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

2007 ◽  
Vol 27 (19) ◽  
pp. 6706-6717 ◽  
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.

Presenilin-1 regulates neuronal differentiation during neurogenesis

Development ◽  
2000 ◽  
Vol 127 (12) ◽  
pp. 2593-2606 ◽  
Author(s):  
M. Handler ◽  
X. Yang ◽  
J. Shen
Keyword(s):  
Cell Death ◽  
Progenitor Cells ◽  
Neuronal Differentiation ◽  
Cell Fate ◽  
Neural Progenitor Cells ◽  
Apoptotic Cell ◽  
Ventricular Zone ◽  
Neural Progenitor ◽  
Apoptotic Cell Death ◽  
Presenilin 1

Mutations in Presenilin-1 (PS1) are a major cause of familial Alzheimer's disease. Our previous studies showed that PS1 is required for murine neural development. Here we report that lack of PS1 leads to premature differentiation of neural progenitor cells, indicating a role for PS1 in a cell fate decision between postmitotic neurons and neural progenitor cells. Neural proliferation and apoptotic cell death during neurogenesis are unaltered in PS1(−/−) mice, suggesting that the reduction in the neural progenitor cells observed in the PS1(−/−) brain is due to premature differentiation of progenitor cells, rather than to increased apoptotic cell death or decreased cell proliferation. In addition, the premature neuronal differentiation in the PS1(−/−) brain is associated with aberrant neuronal migration and disorganization of the laminar architecture of the developing cerebral hemisphere. In the ventricular zone of PS1(−/−) mice, expression of the Notch1 downstream effector gene Hes5 is reduced and expression of the Notch1 ligand Dll1 is elevated, whereas expression of Notch1 is unchanged. The level of Dll1 transcripts is also increased in the presomitic mesoderm of PS1(−/−) embryos, while the level of Notch1 transcripts is unchanged, in contrast to a previous report (Wong et al., 1997, Nature 387, 288–292). These results provide direct evidence that PS1 controls neuronal differentiation in association with the downregulation of Notch signalling during neurogenesis.

Abstract 356: Krueppel-Like Factor 15 Regulates Wnt/β-Catenin Transcription and Controls Cardiac Progenitor Cell Fate in the Postnatal Heart

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Claudia Noack ◽  
Maria P Zafiriou ◽  
Anke Renger ◽  
Hans J Schaeffer ◽  
Martin W Bergmann ◽  
...  
Keyword(s):  
Cell Fate ◽  
Transcriptional Activation ◽  
Progenitor Cell ◽  
Cellular Localization ◽  
Target Genes ◽  
Critical Role ◽  
Isolated Cells ◽  
Cardiac Progenitor Cell

Wnt/β-catenin signaling controls adult heart remodeling partly by regulating cardiac progenitor cell (CPC) differentiation. We now identified and characterized a novel cardiac interaction of the transcription factor Krueppel-like factor 15 (KLF15) with the Wnt/β-catenin signaling on adult CPCs. In vitro mutation, reporter gene assays and co-localization studies revealed that KLF15 requires two distinct domains for nuclear localization and for repression of β-catenin-mediated transcription. KLF15 had no effect on β-catenin stability or cellular localization, but interacted with its co-factor TCF4, which is required for activation of β-catenin target gene expression. Moreover, increased TCF4 ubiquitination was induced by KLF15. In line with this finding we found KLF15 to interact with the Nemo-like kinase, which was shown to phosphorylate and target TCF4 for degradation. In vivo analyses of adult Klf15 functional knock-out (KO) vs. wild-type (WT) mice showed a cardiac β-catenin-mediated transcriptional activation and reduced TCF4 degradation along with cardiac dysfunction assessed by echocardiography (n=10). FACS analysis of the CPC enriched-population of KO vs. WT mice revealed a significant reduction of cardiogenic-committed precursors identified as Sca1+/αMHC+ (0.8±0.2% vs. 1.8±0.1%) and Tbx5+ (3.5±0.3% vs. 5.2±0.5%). In contrast, endothelial Sca1+/CD31+ cells were significantly higher in KO mice (11.3±0.4% vs. 8.6±0.4%; n≥9). In addition, Sca1+ isolated cells of Klf15 KO showed increased RNA expression of endothelial markers von Willebrand Factor, CD105, and Flk1 along with upregulation of β-catenin target genes. CPCs co-cultured on adult fibroblasts resulted in increased endothelial Flk1 cells and reduction of αMHC and Hand1 cardiogenic cells in KO vs. WT CPCs (n=9). Treating these co-cultures with Quercetin, an inhibitor of nuclear β-catenin, resulted in partial rescue of the observed phenotype. This study uncovers a critical role of KLF15 for the maintenance of cardiac tissue homeostasis. Via inhibition of β-catenin transcription, KLF15 controls cardiomyogenic cell fate similar to embryonic cardiogenesis. This knowledge may provide a tool for activation of endogenous CPCs in the postnatal heart.

