2022

Jump to: 2021

22 pages, 3298 KiB

Open AccessReview

Vertebrate Cell Differentiation, Evolution, and Diseases: The Vertebrate-Specific Developmental Potential Guardians VENTX/NANOG and POU5/OCT4 Enter the Stage

by Bertrand Ducos, David Bensimon and Pierluigi Scerbo

Cells 2022, 11(15), 2299; https://doi.org/10.3390/cells11152299 - 26 Jul 2022

Cited by 2 | Viewed by 2911

Abstract

During vertebrate development, embryonic cells pass through a continuum of transitory pluripotent states that precede multi-lineage commitment and morphogenesis. Such states are referred to as “refractory/naïve” and “competent/formative” pluripotency. The molecular mechanisms maintaining refractory pluripotency or driving the transition to competent pluripotency, as [...] Read more.

During vertebrate development, embryonic cells pass through a continuum of transitory pluripotent states that precede multi-lineage commitment and morphogenesis. Such states are referred to as “refractory/naïve” and “competent/formative” pluripotency. The molecular mechanisms maintaining refractory pluripotency or driving the transition to competent pluripotency, as well as the cues regulating multi-lineage commitment, are evolutionarily conserved. Vertebrate-specific “Developmental Potential Guardians” (vsDPGs; i.e., VENTX/NANOG, POU5/OCT4), together with MEK1 (MAP2K1), coordinate the pluripotency continuum, competence for multi-lineage commitment and morphogenesis in vivo. During neurulation, vsDPGs empower ectodermal cells of the neuro-epithelial border (NEB) with multipotency and ectomesenchyme potential through an “endogenous reprogramming” process, giving rise to the neural crest cells (NCCs). Furthermore, vsDPGs are expressed in undifferentiated-bipotent neuro-mesodermal progenitor cells (NMPs), which participate in posterior axis elongation and growth. Finally, vsDPGs are involved in carcinogenesis, whereby they confer selective advantage to cancer stem cells (CSCs) and therapeutic resistance. Intriguingly, the heterogenous distribution of vsDPGs in these cell types impact on cellular potential and features. Here, we summarize the findings about the role of vsDPGs during vertebrate development and their selective advantage in evolution. Our aim to present a holistic view regarding vsDPGs as facilitators of both cell plasticity/adaptability and morphological innovation/variation. Moreover, vsDPGs may also be at the heart of carcinogenesis by allowing malignant cells to escape from physiological constraints and surveillance mechanisms. Full article

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15 pages, 2185 KiB

Open AccessReview

Capturing Transitional Pluripotency through Proline Metabolism

by Gabriella Minchiotti, Cristina D’Aniello, Annalisa Fico, Dario De Cesare and Eduardo Jorge Patriarca

Cells 2022, 11(14), 2125; https://doi.org/10.3390/cells11142125 - 06 Jul 2022

Cited by 4 | Viewed by 2250

Abstract

In this paper, we summarize the current knowledge of the role of proline metabolism in the control of the identity of Embryonic Stem Cells (ESCs). An imbalance in proline metabolism shifts mouse ESCs toward a stable naïve-to-primed intermediate state of pluripotency. Proline-induced cells [...] Read more.

In this paper, we summarize the current knowledge of the role of proline metabolism in the control of the identity of Embryonic Stem Cells (ESCs). An imbalance in proline metabolism shifts mouse ESCs toward a stable naïve-to-primed intermediate state of pluripotency. Proline-induced cells (PiCs), also named primitive ectoderm-like cells (EPLs), are phenotypically metastable, a trait linked to a rapid and reversible relocalization of E-cadherin from the plasma membrane to intracellular membrane compartments. The ESC-to-PiC transition relies on the activation of Erk and Tgfβ/Activin signaling pathways and is associated with extensive remodeling of the transcriptome, metabolome and epigenome. PiCs maintain several properties of naïve pluripotency (teratoma formation, blastocyst colonization and 3D gastruloid development) and acquire a few traits of primed cells (flat-shaped colony morphology, aerobic glycolysis metabolism and competence for primordial germ cell fate). Overall, the molecular and phenotypic features of PiCs resemble those of an early-primed state of pluripotency, providing a robust model to study the role of metabolic perturbations in pluripotency and cell fate decisions. Full article

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18 pages, 1257 KiB

Open AccessFeature PaperReview

Deconstructing Sox2 Function in Brain Development and Disease

by Sara Mercurio, Linda Serra, Miriam Pagin and Silvia K. Nicolis

Cells 2022, 11(10), 1604; https://doi.org/10.3390/cells11101604 - 10 May 2022

Cited by 16 | Viewed by 3428

Abstract

SOX2 is a transcription factor conserved throughout vertebrate evolution, whose expression marks the central nervous system from the earliest developmental stages. In humans, SOX2 mutation leads to a spectrum of CNS defects, including vision and hippocampus impairments, intellectual disability, and motor control problems. [...] Read more.

