scholarly journals How Signaling Promotes Stem Cell Survival: Trophoblast Stem Cells and Shp2

2006 ◽  
Vol 10 (3) ◽  
pp. 275-276 ◽  
Author(s):  
Amy Ralston ◽  
Janet Rossant
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Survival ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Stem Cell Survival

scholarly journals PTBP1/HNRNP I controls intestinal epithelial cell regeneration by maintaining stem cell survival and stemness

2021 ◽  
Author(s):  
Wesley Tung ◽  
Ullas Valiya Chembazhi ◽  
Jing Yang ◽  
Ka Lam Nguyen ◽  
Aryan Lalwani ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Epithelial Cell ◽  
Cell Survival ◽  
Intestinal Epithelial Cell ◽  
Intestinal Stem Cells ◽  
Intestinal Stem Cell ◽  
Cell Regeneration ◽  
Intestinal Epithelial ◽  
Stem Cell Survival

Properly controlled intestinal epithelial cell regeneration is not only vital for protection against insults from environmental hazards but also crucial for preventing intestinal cancer. Intestinal stem cells located in the crypt region provide the driving force for epithelial regeneration, and thus their survival and death must be precisely regulated. We show here that polypyrimidine tract binding protein 1 (PTBP1, also called heterogeneous nuclear ribonucleoprotein I, or HNRNP I), an RNA-binding protein that post-transcriptionally regulates gene expression, is critical for intestinal stem cell survival and stemness. Mechanistically, we show that PTBP1 inhibits the expression of PHLDA3, an AKT repressor, and thereby maintains AKT activity in the intestinal stem cell compartment to promote stem cell survival and proliferation. Furthermore, we show that PTBP1 inhibits the expression of PTBP2, a paralog of PTBP1 that is known to induce neuron differentiation, through repressing inclusion of alternative exon 10 to Ptbp2 transcript. Loss of PTBP1 results in a significant upregulation of PTBP2, which is accompanied by splicing changes in genes that are important for neuron cell development. This finding suggests that PTBP1 prevents aberrant differentiation of intestinal stem cells into neuronal cells through inhibiting PTBP2. Our results thus reveal a novel mechanism whereby PTBP1 maintains intestinal stem cell survival and stemness through the control of gene function post-transcriptionally.

Ablation of MMP9 induces survival and differentiation of cardiac stem cells into cardiomyocytes in the heart of diabetics: a role of extracellular matrix

2012 ◽  
Vol 90 (3) ◽  
pp. 353-360 ◽  
Author(s):  
Paras Kumar Mishra ◽  
Vishalakshi Chavali ◽  
Naira Metreveli ◽  
Suresh C. Tyagi
Keyword(s):  
Stem Cells ◽  
Extracellular Matrix ◽  
Stem Cell ◽  
Confocal Microscopy ◽  
Cell Survival ◽  
Troponin I ◽  
Gelatin Zymography ◽  
Cardiac Stem Cells ◽  
Stem Cell Survival

The contribution of extracellular matrix (ECM) to stem cell survival and differentiation is unequivocal, and matrix metalloproteinase-9 (MMP9) induces ECM turn over; however, the role of MMP9 in the survival and differentiation of cardiac stem cells is unclear. We hypothesize that ablation of MMP9 enhances the survival and differentiation of cardiac stem cells into cardiomyocytes in diabetics. To test our hypothesis, Ins2+/− Akita, C57 BL/6J, and double knock out (DKO: Ins2+/−/MMP9−/−) mice were used. We created the DKO mice by deleting the MMP9 gene from Ins2+/−. The above 3 groups of mice were genotyped. The activity and expression of MMP9 in the 3 groups were determined by in-gel gelatin zymography, Western blotting, and confocal microscopy. To determine the role of MMP9 in ECM stiffness (fibrosis), we measured collagen deposition in the histological sections of hearts using Masson’s trichrome staining. The role of MMP9 in cardiac stem cell survival and differentiation was determined by co-immunoprecipitation (co-IP) of MMP9 with c-kit (a marker of stem cells) and measuring the level of troponin I (a marker of cardiomyocytes) by confocal microscopy in the 3 groups. Our results revealed that ablation of MMP9 (i) reduces the stiffness of ECM by decreasing collagen accumulation (fibrosis), and (ii) enhances the survival (elevated c-kit level) and differentiation of cardiac stem cells into cardiomyocytes (increased troponin I) in diabetes. We conclude that inhibition of MMP9 ameliorates stem cell survival and their differentiation into cardiomyocytes in diabetes.