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

Development ◽  
1999 ◽  
Vol 126 (3) ◽  
pp. 555-566 ◽  
Author(s):  
M.J. Belliveau ◽  
C.L. Cepko
Keyword(s):  
Progenitor Cells ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Amacrine Cell ◽  
Amacrine Cells ◽  
Environment Change ◽  
Rat Retina ◽  
Cell Fate Decisions ◽  
Cone Cells ◽  
Postnatal Environment

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.

scholarly journals Reconstruction of rat retinal progenitor cell lineages in vitro reveals a surprising degree of stochasticity in cell fate decisions

Development ◽  
2010 ◽  
Vol 138 (2) ◽  
pp. 227-235 ◽  
Author(s):  
F. L. A. F. Gomes ◽  
G. Zhang ◽  
F. Carbonell ◽  
J. A. Correa ◽  
W. A. Harris ◽  
...  
Keyword(s):  
Cell Fate ◽  
Progenitor Cell ◽  
Retinal Progenitor Cell ◽  
Cell Fate Decisions ◽  
Cell Lineages ◽  
Retinal Progenitor

scholarly journals Oxytocin alters cell fate selection of rat neural progenitor cells in vitro

PLoS ONE ◽  
2018 ◽  
Vol 13 (1) ◽  
pp. e0191160 ◽  
Author(s):  
Arvind Palanisamy ◽  
Ramaswamy Kannappan ◽  
Zhiqiang Xu ◽  
Audrey Martino ◽  
Matthew B. Friese ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cell Fate ◽  
Neural Progenitor Cells ◽  
Neural Progenitor ◽  
Selection Of

Isolated rat cortical progenitor cells are maintained in division in vitro by membrane-associated factors

Development ◽  
1994 ◽  
Vol 120 (4) ◽  
pp. 999-1008 ◽  
Author(s):  
S. Temple ◽  
A.A. Davis
Keyword(s):  
Cell Division ◽  
Progenitor Cells ◽  
Associated Factors ◽  
Progenitor Cell ◽  
Ventricular Zone ◽  
Single Cells ◽  
Cell Phenotype ◽  
Cortical Progenitor

Ventricular zone cells in the developing CNS undergo extensive cell division in vivo and under certain conditions in vitro. The culture conditions that promote cell division have been studied to determine the role that contact with cell membrane associated factors play in the proliferation of these cells. Progenitor cells have been taken from the ventricular zone of developing rat cerebral cortex and placed into microwells. Small clusters of these cells can generate large numbers of neurons and non-neuronal progeny. In contrast, single progenitor cells largely cease division, approximately 90% acquiring neuron-like characteristics by 1 day in vitro. DiI-labeled, single cells from embryonic day 14 cortex plated onto clusters of unmarked progenitor cells have a significantly higher probability (approximately 3-fold) of maintaining a progenitor cell phenotype than if plated onto the plastic substratum around 100 microns away from the clusters. Contact with purified astrocytes also promotes the progenitor cell phenotype, whereas contact with meningeal fibroblasts or balb3T3 cells promotes their differentiation. Membrane homogenates from cortical astrocytes stimulate significantly more incorporation of BrdU by E14 cortical progenitor cells than membrane homogenates from meningeal fibroblasts. These data indicate that the proliferation of rat cortical progenitor cells can be maintained by cell-type specific, membrane-associated factors.