SOX2 is a transcription factor conserved throughout vertebrate evolution, whose expression marks the central nervous system from the earliest developmental stages. In humans, SOX2 mutation leads to a spectrum of CNS defects, including vision and hippocampus impairments, intellectual disability, and motor control problems. Here, we review how conditional Sox2 knockout (cKO) in mouse with different Cre recombinases leads to very diverse phenotypes in different regions of the developing and postnatal brain. Surprisingly, despite the widespread expression of Sox2 in neural stem/progenitor cells of the developing neural tube, some regions (hippocampus, ventral forebrain) appear much more vulnerable than others to Sox2 deletion. Furthermore, the stage of Sox2 deletion is also a critical determinant of the resulting defects, pointing to a stage-specificity of SOX2 function. Finally, cKOs illuminate the importance of SOX2 function in different cell types according to the different affected brain regions (neural precursors, GABAergic interneurons, glutamatergic projection neurons, Bergmann glia). We also review human genetics data regarding the brain defects identified in patients carrying mutations within human SOX2 and examine the parallels with mouse mutants. Functional genomics approaches have started to identify SOX2 molecular targets, and their relevance for SOX2 function in brain development and disease will be discussed. Full article

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22 pages, 1808 KiB

Open AccessReview

One Size Does Not Fit All: Heterogeneity in Developmental Hematopoiesis

by Cristiana Barone, Roberto Orsenigo, Raffaella Meneveri, Silvia Brunelli and Emanuele Azzoni

Cells 2022, 11(6), 1061; https://doi.org/10.3390/cells11061061 - 21 Mar 2022

Cited by 5 | Viewed by 4735

Abstract

Our knowledge of the complexity of the developing hematopoietic system has dramatically expanded over the course of the last few decades. We now know that, while hematopoietic stem cells (HSCs) firmly reside at the top of the adult hematopoietic hierarchy, multiple HSC-independent progenitor [...] Read more.

Our knowledge of the complexity of the developing hematopoietic system has dramatically expanded over the course of the last few decades. We now know that, while hematopoietic stem cells (HSCs) firmly reside at the top of the adult hematopoietic hierarchy, multiple HSC-independent progenitor populations play variegated and fundamental roles during fetal life, which reflect on adult physiology and can lead to disease if subject to perturbations. The importance of obtaining a high-resolution picture of the mechanisms by which the developing embryo establishes a functional hematopoietic system is demonstrated by many recent indications showing that ontogeny is a primary determinant of function of multiple critical cell types. This review will specifically focus on exploring the diversity of hematopoietic stem and progenitor cells unique to embryonic and fetal life. We will initially examine the evidence demonstrating heterogeneity within the hemogenic endothelium, precursor to all definitive hematopoietic cells. Next, we will summarize the dynamics and characteristics of the so-called “hematopoietic waves” taking place during vertebrate development. For each of these waves, we will define the cellular identities of their components, the extent and relevance of their respective contributions as well as potential drivers of heterogeneity. Full article

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2021

Jump to: 2022

18 pages, 4822 KiB

Open AccessArticle

The NOTCH3 Downstream Target HEYL Is Required for Efficient Human Airway Basal Cell Differentiation

by Manish Bodas, Bharathiraja Subramaniyan, Andrew R. Moore, Jordan P. Metcalf, Sarah R. Ocañas, Willard M. Freeman, Constantin Georgescu, Jonathan D. Wren and Matthew S. Walters

Cells 2021, 10(11), 3215; https://doi.org/10.3390/cells10113215 - 18 Nov 2021

Cited by 5 | Viewed by 3423

Abstract

Basal cells (BCs) are stem/progenitor cells of the mucociliary airway epithelium, and their differentiation is orchestrated by the NOTCH signaling pathway. NOTCH3 receptor signaling regulates BC to club cell differentiation; however, the downstream responses that regulate this process are unknown. Overexpression of the [...] Read more.

