scholarly journals Alternative polyadenylation of Pax3 controls muscle stem cell fate and muscle function

Science ◽  
2019 ◽  
Vol 366 (6466) ◽  
pp. 734-738 ◽  
Author(s):  
Antoine de Morree ◽  
Julian D. D. Klein ◽  
Qiang Gan ◽  
Jean Farup ◽  
Andoni Urtasun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Messenger Rna ◽  
Adult Stem Cells ◽  
Alternative Polyadenylation ◽  
Quiescent State ◽  
Stem Cell Fate ◽  
Activation Rate

Adult stem cells are essential for tissue homeostasis. In skeletal muscle, muscle stem cells (MuSCs) reside in a quiescent state, but little is known about the mechanisms that control homeostatic turnover. Here we show that, in mice, the variation in MuSC activation rate among different muscles (for example, limb versus diaphragm muscles) is determined by the levels of the transcription factor Pax3. We further show that Pax3 levels are controlled by alternative polyadenylation of its transcript, which is regulated by the small nucleolar RNA U1. Isoforms of the Pax3 messenger RNA that differ in their 3′ untranslated regions are differentially susceptible to regulation by microRNA miR206, which results in varying levels of the Pax3 protein in vivo. These findings highlight a previously unrecognized mechanism of the homeostatic regulation of stem cell fate by multiple RNA species.

Constructing stem cell microenvironments using bioengineering approaches

2013 ◽  
Vol 45 (23) ◽  
pp. 1123-1135 ◽  
Author(s):  
David A. Brafman
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Disease Modeling ◽  
Mechanical Stimuli ◽  
Culture Methods ◽  
Stem Cell Fate ◽  
And Function

Within the adult organism, stem cells reside in defined anatomical microenvironments called niches. These architecturally diverse microenvironments serve to balance stem cell self-renewal and differentiation. Proper regulation of this balance is instrumental to tissue repair and homeostasis, and any imbalance can potentially lead to diseases such as cancer. Within each of these microenvironments, a myriad of chemical and physical stimuli interact in a complex (synergistic or antagonistic) manner to tightly regulate stem cell fate. The in vitro replication of these in vivo microenvironments will be necessary for the application of stem cells for disease modeling, drug discovery, and regenerative medicine purposes. However, traditional reductionist approaches have only led to the generation of cell culture methods that poorly recapitulate the in vivo microenvironment. To that end, novel engineering and systems biology approaches have allowed for the investigation of the biological and mechanical stimuli that govern stem cell fate. In this review, the application of these technologies for the dissection of stem cell microenvironments will be analyzed. Moreover, the use of these engineering approaches to construct in vitro stem cell microenvironments that precisely control stem cell fate and function will be reviewed. Finally, the emerging trend of using high-throughput, combinatorial methods for the stepwise engineering of stem cell microenvironments will be explored.

scholarly journals Synthetic Extracellular Microenvironment for Modulating Stem Cell Behaviors

2015 ◽  
Vol 10s1 ◽  
pp. BMI.S20057 ◽  
Author(s):  
Prafulla Chandra ◽  
Sang Jin Lee
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Bioactive Molecules ◽  
Stem Cell Fate ◽  
Cell Behaviors ◽  
Extracellular Microenvironment ◽  
Promising Source

The innate ability of stem cells to self-renew and differentiate into multiple cell types makes them a promising source for tissue engineering and regenerative medicine applications. Their capacity for self-renewal and differentiation is largely influenced by the combination of physical, chemical, and biological signals found in the stem cell niche, both temporally and spatially. Embryonic and adult stem cells are potentially useful for cell-based approaches; however, regulating stem cell behavior remains a major challenge in their clinical use. Most of the current approaches for controlling stem cell fate do not fully address all of the complex signaling pathways that drive stem cell behaviors in their natural microenvironments. To overcome this limitation, a new generation of biomaterials is being developed for use as three-dimensional synthetic microenvironments that can mimic the regulatory characteristics of natural extracellular matrix (ECM) proteins and ECM-bound growth factors. These synthetic microenvironments are currently being investigated as a substrate with surface immobilization and controlled release of bioactive molecules to direct the stem cell fate in vitro, as a tissue template to guide and improve the neo-tissue formation both in vitro and in vivo, and as a delivery vehicle for cell therapy in vivo. The continued advancement of such an intelligent biomaterial system as the synthetic extracellular microenvironment holds the promise of improved therapies for numerous debilitating medical conditions for which no satisfactory cure exists today.