CCAAT Enhancer Binding Protein-α (C/EBPα) Determines Myeloid Versus Erythroid Cell Fate in Multipotential Progenitors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1603-1603
Author(s):  
Hyung-Chan Suh ◽  
John Gooya ◽  
Katie Renn ◽  
Alan Friedman ◽  
Peter Johnson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Myeloid Cell ◽  
Retroviral Vectors ◽  
Erythroid Cell ◽  
Erythroid Cells ◽  
Cell Fate Decisions

Abstract C/EBPα is a bZip transcription factor, which is required for granulocyte development, and loss of C/EBPα function is associated with the development of acute myelogenous leukemia and myelodysplastic syndrome. While the precise mechanisms that regulate cell fate decisions during hematopoietic development are largely unknown, expression of transcription factors (PU.1 and GATA-1) can induce lineage conversion. In this regard, C/EBPα can drive the differentiation of B cells into macrophages, and bi-potential cell lines into granulocytes at the expense of macrophages. C/EBPα can also promote the transdifferentiation of myoblasts into adipocytes. We have recently found that there are increased numbers of erythroid cells in the fetal liver of C/EBPα −/ − mice. Also, C/EBPα is expressed in more primitive progenitor cells than granulocyte/macrophage progenitors (GMP) including hematopoietic stem cells. Therefore, we initiated experiments to evaluate whether C/EBPα has a functional role in regulating cell fate decisions in progenitors more primitive than GMP where it may promote a myeloid versus erythroid cell fate decision. To test this hypothesis, we over-expressed C/EBPα using retroviral vectors in 1) bone marrow cells (BMC) and evaluated their growth and differentiation in vitro, and in vivo when transplanted into mice; 2) purified multipotential progenitors with erythroid and myeloid potential, and erythroid restricted progenitors; and 3) murine erythroid leukemia (MEL) cells. We found that there was a marked decrease in erythroid lineage cells and an increase in myeloid cells in mice transplanted with BMC that over-expressed C/EBPα. We also observed a decrease in erythroid cell growth in vitro with BMC that expressed C/EBPα. Furthermore, when infected with retroviral vectors that express C/EBPα, erythroid restricted progenitors acquired myeloid cell morphology and myeloid specific cell surface markers. In addition, MEL cells that over-express C/EBPα showed increased myeloid gene expression including GM-CSFR, PR3 and myeloid specific esterase, while they showed decreased expression of β-globin and Epo receptor (EpoR) which is required for erythroid cell differentiation and survival. We detected high levels of EpoR in C/EBPα −/ − suggesting an inverse relationship between C/EBPα and EpoR expression. Thus, C/EBPα is a dual function transcription factor that can repress erythroid specific genes while enhancing myeloid lineage gene expression. Consequently, C/EBPα acts as a switch to drive hematopoietic progenitor cells toward myeloid cell development at the expense of erythroid maturation, and can reprogram erythroid cells into myeloid cells. # Funded in part by DHHS #NO1-CO-12400

scholarly journals Redirecting differentiation of mammary progenitor cells by 3D bioprinted sweat gland microenvironment

2019 ◽  
Vol 7 ◽  
Author(s):  
Rui Wang ◽  
Yihui Wang ◽  
Bin Yao ◽  
Tian Hu ◽  
Zhao Li ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cell Fate ◽  
Sweat Gland ◽  
Critical Role ◽  
Three Dimensional ◽  
Control Group ◽  
Specific Marker ◽  
Shh Pathway

