Extrinsic and intrinsic factors control the genesis of amacrine and cone cells in the rat retina

The seven major classes of cells of the vertebrate neural retina are generated from a pool of multipotent progenitor cells. Recent studies suggest a model of retinal development in which both the progenitor cells and the environment change over time (Cepko, C. L., Austin, C. P., Yang, X., Alexiades, M. and Ezzeddine, D. (1996). Proc. Natl. Acad. Sci. USA 93, 589–595). We have utilized a reaggregate culture system to test this model. A labeled population of progenitors from the embryonic rat retina were cultured with an excess of postnatal retinal cells and then assayed for their cell fate choices. We found that the postnatal environment had at least two signals that affected the embryonic cells' choice of fate; one signal inhibited the production of amacrine cells and a second affected the production of cone cells. No increase in cell types generated postnatally was observed. The source of the inhibitor of the amacrine cell fate appeared to be previously generated amacrine cells, suggesting that amacrine cell number is controlled by feedback inhibition. The progenitor cell lost its ability to be inhibited for production of an amacrine cell as it entered M phase of the cell cycle. We suggest that postmitotic cells influence progenitor cell fate decisions, but that they do so in a manner restricted by the intrinsic biases of progenitor cells.

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Deletion of Mtg16, a Target of t(16;21), Alters Hematopoietic Progenitor Cell Proliferation and Lineage Allocation

Molecular and Cellular Biology ◽

10.1128/mcb.00404-08 ◽

2008 ◽

Vol 28 (20) ◽

pp. 6234-6247 ◽

Cited By ~ 49

Author(s):

Brenda J. Chyla ◽

Isabel Moreno-Miralles ◽

Melissa A. Steapleton ◽

Mary Ann Thompson ◽

Srividya Bhaskara ◽

...

Keyword(s):

Cell Proliferation ◽

Progenitor Cells ◽

Cell Fate ◽

Progenitor Cell ◽

Hematopoietic Progenitor Cell ◽

Hematopoietic Progenitor ◽

Erythroid Progenitor ◽

Cell Fate Decisions ◽

Erythroid Progenitor Cells ◽

Progenitor Cell Proliferation

ABSTRACT While a number of DNA binding transcription factors have been identified that control hematopoietic cell fate decisions, only a limited number of transcriptional corepressors (e.g., the retinoblastoma protein [pRB] and the nuclear hormone corepressor [N-CoR]) have been linked to these functions. Here, we show that the transcriptional corepressor Mtg16 (myeloid translocation gene on chromosome 16), which is targeted by t(16;21) in acute myeloid leukemia, is required for hematopoietic progenitor cell fate decisions and for early progenitor cell proliferation. Inactivation of Mtg16 skewed early myeloid progenitor cells toward the granulocytic/macrophage lineage while reducing the numbers of megakaryocyte-erythroid progenitor cells. In addition, inactivation of Mtg16 impaired the rapid expansion of short-term stem cells, multipotent progenitor cells, and megakaryocyte-erythroid progenitor cells that is required under hematopoietic stress/emergency. This impairment appears to be a failure to proliferate rather than an induction of cell death, as expression of c-Myc, but not Bcl2, complemented the Mtg16 − / − defect.

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Deletion of Shp2 in the Brain Leads to Defective Proliferation and Differentiation in Neural Stem Cells and Early Postnatal Lethality

Molecular and Cellular Biology ◽

10.1128/mcb.01225-07 ◽

2007 ◽

Vol 27 (19) ◽

pp. 6706-6717 ◽

Cited By ~ 89

Author(s):

Yuehai Ke ◽

Eric E. Zhang ◽

Kazuki Hagihara ◽

Dongmei Wu ◽

Yuhong Pang ◽

...