Basal cells (BCs) are stem/progenitor cells of the mucociliary airway epithelium, and their differentiation is orchestrated by the NOTCH signaling pathway. NOTCH3 receptor signaling regulates BC to club cell differentiation; however, the downstream responses that regulate this process are unknown. Overexpression of the active NOTCH3 intracellular domain (NICD3) in primary human bronchial epithelial cells (HBECs) on in vitro air–liquid interface culture promoted club cell differentiation. Bulk RNA-seq analysis identified 692 NICD3-responsive genes, including the classical NOTCH target HEYL, which increased in response to NICD3 and positively correlated with SCGB1A1 (club cell marker) expression. siRNA knockdown of HEYL decreased tight junction formation and cell proliferation. Further, HEYL knockdown reduced club, goblet and ciliated cell differentiation. In addition, we observed decreased expression of HEYL in HBECs from donors with chronic obstructive pulmonary disease (COPD) vs. normal donors which correlates with the impaired differentiation capacity of COPD cells. Finally, overexpression of HEYL in COPD HBECs promoted differentiation into club, goblet and ciliated cells, suggesting the impaired capacity of COPD cells to generate a normal airway epithelium is a reversible phenotype that can be regulated by HEYL. Overall, our data identify the NOTCH3 downstream target HEYL as a key regulator of airway epithelial differentiation. Full article

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15 pages, 332 KiB

Open AccessFeature PaperReview

Heterogeneity of Cancer Stem Cells in Tumorigenesis, Metastasis, and Resistance to Antineoplastic Treatment of Head and Neck Tumours

by Nicola Cirillo, Carmen Wu and Stephen S. Prime

Cells 2021, 10(11), 3068; https://doi.org/10.3390/cells10113068 - 08 Nov 2021

Cited by 13 | Viewed by 2031

Abstract

The discovery of a small subset of cancer cells with self-renewal properties that can give rise to phenotypically diverse tumour populations has shifted our understanding of cancer biology. Targeting cancer stem cells (CSCs) is becoming a promising therapeutic strategy in various malignancies, including [...] Read more.

The discovery of a small subset of cancer cells with self-renewal properties that can give rise to phenotypically diverse tumour populations has shifted our understanding of cancer biology. Targeting cancer stem cells (CSCs) is becoming a promising therapeutic strategy in various malignancies, including head and neck squamous cell carcinoma (HNSCC). Diverse sub-populations of head and neck cancer stem cells (HNCSCs) have been identified previously using CSC specific markers, the most common being CD44, Aldehyde Dehydrogenase 1 (ALDH1), and CD133, or by side population assays. Interestingly, distinct HNCSC subsets play different roles in the generation and progression of tumours. This article aims to review the evidence for a role of specific CSCs in HNSCC tumorigenesis, invasion, and metastasis, together with resistance to treatment. Full article

16 pages, 1107 KiB

Open AccessFeature PaperReview

Endothelial Heterogeneity in Development and Wound Healing

by David B. Gurevich, Deena T. David, Ananthalakshmy Sundararaman and Jatin Patel

Cells 2021, 10(9), 2338; https://doi.org/10.3390/cells10092338 - 07 Sep 2021

Cited by 16 | Viewed by 4822

Abstract

The vasculature is comprised of endothelial cells that are heterogeneous in nature. From tissue resident progenitors to mature differentiated endothelial cells, the diversity of these populations allows for the formation, maintenance, and regeneration of the vascular system in development and disease, particularly during [...] Read more.

The vasculature is comprised of endothelial cells that are heterogeneous in nature. From tissue resident progenitors to mature differentiated endothelial cells, the diversity of these populations allows for the formation, maintenance, and regeneration of the vascular system in development and disease, particularly during situations of wound healing. Additionally, the de-differentiation and plasticity of different endothelial cells, especially their capacity to undergo endothelial to mesenchymal transition, has also garnered significant interest due to its implication in disease progression, with emphasis on scarring and fibrosis. In this review, we will pinpoint the seminal discoveries defining the phenotype and mechanisms of endothelial heterogeneity in development and disease, with a specific focus only on wound healing. Full article

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23 pages, 2705 KiB

Open AccessReview

Diversity of Adult Neural Stem and Progenitor Cells in Physiology and Disease

by Zachary Finkel, Fatima Esteban, Brianna Rodriguez, Tianyue Fu, Xin Ai and Li Cai

Cells 2021, 10(8), 2045; https://doi.org/10.3390/cells10082045 - 10 Aug 2021

Cited by 21 | Viewed by 6574

Abstract

Adult neural stem and progenitor cells (NSPCs) contribute to learning, memory, maintenance of homeostasis, energy metabolism and many other essential processes. They are highly heterogeneous populations that require input from a regionally distinct microenvironment including a mix of neurons, oligodendrocytes, astrocytes, ependymal cells, [...] Read more.