BCR-ABL1 Kinase Activity but Not Its Expression Is Dispensable for Ph+ Quiescent Stem Cell Survival Which Depends on the PP2A-Controlled Jak2 Activation and Is Sensitive to FTY720 Treatment

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 515-515 ◽  
Author(s):  
Paolo Neviani ◽  
Jason G Harb ◽  
Joshua J Oaks ◽  
Christopher Walker ◽  
Ramasamy Santhanam ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Survival ◽  
Transcriptional Activity ◽  
Kinase Activity ◽  
Self Renewal ◽  
Cd34 Cells ◽  
Stem Cell Survival ◽  
Quiescent Stem Cells

Abstract Abstract 515 The success of tyrosine kinase inhibitors as first line therapy for t(9;22) Chronic Myelogenous Leukemia (CML) depends on the addiction that Philadelphia-positive (Ph+) hematopoietic progenitors, but not quiescent Ph+ stem cells, have for BCR-ABL1 tyrosine kinase activity. We reported that the activity of the tumor suppressor PP2A is inhibited in a SET-dependent manner in CML progenitors and CD34+/CD38- stem cells from chronic phase (CP) and, to a greater extent, blast crisis (BC) CML patients (Neviani P. et al.: Cancer Cell 2005, J. Clin. Invest 2007, and ASH 2008). Restoration of PP2A activity by the immunosuppressive sphingosine analogue FTY720 markedly decreases the number of Ph+ but not normal long-term culture-initiating cells (LTC-IC) and quiescent stem cells (CFSEMAX/CD34+) by suppressing the BCR/ABL kinase-independent enhancement of b-catenin expression/transcriptional activity (Oaks JJ., et al., ASH 2009). Here we report that FTY720 induces apoptosis of Ph+ CD34+/CD38- cells independent from its phosphorylation as treatment with a phosphorylated FTY720 did not alter the number of Ph+ CFSEMAX/CD34+ cells. By contrast, two non phosphorylatable and non immunosuppressive FTY720 derivatives did significantly affect survival of Ph+ stem/progenitor cells. Interestingly, we also noted that the activity but not expression of BCR-ABL1 is considerably lower in quiescent CFSEMAX/CD34+ than CFSE+/CD34+ cells that underwent at least one division (∼80% decrease; n=3). Conversely, BCR-ABL1 expression is significantly higher in quiescent than proliferating CFSE+/CD34+ cells, suggesting that BCR-ABL1 might serve as a scaffold for other kinase(s) able to sustain survival and quiescence of Ph+ stem cells. Indeed, we found that expression of the K1172R kinase-deficient BCR-ABL1 mutant enhances expression and activity of Jak2, a kinase that is not only associated with BCR-ABL1 but is also capable of inactivating and being inactivated by PP2A. Accordingly, lentiviral shRNA-mediated BCR-ABL1 downregulation in Ph+ CD34+/CD38- stem cells resulted in marked (≥70% inhibition, P<0.05) reduction of Jak2 activity (measured by Jak2pY1007/8 intracellular flow cytometry) and of the PP2A inhibitor SET (≥20% inhibition, P<0.05). Consistent with a role of Jak2 as regulator of Ph+ stem cell survival, pharmacologic Jak2 inhibition (Jak2 inhibitor 1, 1uM; TG101209, 2.5uM; or TG101348, 1uM and 0.5uM) significantly reduces the number of Ph+ CFSEMAX/CD34+ (47% reduction, n=4), impairs LTC-IC Ph+ colony output (60% reduction, n=4), and induces apoptosis of Ph+ CD34+/CD38- cells. Inhibition of Jak2 also resulted in impaired b-catenin dependent transcriptional activity (61% reduction by LET-TCF luciferase assay, n=2), suggesting the existence of an active Jak2-PP2A interplay likely controlling survival and self-renewal of Ph+ stem cells through the Wnt pathway. In this regard, in vivo administration of FTY720 (4 weeks; 10mg/Kg/day) to FVB/N recipient mice transplanted with either GFP-sorted 2×106 whole bone marrow or 3×103 Lin−/Sca-1+/c-Kit+ (LSK) stem cells from leukemic scl-tTA/BCR-ABL/GFP mice not only significantly decreased the number of leukemic common and granulocyte-macrophage (CMP and GMP) progenitors but, more importantly, it resulted in 70–80% reduction in the number of the long-term hematopoietic stem cells (Lin−/Sca-1+/c-Kit+/CD48+/CD150−/Flt3−) compared to untreated leukemic mice. Furthermore, severely impaired engraftment (∼90% untreated vs. ∼37% FTY720-treated) was observed in secondary recipients transplanted with 2×106 bone marrow of FTY720-treated leukemic mice, suggesting that FTY720-induced PP2A activation inhibits the ability of BCR-ABL1-expressing LSK cells to undergo extensive self renewal in primary recipients. Thus, expression but not activity of the oncogenic product of the t(9;22) translocation is important for recruiting and allowing SET-mediated inhibition of PP2A and activation of Jak2; two events important for Ph+ stem cell survival and self renewal. Moreover, the ability of FTY720 and of its non-immunosuppressive derivatives to induce apoptosis of Ph+ progenitors and Ph+ but not normal quiescent stem cells emphasizes the notion that FTY720 and its derivatives represent strong and non-toxic anti-leukemic agents potentially useful not only for the treatment but, perhaps, for eradicating Ph+ leukemias. Disclosures: Holyoake: Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Isolation and characterisation of a novel trophoblast side-population from first trimester placentae