scholarly journals Asymmetric histone inheritance regulates stem cell fate in Drosophila midgut

2020 ◽  
Author(s):  
Emily Zion ◽  
Xin Chen
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Biological Significance ◽  
Cell Lineage ◽  
Germline Stem Cells ◽  
Cell Fates ◽  
Stem Cell Fate ◽  
Distinct Cell

AbstractA fundamental question in developmental biology is how distinct cell fates are established and maintained through epigenetic mechanisms in multicellular organisms. Here, we report that preexisting (old) and newly synthesized (new) histones H3 and H4 are asymmetrically inherited by the distinct daughter cells during asymmetric division of Drosophila intestinal stem cells (ISCs). By contrast, in symmetrically dividing ISCs that produce two self-renewed stem cells, old and new H3 and H4 show symmetric inheritance patterns. These results indicate that asymmetric histone inheritance is tightly associated with the distinct daughter cell fates. To further understand the biological significance of this asymmetry, we express a mutant histone that compromises asymmetric histone inheritance pattern. We find increased symmetric ISC division and ISC tumors during aging under this condition. Together, our results demonstrate that asymmetric histone inheritance is important for establishing distinct cell identities in a somatic stem cell lineage, consistent with previous findings in asymmetrically dividing male germline stem cells in Drosophila. Therefore, this work sheds light on the principles of histone inheritance in regulating stem cell fate in vivo.

Asymmetric organelle inheritance predicts human blood stem cell fate

Blood ◽  
2021 ◽  
Author(s):  
Dirk Loeffler ◽  
Florin Schneiter ◽  
Weijia Wang ◽  
Arne Wehling ◽  
Tobias Kull ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Cell Fate ◽  
Human Blood ◽  
Asymmetric Cell Division ◽  
Cell Fates ◽  
Hematopoietic Stem ◽  
Stem Cell Fate ◽  
Blood Stem Cells

Understanding human hematopoietic stem cell fate control is important for their improved therapeutic manipulation. Asymmetric cell division, the asymmetric inheritance of factors during division instructing future daughter cell fates, was recently described in mouse blood stem cells. In human blood stem cells, the possible existence of asymmetric cell division remained unclear due to technical challenges in its direct observation. Here, we use long-term quantitative single-cell imaging to show that lysosomes and active mitochondria are asymmetrically inherited in human blood stem cells and that their inheritance is a coordinated, non-random process. Furthermore, multiple additional organelles, including autophagosomes, mitophagosomes, autolysosomes and recycling endosomes show preferential asymmetric co-segregation with lysosomes. Importantly, asymmetric lysosomal inheritance predicts future asymmetric daughter cell cycle length, differentiation and stem cell marker expression, while asymmetric inheritance of active mitochondria correlates with daughter metabolic activity. Hence, human hematopoietic stem cell fates are regulated by asymmetric cell division, with both mechanistic evolutionary conservation and differences to the mouse system.

scholarly journals N6-Methyladenosine in RNA and DNA: An Epitranscriptomic and Epigenetic Player Implicated in Determination of Stem Cell Fate

2018 ◽  
Vol 2018 ◽  
pp. 1-18 ◽  
Author(s):  
Pengfei Ji ◽  
Xia Wang ◽  
Nina Xie ◽  
Yujing Li
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Direct Interaction ◽  
Limited Information ◽  
Stem Cell Fate ◽  
Base Modification ◽  
Dna And Rna ◽  
Proliferation And Differentiation

