Skin Cyst: A Pathological Dead-End With a New Twist of Morphogenetic Potentials in Organoid Cultures

A cyst is a closed sac-like structure in which cyst walls wrap certain contents typically including air, fluid, lipid, mucous, or keratin. Cyst cells can retain multipotency to regenerate complex tissue architectures, or to differentiate. Cysts can form in and outside the skin due to genetic problems, errors in embryonic development, cellular defects, chronic inflammation, infections, blockages of ducts, parasites, and injuries. Multiple types of skin cysts have been identified with different cellular origins, with a common structure including the outside cyst wall engulfs differentiated suprabasal layers and keratins. The skin cyst is usually used as a sign in pathological diagnosis. Large or surfaced skin cysts affect patients’ appearance and may cause the dysfunction or accompanying diseases of adjacent tissues. Skin cysts form as a result of the degradation of skin epithelium and appendages, retaining certain characteristics of multipotency. Surprisingly, recent organoid cultures show the formation of cyst configuration as a transient state toward more morphogenetic possibility. These results suggest, if we can learn more about the molecular circuits controlling upstream and downstream cellular events in cyst formation, we may be able to engineer stem cell cultures toward the phenotypes we wish to achieve. For pathological conditions in patients, we speculate it may also be possible to guide the cyst to differentiate or de-differentiate to generate structures more akin to normal architecture and compatible with skin homeostasis.

Download Full-text

The Role of Ubiquitination in Regulating Embryonic Stem Cell Maintenance and Cancer Development

International Journal of Molecular Sciences ◽

10.3390/ijms20112667 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2667 ◽

Cited By ~ 1

Author(s):

Dian Wang ◽

Fan Bu ◽

Weiwei Zhang

Keyword(s):

Stem Cell ◽

Embryonic Stem Cell ◽

Cancer Biology ◽

Embryonic Stem ◽

Developmental Defects ◽

Stem Cell Maintenance ◽

Substrate Protein ◽

Cellular Events ◽

Ubiquitin Conjugating Enzymes ◽

Cell Maintenance

Ubiquitination regulates nearly every aspect of cellular events in eukaryotes. It modifies intracellular proteins with 76-amino acid polypeptide ubiquitin (Ub) and destines them for proteolysis or activity alteration. Ubiquitination is generally achieved by a tri-enzyme machinery involving ubiquitin activating enzymes (E1), ubiquitin conjugating enzymes (E2) and ubiquitin ligases (E3). E1 activates Ub and transfers it to the active cysteine site of E2 via a transesterification reaction. E3 coordinates with E2 to mediate isopeptide bond formation between Ub and substrate protein. The E1-E2-E3 cascade can create diverse types of Ub modifications, hence effecting distinct outcomes on the substrate proteins. Dysregulation of ubiquitination results in severe consequences and human diseases. There include cancers, developmental defects and immune disorders. In this review, we provide an overview of the ubiquitination machinery and discuss the recent progresses in the ubiquitination-mediated regulation of embryonic stem cell maintenance and cancer biology.

Download Full-text

The actin-binding protein profilin is required for germline stem cell maintenance and germ cell enclosure by somatic cyst cells

Development ◽

10.1242/dev.101931 ◽

2013 ◽

Vol 141 (1) ◽

pp. 73-82 ◽

Cited By ~ 24

Author(s):

A. R. Shields ◽

A. C. Spence ◽

Y. M. Yamashita ◽

E. L. Davies ◽

M. T. Fuller

Keyword(s):

Stem Cell ◽

Germ Cell ◽

Binding Protein ◽

Actin Binding ◽

Germline Stem Cell ◽

Actin Binding Protein ◽

Stem Cell Maintenance ◽

Cyst Cells ◽

Cell Maintenance

Download Full-text

Mitochondrial uncoupling protein 2 (UCP2), but not UCP3, is sensitive to oxygen concentration in cells

10.1101/2020.07.01.181768 ◽

2020 ◽

Author(s):

Karolina E. Hilse ◽

Anne Rupprecht ◽

Kristopher Ford ◽

Olena Andrukhova ◽

Reinhold Erben ◽

...

