Control of Hematopoietic Stem/Progenitor Cell Fate by Transforming Growth Factor-β

2003 ◽  
Vol 13 (6) ◽  
pp. 445-453 ◽  
Author(s):  
Nicolas Olivier Fortunel ◽  
Jacques Alexandre Hatzfeld ◽  
Marie-Noëlle Monier ◽  
Antoinette Hatzfeld
Keyword(s):  
Growth Factor ◽  
Cell Fate ◽  
Progenitor Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Hematopoietic Stem

scholarly journals Smad7 Regulates the Adult Neural Stem/Progenitor Cell Pool in a Transforming Growth Factor β- and Bone Morphogenetic Protein-Independent Manner

2010 ◽  
Vol 30 (14) ◽  
pp. 3685-3694 ◽  
Author(s):  
Monika Krampert ◽  
Sridhar Reddy Chirasani ◽  
Frank-Peter Wachs ◽  
Robert Aigner ◽  
Ulrich Bogdahn ◽  
...  
Keyword(s):  
Growth Factor ◽  
Progenitor Cell ◽  
Egf Receptor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Adult Brain ◽  
Independent Manner ◽  
Mutant Cells

ABSTRACT Members of the transforming growth factor β (TGF-β) family of proteins modulate the proliferation, differentiation, and survival of many different cell types. Neural stem and progenitor cells (NPCs) in the adult brain are inhibited in their proliferation by TGF-β and by bone morphogenetic proteins (BMPs). Here, we investigated neurogenesis in a hypomorphic mouse model for the TGF-β and BMP inhibitor Smad7, with the hypothesis that NPC proliferation might be reduced due to increased TGF-β and BMP signaling. Unexpectedly, we found enhanced NPC proliferation as well as an increased number of label-retaining cells in vivo. The enhanced proliferation potential of mutant cells was retained in vitro in neurosphere cultures. We observed a higher sphere-forming capacity as well as faster growth and cell cycle progression. Use of specific inhibitors revealed that these effects were independent of TGF-β and BMP signaling. The enhanced proliferation might be at least partially mediated by elevated signaling via epidermal growth factor (EGF) receptor, as mutant cells showed higher expression and activation levels of the EGF receptor. Conversely, an EGF receptor inhibitor reduced the proliferation of these cells. Our data indicate that endogenous Smad7 regulates neural stem/progenitor cell proliferation in a TGF-β- and BMP-independent manner.

scholarly journals Molecular mechanism of transforming growth factor β–mediated cell-cycle modulation in primary human CD34+ progenitors

Blood ◽  
2002 ◽  
Vol 99 (2) ◽  
pp. 499-506 ◽  
Author(s):  
Mo A. Dao ◽  
Joseph Hwa ◽  
Jan A. Nolta
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Transforming Growth Factor Β ◽  
Hematopoietic Stem ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Human Cd34 ◽  
Cell Cycle Modulation ◽  
Negative Effect

Abstract The mechanisms by which transforming growth factor β (TGF-β) exerts a negative effect on cell-cycle entry in primary human hematopoietic stem/progenitor cells were examined at the molecular and cellular levels. After treatment of primary human CD34+progenitors with TGF-β there was a decrease in the levels of cyclin D2 protein and an increase in levels of the cyclin-dependent kinase inhibitor (CDKI) p15 as compared to the levels in untreated cells. The converse was true after addition of neutralizing anti–TGF-β antibody. Administration of TGF-β to CD34+ cells in the presence of cytokines prevented retinoblastoma protein (pRb) phosphorylation, which occurred in the same cells treated with cytokines alone or cytokines and anti–TGF-β antibody. Neutralization of TGF-β during 24 to 48 hours of culture with cytokines significantly increased the number of colony-forming progenitors, but did not modulate the human stem cell pool, as measured in 6- to 12-month xenotransplantation assays. Equivalent numbers of human B, T, and myeloid cells were obtained after transplantation of cells treated with or without neutralization of TGF-β.

scholarly journals The Intracellular Form of Notch Blocks Transforming Growth Factor β-Mediated Growth Arrest in Mv1Lu Epithelial Cells

2003 ◽  
Vol 23 (18) ◽  
pp. 6694-6701 ◽  
Author(s):  
Prakash Rao ◽  
Tom Kadesch
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Cell Growth ◽  
Epithelial Cells ◽  
Cell Fate ◽  
Transforming Growth Factor ◽  
Cell Cycle Control ◽  
Transforming Growth Factor Β ◽  
Cell Fate Decisions ◽  
Growth Inhibitory

ABSTRACT Notch signaling influences a variety of cell fate decisions during development, and constitutive activation of the pathway can provoke unbridled cell growth and cancer. The mechanisms by which Notch affects cell growth are not well established. We describe here a novel link between Notch and cell cycle control. We found that Mv1Lu epithelial cells harboring an oncogenic form of Notch (NICD) are resistant to the cell cycle-inhibitory effects of transforming growth factor β (TGF-β). NICD did not affect TGF-β signaling per se but blocked induction of the Cdk inhibitor p15INK4B. c-Myc, whose down-regulation by TGF-β is required for p15INK4B induction, remained elevated in the NICD-expressing cells. c-Myc expression was also maintained in low serum, indicating that Notch's effects on c-Myc are not specific to TGF-β. Our results are consistent with a model in which a strong Notch signal indirectly deregulates c-Myc expression and thereby renders Mv1Lu epithelial cells resistant to growth-inhibitory signals.

scholarly journals Stem and progenitor cell alterations in myelodysplastic syndromes

Blood ◽  
2017 ◽  
Vol 129 (12) ◽  
pp. 1586-1594 ◽  
Author(s):  
Aditi Shastri ◽  
Britta Will ◽  
Ulrich Steidl ◽  
Amit Verma
Keyword(s):  
Stem Cells ◽  
Myelodysplastic Syndromes ◽  
Progenitor Cell ◽  
Transforming Growth Factor ◽  
Interleukin 1 ◽  
Tumor Necrosis Factor Receptor ◽  
Transforming Growth Factor Β ◽  
Small Population ◽  
Driver Mutations ◽  
Hematopoietic Stem

Abstract Recent studies have demonstrated that myelodysplastic syndromes (MDSs) arise from a small population of disease-initiating hematopoietic stem cells (HSCs) that persist and expand through conventional therapies and are major contributors to disease progression and relapse. MDS stem and progenitor cells are characterized by key founder and driver mutations and are enriched for cytogenetic alterations. Quantitative alterations in hematopoietic stem and progenitor cell (HSPC) numbers are also seen in a stage-specific manner in human MDS samples as well as in murine models of the disease. Overexpression of several markers such as interleukin-1 (IL-1) receptor accessory protein (IL1RAP), CD99, T-cell immunoglobulin mucin-3, and CD123 have begun to differentiate MDS HSPCs from healthy counterparts. Overactivation of innate immune components such as Toll-like receptors, IL-1 receptor–associated kinase/tumor necrosis factor receptor–associated factor-6, IL8/CXCR2, and IL1RAP signaling pathways has been demonstrated in MDS HSPCs and is being targeted therapeutically in preclinical and early clinical studies. Other dysregulated pathways such as signal transducer and activator of transcription 3, tyrosine kinase with immunoglobulinlike and EGF-like domains 1/angiopoietin-1, p21-activated kinase, microRNA 21, and transforming growth factor β are also being explored as therapeutic targets against MDS HSPCs. Taken together, these studies have demonstrated that MDS stem cells are functionally critical for the initiation, transformation, and relapse of disease and need to be targeted therapeutically for future curative strategies in MDSs.

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