Adult neural stem and progenitor cells (NSPCs) contribute to learning, memory, maintenance of homeostasis, energy metabolism and many other essential processes. They are highly heterogeneous populations that require input from a regionally distinct microenvironment including a mix of neurons, oligodendrocytes, astrocytes, ependymal cells, NG2+ glia, vasculature, cerebrospinal fluid (CSF), and others. The diversity of NSPCs is present in all three major parts of the CNS, i.e., the brain, spinal cord, and retina. Intrinsic and extrinsic signals, e.g., neurotrophic and growth factors, master transcription factors, and mechanical properties of the extracellular matrix (ECM), collectively regulate activities and characteristics of NSPCs: quiescence/survival, proliferation, migration, differentiation, and integration. This review discusses the heterogeneous NSPC populations in the normal physiology and highlights their potentials and roles in injured/diseased states for regenerative medicine. Full article

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22 pages, 1157 KiB

Open AccessReview

Sex-Specific Differences in Glioblastoma

by Anna Carrano, Juan Jose Juarez, Diego Incontri, Antonio Ibarra and Hugo Guerrero Cazares

Cells 2021, 10(7), 1783; https://doi.org/10.3390/cells10071783 - 14 Jul 2021

Cited by 56 | Viewed by 6027

Abstract

Sex differences have been well identified in many brain tumors. Even though glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has the worst outcome, well-established differences between men and women are limited to incidence and outcome. Little is [...] Read more.

Sex differences have been well identified in many brain tumors. Even though glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has the worst outcome, well-established differences between men and women are limited to incidence and outcome. Little is known about sex differences in GBM at the disease phenotype and genetical/molecular level. This review focuses on a deep understanding of the pathophysiology of GBM, including hormones, metabolic pathways, the immune system, and molecular changes, along with differences between men and women and how these dimorphisms affect disease outcome. The information analyzed in this review shows a greater incidence and worse outcome in male patients with GBM compared with female patients. We highlight the protective role of estrogen and the upregulation of androgen receptors and testosterone having detrimental effects on GBM. Moreover, hormones and the immune system work in synergy to directly affect the GBM microenvironment. Genetic and molecular differences have also recently been identified. Specific genes and molecular pathways, either upregulated or downregulated depending on sex, could potentially directly dictate GBM outcome differences. It appears that sexual dimorphism in GBM affects patient outcome and requires an individualized approach to management considering the sex of the patient, especially in relation to differences at the molecular level. Full article

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17 pages, 1079 KiB

Open AccessReview

Dopamine Neuron Diversity: Recent Advances and Current Challenges in Human Stem Cell Models and Single Cell Sequencing

by Alessandro Fiorenzano, Edoardo Sozzi, Malin Parmar and Petter Storm

Cells 2021, 10(6), 1366; https://doi.org/10.3390/cells10061366 - 01 Jun 2021

Cited by 9 | Viewed by 6026

Abstract

Human midbrain dopamine (DA) neurons are a heterogeneous group of cells that share a common neurotransmitter phenotype and are in close anatomical proximity but display different functions, sensitivity to degeneration, and axonal innervation targets. The A9 DA neuron subtype controls motor function and [...] Read more.

Human midbrain dopamine (DA) neurons are a heterogeneous group of cells that share a common neurotransmitter phenotype and are in close anatomical proximity but display different functions, sensitivity to degeneration, and axonal innervation targets. The A9 DA neuron subtype controls motor function and is primarily degenerated in Parkinson’s disease (PD), whereas A10 neurons are largely unaffected by the condition, and their dysfunction is associated with neuropsychiatric disorders. Currently, DA neurons can only be reliably classified on the basis of topographical features, including anatomical location in the midbrain and projection targets in the forebrain. No systematic molecular classification at the genome-wide level has been proposed to date. Although many years of scientific efforts in embryonic and adult mouse brain have positioned us to better understand the complexity of DA neuron biology, many biological phenomena specific to humans are not amenable to being reproduced in animal models. The establishment of human cell-based systems combined with advanced computational single-cell transcriptomics holds great promise for decoding the mechanisms underlying maturation and diversification of human DA neurons, and linking their molecular heterogeneity to functions in the midbrain. Human pluripotent stem cells have emerged as a useful tool to recapitulate key molecular features of mature DA neuron subtypes. Here, we review some of the most recent advances and discuss the current challenges in using stem cells, to model human DA biology. We also describe how single cell RNA sequencing may provide key insights into the molecular programs driving DA progenitor specification into mature DA neuron subtypes. Exploiting the state-of-the-art approaches will lead to a better understanding of stem cell-derived DA neurons and their use in disease modeling and regenerative medicine. Full article