Keyword(s):

Stem Cell ◽

Oxygen Concentration ◽

Uncoupling Protein ◽

Ischemia Reperfusion ◽

Stem Cell Differentiation ◽

Embryonic Stem Cell Differentiation ◽

Mitochondrial Uncoupling ◽

Homologous Proteins ◽

Mitochondrial Uncoupling Protein ◽

Pathological Conditions

AbstractOne of the important hallmarks of cardiovascular disease is mitochondrial dysfunction, which results in abnormal energy metabolism and increased ROS production in cardiomyocytes. Members of the mitochondrial uncoupling protein family, UCP2 and UCP3, are thought to be beneficial by reducing ROS due to mild uncoupling. More recent hypotheses suggest the involvement of both proteins in cell metabolism by the transport of yet unknown substrates. The protein expression pattern under physiological and pathological conditions is an important clue for the evaluation of UCP2/UCP3 function, however, there is still no consensus about it. Previously, we demonstrated that only UCP3 is present in the adult murine heart under physiological conditions and correlated it with the predominant use of fatty acids for oxidation. In contrast, UCP2 was found only in very young (stem cell – like) cardiomyocytes, that rely mostly on glycolysis. Here, we employed three different models (ex vivo heart ischemia-reperfusion model, myocardial infarction model, and embryonic stem cell differentiation into cardiomyocytes under hypoxic conditions) to evaluate the abundance of both proteins under ischemia and hypoxia conditions. We found that (i) oxygen shortage or bursts did not influence UCP3 levels in the heart and ii) UCP2 was not present in healthy, ischemic, or re-perfused hearts. However, (iii) UCP2 was sensitive to the oxygen concentration in stem cells, in which UCP2 is normally expressed. These results further support the idea, that two highly homologous proteins – UCP2 and UCP3 – are abundant in different cells and tissues, and differently regulated under physiological and pathological conditions.

Download Full-text

Eotaxin Modulates Myelopoiesis and Mast Cell Development From Embryonic Hematopoietic Progenitors

Blood ◽

10.1182/blood.v92.6.1887 ◽

1998 ◽

Vol 92 (6) ◽

pp. 1887-1897 ◽

Cited By ~ 43

Author(s):

Elizabeth J. Quackenbush ◽

Barry K. Wershil ◽

Vincent Aguirre ◽

Jose-Carlos Gutierrez-Ramos

Keyword(s):

Mast Cell ◽

Stem Cell ◽

Mast Cells ◽

Stem Cell Factor ◽

Fetal Liver ◽

Hematopoietic Progenitors ◽

Embryonic Tissues ◽

Pathological Conditions ◽

Gi Protein ◽

American Society

Abstract Eotaxin is a potent chemoattractant for eosinophils during inflammation and allergic reactions in the adult, but its role in the embryonic development of the hematopoietic system has not been examined. We report here that eotaxin and its receptor, CCR-3, are expressed by embryonic tissues responsible for blood development, such as fetal liver (FL), yolk sac (YS), and peripheral blood. We found that eotaxin acts synergistically with stem cell factor to accelerate the differentiation of embryonic mast cell progenitors, and this response can be suppressed by pertussis toxin, an inhibitor of chemokine-induced signaling through Gi protein and chemotaxis. Eotaxin promotes the differentiation of fetal mast cell progenitors into differentiated mast cells as defined by the expression of mast cell specific proteases. Furthermore, in combination with stem cell factor (SCF), it promotes the growth of Mac-1+myeloid cells from embryonic progenitors. These studies suggest that eotaxin may be involved in the growth of granulocytic progenitors and the differentiation and/or function of mast cells during embryogenesis and/or pathological conditions that induce high levels of eotaxin, such as allergic responses. © 1998 by The American Society of Hematology.

Download Full-text

Advances in therapeutic applications of extracellular vesicles

Science Translational Medicine ◽

10.1126/scitranslmed.aav8521 ◽

2019 ◽

Vol 11 (492) ◽

pp. eaav8521 ◽

Cited By ~ 118

Author(s):

Oscar P. B. Wiklander ◽

Meadhbh Á. Brennan ◽

Jan Lötvall ◽

Xandra O. Breakefield ◽

Samir EL Andaloussi

Keyword(s):

Stem Cell ◽

Extracellular Vesicles ◽

Tissue Regeneration ◽

Immune Modulation ◽

Lipid Membrane ◽

Therapeutic Agents ◽

Bioactive Components ◽

Pathological Conditions ◽

Delivery Vehicles ◽

And Function

Extracellular vesicles (EVs) are nanometer-sized, lipid membrane–enclosed vesicles secreted by most, if not all, cells and contain lipids, proteins, and various nucleic acid species of the source cell. EVs act as important mediators of intercellular communication that influence both physiological and pathological conditions. Given their ability to transfer bioactive components and surmount biological barriers, EVs are increasingly being explored as potential therapeutic agents. EVs can potentiate tissue regeneration, participate in immune modulation, and function as potential alternatives to stem cell therapy, and bioengineered EVs can act as delivery vehicles for therapeutic agents. Here, we cover recent approaches and advances of EV-based therapies.