Vast emerging evidences are linking the base modifications and determination of stem cell fate such as proliferation and differentiation. Among the base modification markers extensively studied, 5-methylcytosine (5-mC) and its oxidative derivatives (5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC), and 5-carboxylcytosine (5-caC)) dynamically occur in DNA and RNA and have been acknowledged as important epigenetic markers involved in regulation of cellular biological processes. N6-Methyladenosine modification in DNA (m6dA), mRNA (m6A), tRNA, and other noncoding RNAs has been defined as another important epigenetic and epitranscriptomic marker in eukaryotes in recent years. The mRNA m6A modification has been characterized biochemically, molecularly, and phenotypically, including elucidation of its methyltransferase complexes (m6A writer), demethylases (m6A eraser), and direct interaction proteins (readers), while limited information on the DNA m6dA is available. The levels and the landscapes of m6A in the epitranscriptomes and epigenomes are precisely and dynamically regulated by the fine-tuned coordination of the writers and erasers in accordance with stages of the growth, development, and reproduction as naturally programmed during the lifespan. Additionally, progress has been made in appreciation of the link between aberrant m6A modification in stem cells and diseases, like cancers and neurodegenerative disorders. These achievements are inspiring scientists to further uncover the epigenetic mechanisms for stem cell development and to dissect pathogenesis of the multiple diseases conferred by development aberration of the stem cells. This review article will highlight the research advances in the role of m6A methylation modifications of DNA and RNA in the regulation of stem cell and genesis of the closely related disorders. Additionally, this article will also address the research directions in the future.

scholarly journals Regulation and Directing Stem Cell Fate by Tissue Engineering Functional Microenvironments: Scaffold Physical and Chemical Cues

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Fei Xing ◽  
Lang Li ◽  
Changchun Zhou ◽  
Cheng Long ◽  
Lina Wu ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Stem Cells ◽  
Stem Cell ◽  
Growth Factors ◽  
Cell Fate ◽  
Chemical Cues ◽  
Physical Factors ◽  
Stem Cell Fate ◽  
Physical And Chemical

It is well known that stem cells reside within tissue engineering functional microenvironments that physically localize them and direct their stem cell fate. Recent efforts in the development of more complex and engineered scaffold technologies, together with new understanding of stem cell behavior in vitro, have provided a new impetus to study regulation and directing stem cell fate. A variety of tissue engineering technologies have been developed to regulate the fate of stem cells. Traditional methods to change the fate of stem cells are adding growth factors or some signaling pathways. In recent years, many studies have revealed that the geometrical microenvironment played an essential role in regulating the fate of stem cells, and the physical factors of scaffolds including mechanical properties, pore sizes, porosity, surface stiffness, three-dimensional structures, and mechanical stimulation may affect the fate of stem cells. Chemical factors such as cell-adhesive ligands and exogenous growth factors would also regulate the fate of stem cells. Understanding how these physical and chemical cues affect the fate of stem cells is essential for building more complex and controlled scaffolds for directing stem cell fate.

Directing Stem Cell Fate in 3D Through Cell Inert and Adhesive Diblock Copolymer Domains

2013 ◽  
Author(s):  
Somyot Chirasatitsin ◽  
Priyalakshmi Viswanathan ◽  
Giuseppe Battaglia ◽  
Adam J. Engler
Keyword(s):  
Extracellular Matrix ◽  
Stem Cell ◽  
Cell Adhesion ◽  
Cell Fate ◽  
Diblock Copolymer ◽  
Stem Cell Differentiation ◽  
Stem Cell Fate ◽  
Cell Behaviors ◽  
Cell Structures

Adhesions are important cell structures required to transduce a variety of chemical and mechanics signals from outside-in and vice versa, all of which regulate cell behaviors, including stem cell differentiation (1). Though most biomaterials are coated with an adhesive ligand to promote adhesion, they do not often have a uniform distribution that does not match the heterogeneously adhesive extracellular matrix (ECM) in vivo (2). We have previously shown that diblock copolymer (DBC) mixtures undergo interface-confined de-mixing to form nanodomins of one copolymer in another (3). Here we demonstrate how diblock copolymer mixtures can be made into foams with nanodomains to better recapitulate native ECM adhesion regions and influence cell adhesion.

scholarly journals Tuning Adipogenic Differentiation in ADSCs by Metformin and Vitamin D: Involvement of miRNAs

