are accessible from the naïve state. Interestingly, long-term cultured CDK8/19i-naïve human PSCs differentiated into PGCLCs with a similar efficiency to their primed counterparts. Also, long-term cultured CDK8/19i-naïve human PSCs were able to differentiate into TSCs, a transition that was not possible for primed PSCs. We conclude that inhibition of CDK8/19 stabilizes human PSCs in a functional naïve state that preserves imprinting and potency over long-term culture.

scholarly journals Expression Profile of New Marker Genes Involved in Differentiation of Canine Adipose-Derived Stem Cells into Osteoblasts

2021 ◽  
Vol 22 (13) ◽  
pp. 6663
Author(s):  
Maurycy Jankowski ◽  
Mariusz Kaczmarek ◽  
Grzegorz Wąsiatycz ◽  
Claudia Dompe ◽  
Paul Mozdziak ◽  
...  
Keyword(s):  
Stem Cells ◽  
In Vitro Culture ◽  
Osteogenic Differentiation ◽  
Molecular Mechanisms ◽  
Marker Genes ◽  
P Value ◽  
Illumina Platform

Next-generation sequencing (RNAseq) analysis of gene expression changes during the long-term in vitro culture and osteogenic differentiation of ASCs remains to be important, as the analysis provides important clues toward employing stem cells as a therapeutic intervention. In this study, the cells were isolated from adipose tissue obtained during routine surgical procedures and subjected to 14-day in vitro culture and differentiation. The mRNA transcript levels were evaluated using the Illumina platform, resulting in the detection of 19,856 gene transcripts. The most differentially expressed genes (fold change >|2|, adjusted p value < 0.05), between day 1, day 14 and differentiated cell cultures were extracted and subjected to bioinformatical analysis based on the R programming language. The results of this study provide molecular insight into the processes that occur during long-term in vitro culture and osteogenic differentiation of ASCs, allowing the re-evaluation of the roles of some genes in MSC progression towards a range of lineages. The results improve the knowledge of the molecular mechanisms associated with long-term in vitro culture and differentiation of ASCs, as well as providing a point of reference for potential in vivo and clinical studies regarding these cells’ application in regenerative medicine.

scholarly journals Utilising Induced Pluripotent Stem Cells in Neurodegenerative Disease Research: Focus on Glia

2021 ◽  
Vol 22 (9) ◽  
pp. 4334
Author(s):  
Katrina Albert ◽  
Jonna Niskanen ◽  
Sara Kälvälä ◽  
Šárka Lehtonen
Keyword(s):  
Stem Cells ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Induced Pluripotent Stem Cells ◽  
Glial Cells ◽  
Pluripotent Stem Cells ◽  
Cell Types ◽  
Human Ipscs ◽  
Induced Pluripotent

Induced pluripotent stem cells (iPSCs) are a self-renewable pool of cells derived from an organism’s somatic cells. These can then be programmed to other cell types, including neurons. Use of iPSCs in research has been two-fold as they have been used for human disease modelling as well as for the possibility to generate new therapies. Particularly in complex human diseases, such as neurodegenerative diseases, iPSCs can give advantages over traditional animal models in that they more accurately represent the human genome. Additionally, patient-derived cells can be modified using gene editing technology and further transplanted to the brain. Glial cells have recently become important avenues of research in the field of neurodegenerative diseases, for example, in Alzheimer’s disease and Parkinson’s disease. This review focuses on using glial cells (astrocytes, microglia, and oligodendrocytes) derived from human iPSCs in order to give a better understanding of how these cells contribute to neurodegenerative disease pathology. Using glia iPSCs in in vitro cell culture, cerebral organoids, and intracranial transplantation may give us future insight into both more accurate models and disease-modifying therapies.

scholarly journals First blood: the endothelial origins of hematopoietic progenitors

Angiogenesis ◽  
2021 ◽  
Author(s):  
Giovanni Canu ◽  
Christiana Ruhrberg
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Vascular Endothelial Cells ◽  
Fetal Liver ◽  
Cell Types ◽  
Yolk Sac ◽  
Vascular Endothelial ◽  
Hematopoietic Stem ◽  
Close Proximity ◽  
Clinical Interest

AbstractHematopoiesis in vertebrate embryos occurs in temporally and spatially overlapping waves in close proximity to blood vascular endothelial cells. Initially, yolk sac hematopoiesis produces primitive erythrocytes, megakaryocytes, and macrophages. Thereafter, sequential waves of definitive hematopoiesis arise from yolk sac and intraembryonic hemogenic endothelia through an endothelial-to-hematopoietic transition (EHT). During EHT, the endothelial and hematopoietic transcriptional programs are tightly co-regulated to orchestrate a shift in cell identity. In the yolk sac, EHT generates erythro-myeloid progenitors, which upon migration to the liver differentiate into fetal blood cells, including erythrocytes and tissue-resident macrophages. In the dorsal aorta, EHT produces hematopoietic stem cells, which engraft the fetal liver and then the bone marrow to sustain adult hematopoiesis. Recent studies have defined the relationship between the developing vascular and hematopoietic systems in animal models, including molecular mechanisms that drive the hemato-endothelial transcription program for EHT. Moreover, human pluripotent stem cells have enabled modeling of fetal human hematopoiesis and have begun to generate cell types of clinical interest for regenerative medicine.

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