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20 pages, 866 KiB

Open AccessReview

Considerations to Model Heart Disease in Women with Preeclampsia and Cardiovascular Disease

by Clara Liu Chung Ming, Kimberly Sesperez, Eitan Ben-Sefer, David Arpon, Kristine McGrath, Lana McClements and Carmine Gentile

Cells 2021, 10(4), 899; https://doi.org/10.3390/cells10040899 - 14 Apr 2021

Cited by 6 | Viewed by 3636

Abstract

Preeclampsia is a multifactorial cardiovascular disorder diagnosed after 20 weeks of gestation, and is the leading cause of death for both mothers and babies in pregnancy. The pathophysiology remains poorly understood due to the variability and unpredictability of disease manifestation when studied in [...] Read more.

Preeclampsia is a multifactorial cardiovascular disorder diagnosed after 20 weeks of gestation, and is the leading cause of death for both mothers and babies in pregnancy. The pathophysiology remains poorly understood due to the variability and unpredictability of disease manifestation when studied in animal models. After preeclampsia, both mothers and offspring have a higher risk of cardiovascular disease (CVD), including myocardial infarction or heart attack and heart failure (HF). Myocardial infarction is an acute myocardial damage that can be treated through reperfusion; however, this therapeutic approach leads to ischemic/reperfusion injury (IRI), often leading to HF. In this review, we compared the current in vivo, in vitro and ex vivo model systems used to study preeclampsia, IRI and HF. Future studies aiming at evaluating CVD in preeclampsia patients could benefit from novel models that better mimic the complex scenario described in this article. Full article

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13 pages, 5350 KiB

Open AccessArticle

Progressive and Coordinated Mobilization of the Skeletal Muscle Niche throughout Tissue Repair Revealed by Single-Cell Proteomic Analysis

by Matthew Borok, Nathalie Didier, Francesca Gattazzo, Teoman Ozturk, Aurelien Corneau, Helene Rouard and Frederic Relaix

Cells 2021, 10(4), 744; https://doi.org/10.3390/cells10040744 - 28 Mar 2021

Cited by 11 | Viewed by 4092

Abstract

Background: Skeletal muscle is one of the only mammalian tissues capable of rapid and efficient regeneration after trauma or in pathological conditions. Skeletal muscle regeneration is driven by the muscle satellite cells, the stem cell population in interaction with their niche. Upon [...] Read more.

Background: Skeletal muscle is one of the only mammalian tissues capable of rapid and efficient regeneration after trauma or in pathological conditions. Skeletal muscle regeneration is driven by the muscle satellite cells, the stem cell population in interaction with their niche. Upon injury, muscle fibers undergo necrosis and muscle stem cells activate, proliferate and fuse to form new myofibers. In addition to myogenic cell populations, interaction with other cell types such as inflammatory cells, mesenchymal (fibroadipogenic progenitors—FAPs, pericytes) and vascular (endothelial) lineages are important for efficient muscle repair. While the role of the distinct populations involved in skeletal muscle regeneration is well characterized, the quantitative changes in the muscle stem cell and niche during the regeneration process remain poorly characterized. Methods: We have used mass cytometry to follow the main muscle cell types (muscle stem cells, vascular, mesenchymal and immune cell lineages) during early activation and over the course of muscle regeneration at D0, D2, D5 and D7 compared with uninjured muscles. Results: Early activation induces a number of rapid changes in the proteome of multiple cell types. Following the induction of damage, we observe a drastic loss of myogenic, vascular and mesenchymal cell lineages while immune cells invade the damaged tissue to clear debris and promote muscle repair. Immune cells constitute up to 80% of the mononuclear cells 5 days post-injury. We show that muscle stem cells are quickly activated in order to form new myofibers and reconstitute the quiescent muscle stem cell pool. In addition, our study provides a quantitative analysis of the various myogenic populations during muscle repair. Conclusions: We have developed a mass cytometry panel to investigate the dynamic nature of muscle regeneration at a single-cell level. Using our panel, we have identified early changes in the proteome of stressed satellite and niche cells. We have also quantified changes in the major cell types of skeletal muscle during regeneration and analyzed myogenic transcription factor expression in satellite cells throughout this process. Our results highlight the progressive dynamic shifts in cell populations and the distinct states of muscle stem cells adopted during skeletal muscle regeneration. Our findings give a deeper understanding of the cellular and molecular aspects of muscle regeneration. Full article

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Molecular Basis of Cellular Heterogeneity in Physiology and Disease: Diversity Matters

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