Keyword(s):

Progenitor Cells ◽

Cell Fate ◽

Intracellular Signaling ◽

Progenitor Cell ◽

Neural Progenitor Cells ◽

Ventricular Zone ◽

Tyrosine Phosphatase ◽

Critical Role ◽

Cell Fate Decisions

ABSTRACT The intracellular signaling controlling neural stem/progenitor cell (NSC) self-renewal and neuronal/glial differentiation is not fully understood. We show here that Shp2, an introcellular tyrosine phosphatase with two SH2 domains, plays a critical role in NSC activities. Conditional deletion of Shp2 in neural progenitor cells mediated by Nestin-Cre resulted in early postnatal lethality, impaired corticogenesis, and reduced proliferation of progenitor cells in the ventricular zone. In vitro analyses suggest that Shp2 mediates basic fibroblast growth factor signals in stimulating self-renewing proliferation of NSCs, partly through control of Bmi-1 expression. Furthermore, Shp2 regulates cell fate decisions, by promoting neurogenesis while suppressing astrogliogenesis, through reciprocal regulation of the Erk and Stat3 signaling pathways. Together, these results identify Shp2 as a critical signaling molecule in coordinated regulation of progenitor cell proliferation and neuronal/astroglial cell differentiation.

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GATA-targeted compounds modulate cardiac subtype cell differentiation in dual reporter stem cell line

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02259-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Mika J. Välimäki ◽

Robert S. Leigh ◽

Sini M. Kinnunen ◽

Alexander R. March ◽

Ana Hernández de Sande ◽

...

Keyword(s):

Gene Expression ◽

Progenitor Cells ◽

Cell Fate ◽

Reporter Gene ◽

Gene Regulatory Networks ◽

Regulatory Networks ◽

Cell Fate Decisions ◽

Dual Reporter ◽

Gene Regulatory ◽

Reporter Gene Assays

AbstractBackgroundPharmacological modulation of cell fate decisions and developmental gene regulatory networks holds promise for the treatment of heart failure. Compounds that target tissue-specific transcription factors could overcome non-specific effects of small molecules and lead to the regeneration of heart muscle following myocardial infarction. Due to cellular heterogeneity in the heart, the activation of gene programs representing specific atrial and ventricular cardiomyocyte subtypes would be highly desirable. Chemical compounds that modulate atrial and ventricular cell fate could be used to improve subtype-specific differentiation of endogenous or exogenously delivered progenitor cells in order to promote cardiac regeneration.MethodsTranscription factor GATA4-targeted compounds that have previously shown in vivo efficacy in cardiac injury models were tested for stage-specific activation of atrial and ventricular reporter genes in differentiating pluripotent stem cells using a dual reporter assay. Chemically induced gene expression changes were characterized by qRT-PCR, global run-on sequencing (GRO-seq) and immunoblotting, and the network of cooperative proteins of GATA4 and NKX2-5 were further explored by the examination of the GATA4 and NKX2-5 interactome by BioID. Reporter gene assays were conducted to examine combinatorial effects of GATA-targeted compounds and bromodomain and extraterminal domain (BET) inhibition on chamber-specific gene expression.ResultsGATA4-targeted compounds 3i-1000 and 3i-1103 were identified as differential modulators of atrial and ventricular gene expression. More detailed structure-function analysis revealed a distinct subclass of GATA4/NKX2-5 inhibitory compounds with an acetyl lysine-like domain that contributed to ventricular cells (%Myl2-eGFP+). Additionally, BioID analysis indicated broad interaction between GATA4 and BET family of proteins, such as BRD4. This indicated the involvement of epigenetic modulators in the regulation of GATA-dependent transcription. In this line, reporter gene assays with combinatorial treatment of 3i-1000 and the BET bromodomain inhibitor (+)-JQ1 demonstrated the cooperative role of GATA4 and BRD4 in the modulation of chamber-specific cardiac gene expression.ConclusionsCollectively, these results indicate the potential for therapeutic alteration of cell fate decisions and pathological gene regulatory networks by GATA4-targeted compounds modulating chamber-specific transcriptional programs in multipotent cardiac progenitor cells and cardiomyocytes. The compound scaffolds described within this study could be used to develop regenerative strategies for myocardial regeneration.

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Phosphorylation state of the histone variant H2A.X controls human stem and progenitor cell fate decisions

Cell Reports ◽

10.1016/j.celrep.2021.108818 ◽

2021 ◽

Vol 34 (10) ◽

pp. 108818

Author(s):

Luca Orlando ◽

Borko Tanasijevic ◽

Mio Nakanishi ◽

Jennifer C. Reid ◽

Juan L. García-Rodríguez ◽

...