Reproduction ◽  
2015 ◽  
Vol 150 (5) ◽  
pp. 449-462 ◽  
Author(s):  
J L James ◽  
D G Hurley ◽  
T K J B Gamage ◽  
T Zhang ◽  
R Vather ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Side Population ◽  
First Trimester ◽  
Placental Development ◽  
Human Trophoblast ◽  
Trophoblast Stem Cells ◽  
Trophoblast Stem ◽  
Future Work ◽  
Extravillous Trophoblasts

The placenta is responsible for all nutrient and gas exchange between mother and baby during pregnancy. The differentiation of specialised placental epithelial cells called trophoblasts is essential for placental function, but we understand little about how these populations arise. Mouse trophoblast stem cells have allowed us to understand many of the factors that regulate murine trophoblast lineage development, but the human placenta is anatomically very different from the mouse, and it is imperative to isolate a human trophoblast stem cell to understand human placental development. Here we have developed a novel methodology to isolate a Hoechst side-population of trophoblasts from early gestation placentae and compared their transcriptome to differentiated trophoblast populations (cytotrophoblasts and extravillous trophoblasts) using microarray technology. Side-population trophoblasts clustered as a transcriptomically distinct population but were more closely related to cytotrophoblasts than extravillous trophoblasts. Side-population trophoblasts up-regulated a number of genes characteristic of trophectoderm and murine trophoblast stem cells in comparison to cytotrophoblasts or extravillous trophoblasts and could be distinguished from both of these more mature populations by a unique set of 22 up-regulated genes, which were enriched for morphogenesis and organ development and the regulation of growth functions. Cells expressing two of these genes (LAMA2 and COL6A3) were distributed throughout the cytotrophoblast layer at the trophoblast/mesenchymal interface. Comparisons to previously published trophoblast progenitor populations suggest that the side-population trophoblasts isolated in this work are a novel human trophoblast population. Future work will determine whether these cells exhibit functional progenitor/stem cell attributes.

Abstract 20: Manipulating PHD2 to Promote Efficacy of Stem Cell Therapy for Myocardial Infarction

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Wei Eric Wang ◽  
Dezhong Yang ◽  
Liangpeng Li ◽  
Yulan Peng ◽  
Wei Wang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Infarct Size ◽  
Cell Survival ◽  
Conditioned Medium ◽  
Stem Cell Survival ◽  
Cardioprotective Effects ◽  
Nf Kappab