Download Full-text

Transcriptome-based molecular staging of human stem cell-derived retinal organoids uncovers accelerated photoreceptor differentiation by 9-cis retinal

10.1101/733071 ◽

2019 ◽

Cited By ~ 1

Author(s):

Koray D. Kaya ◽

Holly Y. Chen ◽

Matthew J. Brooks ◽

Ryan A. Kelley ◽

Hiroko Shimada ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Retinoic Acid ◽

Pluripotent Stem Cells ◽

Human Pluripotent Stem Cells ◽

Mitochondrial Morphology ◽

Rod Photoreceptor ◽

Molecular Staging ◽

Organoid Cultures

ABSTRACTRetinal organoids generated from human pluripotent stem cells exhibit considerable variability in temporal dynamics of differentiation. To assess the maturity of neural retina in vitro, we performed transcriptome analyses of developing organoids from human embryonic and induced pluripotent stem cell lines. We show that the developmental variability in organoids was reflected in gene expression profiles and could be evaluated by molecular staging with the human fetal and adult retinal transcriptome data. We also demonstrated that addition of 9-cis retinal, instead of widely-used all-trans retinoic acid, accelerated rod photoreceptor differentiation in organoid cultures, with higher rhodopsin expression and more mature mitochondrial morphology evident by day 120. Our studies thus provide an objective transcriptome-based modality for determining the differentiation state of retinal organoids, which should facilitate disease modeling and evaluation of therapies in vitro.Summary StatementThree-dimensional organoids derived from human pluripotent stem cells have been extensively applied for investigating organogenesis, modeling diseases and development of therapies. However, substantial variations within organoids pose challenges for comparison among different cultures and studies. We generated transcriptomes of multiple distinct retinal organoids and compared these to human fetal and adult retina gene profiles for molecular staging of differentiation state of the cultures. Our analysis revealed the advantage of using 9-cis retinal, instead of the widely-used all-trans retinoic acid, in facilitating rod photoreceptor differentiation. Thus, a transcriptome-based comparison can provide an objective method to uncover the maturity of organoid cultures across different lines and in various study platforms.

Download Full-text

Stem cells commit to differentiation following multiple induction events in the Drosophila testis.

10.1101/2021.05.20.444930 ◽

2021 ◽

Author(s):

Marc Amoyel ◽

Alice C Yuen ◽

Kenzo-Hugo Hillion

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Germ Cells ◽

Intercellular Communication ◽

Self Renewal ◽

Tor Pathway ◽

Daughter Cells ◽

Cyst Cells ◽

Drosophila Testis ◽

Primed State

How and when potential becomes restricted in differentiating stem cell daughters is poorly understood. While it is thought that signals from the niche are actively required to prevent differentiation, another model proposes that stem cells can reversibly transit between multiple states, some of which are primed, but not committed, to differentiate. In the Drosophila testis, somatic cyst stem cells (CySCs) generate cyst cells, which encapsulate the germline to support its development. We find that CySCs are maintained independently of niche self-renewal signals if activity of the PI3K/Tor pathway is inhibited. Conversely, PI3K/Tor is not sufficient alone to drive differentiation, suggesting that it acts to license cells for differentiation. Indeed, we find that the germline is required for differentiation of CySCs in response to PI3K/Tor elevation, indicating that final commitment to differentiation involves several steps and intercellular communication. We propose that CySC daughter cells are plastic, that their fate depends on the availability of neighbouring germ cells, and that PI3K/Tor acts to induce a primed state for CySC daughters to enable coordinated differentiation with the germline.