2020 ◽  
Vol 21 (17) ◽  
pp. 6181
Author(s):  
Sara Cruciani ◽  
Giuseppe Garroni ◽  
Francesca Balzano ◽  
Renzo Pala ◽  
Emanuela Bellu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Vitamin D ◽  
Stem Cell ◽  
Cell Fate ◽  
Adipogenic Differentiation ◽  
Adipose Derived Stem Cells ◽  
Vitamin D Metabolism ◽  
Stem Cell Fate ◽  
Cellular Phenotypes

Fat tissue represents an important source of adipose-derived stem cells (ADSCs), which can differentiate towards several phenotypes under certain stimuli. Definite molecules as vitamin D are able to influence stem cell fate, acting on the expression of specific genes. In addition, miRNAs are important modulating factors in obesity and numerous diseases. We previously identified specific conditioned media able to commit stem cells towards defined cellular phenotypes. In the present paper, we aimed at evaluating the role of metformin on ADSCs differentiation. In particular, ADSCs were cultured in a specific adipogenic conditioned medium (MD), in the presence of metformin, alone or in combination with vitamin D. Our results showed that the combination of the two compounds is able to counteract the appearance of an adipogenic phenotype, indicating a feedforward regulation on vitamin D metabolism by metformin, acting on CYP27B1 and CYP3A4. We then evaluated the role of specific epigenetic modulating genes and miRNAs in controlling stem cell adipogenesis. The combination of the two molecules was able to influence stem cell fate, by modulating the adipogenic phenotype, suggesting their possible application in clinical practice in counteracting uncontrolled lipogenesis and obesity-related diseases.

scholarly journals Effect of the 3D Artificial Nichoid on the Morphology and Mechanobiological Response of Mesenchymal Stem Cells Cultured In Vitro

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1873 ◽  
Author(s):  
Andrea Remuzzi ◽  
Barbara Bonandrini ◽  
Matteo Tironi ◽  
Lorena Longaretti ◽  
Marina Figliuzzi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Cultured Cells ◽  
Three Dimensions ◽  
Nuclear Pore ◽  
Cells Cultured

Stem cell fate and behavior are affected by the bidirectional communication of cells and their local microenvironment (the stem cell niche), which includes biochemical cues, as well as physical and mechanical factors. Stem cells are normally cultured in conventional two-dimensional monolayer, with a mechanical environment very different from the physiological one. Here, we compare culture of rat mesenchymal stem cells on flat culture supports and in the “Nichoid”, an innovative three-dimensional substrate micro-engineered to recapitulate the architecture of the physiological niche in vitro. Two versions of the culture substrates Nichoid (single-layered or “2D Nichoid” and multi-layered or “3D Nichoid”) were fabricated via two-photon laser polymerization in a biocompatible hybrid organic-inorganic photoresist (SZ2080). Mesenchymal stem cells, isolated from rat bone marrow, were seeded on flat substrates and on 2D and 3D Nichoid substrates and maintained in culture up to 2 weeks. During cell culture, we evaluated cell morphology, proliferation, cell motility and the expression of a panel of 89 mesenchymal stem cells’ specific genes, as well as intracellular structures organization. Our results show that mesenchymal stem cells adhered and grew in the 3D Nichoid with a comparable proliferation rate as compared to flat substrates. After seeding on flat substrates, cells displayed large and spread nucleus and cytoplasm, while cells cultured in the 3D Nichoid were spatially organized in three dimensions, with smaller and spherical nuclei. Gene expression analysis revealed the upregulation of genes related to stemness and to mesenchymal stem cells’ features in Nichoid-cultured cells, as compared to flat substrates. The observed changes in cytoskeletal organization of cells cultured on 3D Nichoids were also responsible for a different localization of the mechanotransducer transcription factor YAP, with an increase of the cytoplasmic retention in cells cultured in the 3D Nichoid. This difference could be explained by alterations in the import of transcription factors inside the nucleus due to the observed decrease of mean nuclear pore diameter, by transmission electron microscopy. Our data show that 3D distribution of cell volume has a profound effect on mesenchymal stem cells structure and on their mechanobiological response, and highlight the potential use of the 3D Nichoid substrate to strengthen the potential effects of MSC in vitro and in vivo.

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