Keyword(s):

Cell Fate ◽

Progenitor Cell ◽

Histone Variant ◽

Phosphorylation State ◽

Cell Fate Decisions

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Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: possible role in 20q− polycythemia vera

Blood ◽

10.1182/blood-2010-02-270611 ◽

2010 ◽

Vol 116 (15) ◽

pp. 2812-2821 ◽

Cited By ~ 39

Author(s):

Fabiana Perna ◽

Nadia Gurvich ◽

Ruben Hoya-Arias ◽

Omar Abdel-Wahab ◽

Ross L. Levine ◽

...

Keyword(s):

Polycythemia Vera ◽

Progenitor Cells ◽

Cell Fate ◽

Myeloproliferative Neoplasms ◽

Erythroid Differentiation ◽

Polycomb Group ◽

Human Cord Blood ◽

Hematopoietic Stem ◽

Cell Fate Decisions ◽

Cd34 Cells

Abstract L3MBTL1, the human homolog of the Drosophila L(3)MBT polycomb group tumor suppressor gene, is located on chromosome 20q12, within the common deleted region identified in patients with 20q deletion-associated polycythemia vera, myelodysplastic syndrome, and acute myeloid leukemia. L3MBTL1 is expressed within hematopoietic CD34+ cells; thus, it may contribute to the pathogenesis of these disorders. To define its role in hematopoiesis, we knocked down L3MBTL1 expression in primary hematopoietic stem/progenitor (ie, CD34+) cells isolated from human cord blood (using short hairpin RNAs) and observed an enhanced commitment to and acceleration of erythroid differentiation. Consistent with this effect, overexpression of L3MBTL1 in primary hematopoietic CD34+ cells as well as in 20q− cell lines restricted erythroid differentiation. Furthermore, L3MBTL1 levels decrease during hemin-induced erythroid differentiation or erythropoietin exposure, suggesting a specific role for L3MBTL1 down-regulation in enforcing cell fate decisions toward the erythroid lineage. Indeed, L3MBTL1 knockdown enhanced the sensitivity of hematopoietic stem/progenitor cells to erythropoietin (Epo), with increased Epo-induced phosphorylation of STAT5, AKT, and MAPK as well as detectable phosphorylation in the absence of Epo. Our data suggest that haploinsufficiency of L3MBTL1 contributes to some (20q−) myeloproliferative neoplasms, especially polycythemia vera, by promoting erythroid differentiation.

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Basal stem cell fate specification is mediated by SMAD signaling in the developing human lung

10.1101/461103 ◽

2018 ◽

Cited By ~ 3

Author(s):

Alyssa J. Miller ◽

Qianhui Yu ◽

Michael Czerwinski ◽

Yu-Hwai Tsai ◽

Renee F. Conway ◽

...

Keyword(s):

Single Cell ◽

Progenitor Cells ◽

Cell Fate ◽

Basal Cell ◽

Human Lung ◽

Branching Morphogenesis ◽

Basal Cells ◽

Smad Signaling ◽

Cell Fate Decisions ◽

Cell Transition

AbstractBasal stem cells (basal cells), located in the bronchi and trachea of the human lung epithelium, play a critical role in normal airway homeostasis and repair, and have been implicated in the development of diseases such as cancer1-4. Additionally, basal-like cells contribute to alveolar regeneration and fibrosis following severe injury5-8. However, the developmental origin of basal cells in humans is unclear. Previous work has shown that specialized progenitor cells exist at the tips of epithelial tubes during lung branching morphogenesis, and in mice, give rise to all alveolar and airway lineages9,10. These ‘bud tip progenitor cells’ have also been described in the developing human lung11-13, but the mechanisms controlling bud tip differentiation into specific cell lineages, including basal cells, are unknown. Here, we interrogated the bud tip-to-basal cell transition using human tissue specimens, bud tip progenitor organoid cultures11, and single-cell transcriptomics. We used single-cell mRNA sequencing (scRNAseq) of developing human lung specimens from 15-21 weeks gestation to identify molecular signatures and cell states in the developing human airway epithelium. We then inferred differentiation trajectories during bud tip-to-airway differentiation, which revealed a previously undescribed transitional cell state (‘hub progenitors’) and implicated SMAD signaling as a regulator of the bud tip-to-basal cell transition. We used bud tip progenitor organoids to show that TGFT1 and BMP4 mediated SMAD signaling robustly induced the transition into functional basal-like cells, and these in vitro-derived basal cells exhibited clonal expansion, self-renewal and multilineage differentiation. This work provides a framework for deducing and validating key regulators of cell fate decisions using single cell transcriptomics and human organoid models. Further, the identification of SMAD signaling as a critical regulator of newly born basal cells in the lung may have implications for regenerative medicine, basal cell development in other organs, and understanding basal cell misregulation in disease.