Abstract Background Mammary progenitor cells (MPCs) maintain their reproductive potency through life, and their specific microenvironments exert a deterministic control over these cells. MPCs provides one kind of ideal tools for studying engineered microenvironmental influence because of its accessibility and continually undergoes postnatal developmental changes. The aim of our study is to explore the critical role of the engineered sweat gland (SG) microenvironment in reprogramming MPCs into functional SG cells. Methods We have utilized a three-dimensional (3D) SG microenvironment composed of gelatin-alginate hydrogels and components from mouse SG extracellular matrix (SG-ECM) proteins to reroute the differentiation of MPCs to study the functions of this microenvironment. MPCs were encapsulated into the artificial SG microenvironment and were printed into a 3D cell-laden construct. The expression of specific markers at the protein and gene levels was detected after cultured 14 days. Results Compared with the control group, immunofluorescence and gene expression assay demonstrated that MPCs encapsulated in the bioprinted 3D-SG microenvironment could significantly express the functional marker of mouse SG, sodium/potassium channel protein ATP1a1, and tend to express the specific marker of luminal epithelial cells, keratin-8. When the Shh pathway is inhibited, the expression of SG-associated proteins in MPCs under the same induction environment is significantly reduced. Conclusions Our evidence proved the ability of differentiated mouse MPCs to regenerate SG cells by engineered SG microenvironment in vitro and Shh pathway was found to be correlated with the changes in the differentiation. These results provide insights into regeneration of damaged SG by MPCs and the role of the engineered microenvironment in reprogramming cell fate.

A soluble form of human Delta-like-1 inhibits differentiation of hematopoietic progenitor cells

Blood ◽  
2000 ◽  
Vol 95 (5) ◽  
pp. 1616-1625 ◽  
Author(s):  
Wei Han ◽  
Qian Ye ◽  
Malcolm A. S. Moore
Keyword(s):  
Progenitor Cells ◽  
Cell Fate ◽  
Hematopoietic Progenitor Cells ◽  
Soluble Form ◽  
Proliferative Potential ◽  
Hematopoietic Progenitor ◽  
Differentiation Markers ◽  
Cell Fate Decisions ◽  
Stromal Cell Line

Two Notch ligand families, Delta and Serrate/Jagged, have been identified in vertebrates. Members of the Jagged family have been shown to affect in vitro hematopoiesis. To determine whether members of the Delta family might play a similar role in hematopoiesis, we examined the expression of mouse Delta-like-1 (mDll1). mDll1 protein was detected in whole marrow and in a marrow stromal cell line MS-5. At the RNA level, both mDll1 and Notch1 were seen in marrow precursor, differentiated hematopoietic, marrow stromal, and MS-5 cells. We isolated a cDNA encoding the human homologue of mDll1, designated human Delta-like-1 (hDll1). A soluble form of hDll1, hDll1NDSL, containing the DSL domain and the N-terminal sequences, was expressed and purified from bacteria as a glutathione S-transferase (GST) fusion protein. We observed that hDll1NDSL delayed the acquisition of differentiation markers by murine hematopoietic progenitor cells (Lin−) cultured in vitro with cytokines. In addition, it promoted greater expansion (more than 3 times) of the primitive hematopoietic precursor cell population, measured in high-proliferative potential colony assay and day 12 colony-forming unit spleen (CFU-S) assay, than GST controls. We also observed that the percentage of apoptotic cells decreased and that the number of cells in the S-phase of the cell cycle increased in the cultures of Lin−cells with hDll1NDSL. The effects of hDll1NDSL were blocked by antibody against the mouse counterpart of hDll1NDSL, mDll1NDSL. These observations demonstrate that hDll1 plays a role in mediating cell fate decisions during hematopoiesis.

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