OBJECTIVE: Stem cell transplantation has had modest success as a treatment for myocardial infarction (MI). One of the limitations is the poor stem cell survival and function in the diseased microenvironment. We studied whether and how prolyl hydroxylase domain protein 2 (PHD2), a cellular oxygen sensor, enhances stem cell cardioprotective effects after transplantation into infarcted hearts. METHODS and RESULTS: Both adipose-derived stem cells (ADSCs) and bone marrow mesenchymal stem cells (BM-MSCs) were used. Stem cells were transduced with lentiviral short hairpin RNA to silence PHD2 (shPHD2) and intramyocardially injected into infarcted heart in mice. ADSCs reduced cardiomyocyte apoptosis, fibrosis, and infarct size (MI+ADSCs: 39.4±3.3%;MI+PBS: 48.4±4.5%) and improved cardiac function (MI+ADSCs: 43.8±5.6%; MI+PBS: 37.2±3.0%). shPHD2-ADSCs exerted significantly more protection (infarct size: 22.6±3.0%; LVEF: 67.3±6.8%; p<0.05 vs. MI+ADSCs). PHD2 silencing induced greater ADSC survival (survival rate at 7 days post-transplantation: shPHD2-ADSCs: 14.7±4.2% vs. ADSCs: 3.4±0.8%, p<0.05), which was abolished by HIF-1alpha silencing. No ADSC gave rise to cardiomyocyte and ADSCs induced cardioprotection was mainly induced by paracrine function. Conditioned medium from shPHD2-ADSCs decreased cardiomyocyte apoptosis. Insulin-like growth factor-1 (IGF-1) levels were 3.8 times higher in the conditioned medium of shPHD2-ADSCs than ADSCs, and depletion of IGF-1 attenuated the cardioprotective effects of shPHD2-ADSC-conditioned medium. NF-kappaB activation was induced by shPHD2 to stimulate IGF-1 secretion via binding to the IGF-1 gene promoter. A combination of HIF-1alpha silencing and IGF-1 neurtralization blocked the beneficial effects of shPHD2-ADSCs for MI. Similar findings were observed with BM-MSCs. CONCLUSIONS: PHD2 silencing promotes stem cell survival in infarcted hearts and enhances their paracrine function to protect cardiomyocytes. Its prosurvival effect on stem cells is HIF-1alpha dependent, while it enhances stem cell paracrine function through NF-kappaB-mediated IGF-1 upregulation. PHD2 silencing in stem cells may be a novel strategy for enhancing the effectiveness of stem cell therapy after MI.

scholarly journals An Shp2/SFK/Ras/Erk Signaling Pathway Controls Trophoblast Stem Cell Survival

2006 ◽  
Vol 10 (3) ◽  
pp. 317-327 ◽  
Author(s):  
Wentian Yang ◽  
Lori D. Klaman ◽  
Binbin Chen ◽  
Toshiyuki Araki ◽  
Hisashi Harada ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Survival ◽  
Signaling Pathway ◽  
Erk Signaling ◽  
Trophoblast Stem ◽  
Stem Cell Survival ◽  
Trophoblast Stem Cell

scholarly journals Inhibition of HSP90 Promotes Neural Stem Cell Survival from Oxidative Stress through Attenuating NF-κB/p65 Activation

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Qian Liu ◽  
Yun Li ◽  
Wenkai Jiang ◽  
Yunzi Li ◽  
Lin Zhou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Stem Cell ◽  
Oxidative Damage ◽  
Cell Survival ◽  
Specific Inhibitor ◽  
Heat Shock Protein 90 ◽  
Signalling Pathways ◽  
Stem Cell Survival ◽  
Stem Cell Treatment

Stem cell survival after transplantation determines the efficiency of stem cell treatment, which develops as a novel potential therapy for several central nervous system (CNS) diseases in recent decades. The engrafted stem cells face the damage of oxidative stress, inflammation, and immune response at the lesion point in host. Among the damaging pathologies, oxidative stress directs stem cells to apoptosis and even death through several signalling pathways and DNA damage. However, the in-detail mechanism of stem cell survival from oxidative stress has not been revealed clearly. Here, in this study, we used hydrogen peroxide (H2O2) to induce the oxidative damage on neural stem cells (NSCs). The damage was in consequence demonstrated involving the activation of heat shock protein 90 (HSP90) and NF-κB/p65 signalling pathways. Further application of the pharmacological inhibitors, respectively, targeting at each signalling indicated an upper-stream role of HSP90 upon NF-κB/p65 on NSCs survival. Preinhibition of HSP90 with the specific inhibitor displayed a significant protection on NSCs against oxidative stress. In conclusion, inhibition of HSP90 would attenuate NF-κB/p65 activation by oxidative induction and promote NSCs survival from oxidative damage. The HSP90/NF-κB mechanism provides a new evidence on rescuing NSCs from oxidative stress and also promotes the stem cell application on CNS pathologies.

Rho GDIalpha Modulates Rabbit Trophoblast Stem Cell Survival and Migration1

2015 ◽  
Vol 93 (6) ◽  
Author(s):  
Jinjuan Zhang ◽  
Tianjie Li ◽  
Weizhi Ji ◽  
Yang Yu ◽  
Tao Tan
Keyword(s):  
Stem Cell ◽  
Cell Survival ◽  
Trophoblast Stem ◽  
Stem Cell Survival ◽  
Trophoblast Stem Cell
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