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Nucleocytoplasmic Transport of RNA-Binding Proteins Regulates Neural Stem Cell Fates

10.21203/rs.3.rs-115227/v1 ◽

2020 ◽

Author(s):

Melissa J. MacPherson ◽

Sarah L Erickson ◽

Drayden Kopp ◽

Pengqiang Wen ◽

Mohammadreza Aghanoori ◽

...

Keyword(s):

Progenitor Cells ◽

Cell Fate ◽

Rna Binding ◽

Rna Binding Proteins ◽

Neurodevelopmental Disorder ◽

Neural Progenitor ◽

Nucleocytoplasmic Transport ◽

Transcriptional Level ◽

Cell Fates ◽

Cell Fate Decisions

Abstract The formation of the cerebral cortex requires balanced expansion and differentiation of neural progenitor cells, the fate choice of which requires regulation at many steps of gene expression. As progenitor cells often exhibit transcriptomic stochasticity, the ultimate output of cell fate-determining genes must be carefully controlled at the post-transcriptional level, but how this is orchestrated is poorly understood. Here we report that de novo missense variants in an RNA-binding protein CELF2 cause human cortical malformations and perturb neural progenitor cell fate decisions in mice by disrupting the nucleocytoplasmic transport of CELF2. In self-renewing neural progenitors, CELF2 is localized in the cytoplasm where it binds and coordinates mRNAs that encode cell fate regulators and neurodevelopmental disorder-related factors. The translocation of CELF2 into the nucleus releases mRNAs for translation and thereby triggers neural progenitor differentiation. Our results reveal a mechanism by which transport of CELF2 between discrete subcellular compartments orchestrates an RNA regulon to instruct cell fates in cerebral cortical development.

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Importance of Intrinsic Mechanisms in Cell Fate Decisions in the Developing Rat Retina

Neuron ◽

10.1016/s0896-6273(03)00756-6 ◽

2003 ◽

Vol 40 (5) ◽

pp. 897-904 ◽

Cited By ~ 111

Author(s):

Michel Cayouette ◽

Ben A Barres ◽

Martin Raff

Keyword(s):

Cell Fate ◽

Rat Retina ◽

Cell Fate Decisions ◽

Developing Rat

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Hyaluronan-Based Three-Dimensional Microenvironment Potently Induces Cardiovascular Progenitor Cell Populations

ISRN Tissue Engineering ◽

10.1155/2013/752620 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7

Author(s):

Jessica M. Gluck ◽

Jennifer Chyu ◽

Connor Delman ◽

Sepideh Heydarkhan-Hagvall ◽

W. Robb MacLellan ◽

...

Keyword(s):

Cell Fate ◽

Progenitor Cell ◽

Three Dimensional ◽

Extrinsic Factors ◽

Cell Fate Decisions ◽

3D Microenvironment ◽

Cell Niche ◽

The Relationship ◽

Stem Cell Niches

The relationship between stem cell niches in vivo and their surrounding microenvironment is still relatively unknown. Recent advances have indicated that extrinsic factors within the cardiovascular progenitor cell niche influence maintenance of a multipotent state as well as drive cell-fate decisions. We have previously shown the direct effects of extracellular matrix (ECM) proteins and have now investigated the effects of dimension on the induction of a cardiovascular progenitor cell (CPC) population. We have shown here that the three-dimensionality of a hyaluronan-based hydrogel greatly induces a CPC population, as marked by Flk-1. We have compared the effects of a 3D microenvironment to those of conventional 2D cell culture practices and have found that the 3D microenvironment potently induces a progenitor cell state.

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