Download Full-text

Zebrafish dazl regulates cystogenesis and germline stem cell specification during the primordial germ cell to germline stem cell transition

Development ◽

10.1242/dev.187773 ◽

2021 ◽

Vol 148 (7) ◽

Author(s):

Sylvain Bertho ◽

Mara Clapp ◽

Torsten U. Banisch ◽

Jan Bandemer ◽

Erez Raz ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Rna Binding ◽

Process Analysis ◽

Primordial Germ Cell ◽

Cyst Formation ◽

Rapid Expansion ◽

Germline Stem Cell ◽

Cell Specification ◽

Ring Canals

ABSTRACT Fertility and gamete reserves are maintained by asymmetric divisions of the germline stem cells to produce new stem cells or daughters that differentiate as gametes. Before entering meiosis, differentiating germ cells (GCs) of sexual animals typically undergo cystogenesis. This evolutionarily conserved process involves synchronous and incomplete mitotic divisions of a GC daughter (cystoblast) to generate sister cells connected by intercellular bridges that facilitate the exchange of materials to support rapid expansion of the gamete progenitor population. Here, we investigated cystogenesis in zebrafish and found that early GCs are connected by ring canals, and show that Deleted in azoospermia-like (Dazl), a conserved vertebrate RNA-binding protein (Rbp), is a regulator of this process. Analysis of dazl mutants revealed the essential role of Dazl in regulating incomplete cytokinesis, germline cyst formation and germline stem cell specification before the meiotic transition. Accordingly, dazl mutant GCs form defective ring canals, and ultimately remain as individual cells that fail to differentiate as meiocytes. In addition to promoting cystoblast divisions and meiotic entry, dazl is required for germline stem cell establishment and fertility.

Download Full-text

Cardiomyocyte Maturation

Circulation Research ◽

10.1161/circresaha.119.315862 ◽

2020 ◽

Vol 126 (8) ◽

pp. 1086-1106 ◽

Cited By ~ 17

Author(s):

Yuxuan Guo ◽

William T. Pu

Keyword(s):

Stem Cell ◽

Heart Development ◽

Pluripotent Stem Cell ◽

Therapeutic Strategies ◽

Antagonistic Effect ◽

Regulatory Mechanisms ◽

Potential Contribution ◽

Significant Progress ◽

Cellular Events ◽

Novel Therapeutic Strategies

Maturation is the last phase of heart development that prepares the organ for strong, efficient, and persistent pumping throughout the mammal’s lifespan. This process is characterized by structural, gene expression, metabolic, and functional specializations in cardiomyocytes as the heart transits from fetal to adult states. Cardiomyocyte maturation gained increased attention recently due to the maturation defects in pluripotent stem cell–derived cardiomyocyte, its antagonistic effect on myocardial regeneration, and its potential contribution to cardiac disease. Here, we review the major hallmarks of ventricular cardiomyocyte maturation and summarize key regulatory mechanisms that promote and coordinate these cellular events. With advances in the technical platforms used for cardiomyocyte maturation research, we expect significant progress in the future that will deepen our understanding of this process and lead to better maturation of pluripotent stem cell–derived cardiomyocyte and novel therapeutic strategies for heart disease.

Download Full-text

Use of Human Tissue Stem Cell-Derived Organoid Cultures to Model Enterohepatic Circulation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00177.2021 ◽

2021 ◽

Author(s):

Sarah Elizabeth Blutt ◽

Sue Crawford ◽

Carolyn Bomidi ◽

Xi-Lei Zeng ◽

James Broughman ◽

...

Keyword(s):

Stem Cell ◽

Bile Acid ◽

Medical Care ◽

Bile Acids ◽

Human Tissue ◽

Enterohepatic Circulation ◽

Model Systems ◽

Acid Uptake ◽

Organoid Cultures

The use of human tissue stem cell-derived organoids has advanced our knowledge of human physiologic and pathophysiological processes that are unable to be studied using other model systems. Increases in the understanding of human epithelial tissues including intestine, stomach, liver, pancreas, lung, and brain have been achieved using organoids. However, it is not yet clear whether these cultures recapitulate in vivo organ-to-organ signaling or communication. In this work, we demonstrate that mature stem cell-derived intestinal and liver organoid cultures each express functional molecules that modulate bile acid uptake and recycling. These organoid cultures can be physically coupled in a Transwell® system and display increased secretion of FGF19 (intestine) and downregulation of CYP7A (liver) in response to apical exposure of the intestine to bile acids. This work establishes that organoid cultures can be used to study and therapeutically modulate interorgan interactions and advance the development of personalized approaches to medical care.

Download Full-text