scholarly journals Forkhead Protein FoxO1 Acts as a Repressor to Inhibit Cell Differentiation in Human Fetal Pancreatic Progenitor Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-6 ◽  
Author(s):  
Zongzhe Jiang ◽  
Jingjing Tian ◽  
Wenjian Zhang ◽  
Hao Yan ◽  
Liping Liu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Progenitor Cells ◽  
Nude Mice ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Pancreatic Progenitor ◽  
Pancreatic Progenitor Cells ◽  
In Vitro Induction

Our colleagues have reported previously that human pancreatic progenitor cells can readily differentiate into insulin-containing cells. Particularly, transplantation of these cell clusters upon in vitro induction for 3-4 w partially restores hyperglycemia in diabetic nude mice. In this study, we used human fetal pancreatic progenitor cells to identify the forkhead protein FoxO1 as the key regulator for cell differentiation. Thus, induction of human fetal pancreatic progenitor cells for 1 week led to increase of the pancreatic β cell markers such as Ngn3, but decrease of stem cell markers including Oct4, Nanog, and CK19. Of note, FoxO1 knockdown or FoxO1 inhibitor significantly upregulated Ngn3 and insulin as well as the markers such as Glut2, Kir6.2, SUR1, and VDCC, which are designated for mature β cells. On the contrary, overexpression of FoxO1 suppressed the induction and reduced expression of these β cell markers. Taken together, these results suggest that FoxO1 may act as a repressor to inhibit cell differentiation in human fetal pancreatic progenitor cells.

scholarly journals Multiple Lineages of Human Breast Cancer Stem/Progenitor Cells Identified by Profiling with Stem Cell Markers

PLoS ONE ◽  
2009 ◽  
Vol 4 (12) ◽  
pp. e8377 ◽  
Author(s):  
Wendy W. Hwang-Verslues ◽  
Wen-Hung Kuo ◽  
Po-Hao Chang ◽  
Chi-Chun Pan ◽  
Hsing-Hui Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Human Breast Cancer ◽  
Stem Cell Markers ◽  
Human Breast ◽  
Cell Markers

scholarly journals Focal Adhesion Kinase Inhibition Contributes to Tumor Cell Survival and Motility in Neuroblastoma Patient-Derived Xenografts

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Laura L. Stafman ◽  
Adele P. Williams ◽  
Raoud Marayati ◽  
Jamie M. Aye ◽  
Hooper R. Markert ◽  
...  
Keyword(s):  
Stem Cell ◽  
Tumor Cell ◽  
Cell Survival ◽  
Cell Lines ◽  
Human Condition ◽  
Migration And Invasion ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Cycle Arrest

Abstract Patient-derived xenografts (PDXs) provide an opportunity to evaluate the effects of therapies in an environment that more closely resembles the human condition than that seen with long-term passage cell lines. In the current studies, we investigated the effects of FAK inhibition on two neuroblastoma PDXs in vitro. Cells were treated with two small molecule inhibitors of FAK, PF-573,228 (PF) and 1,2,4,5-benzentetraamine tetrahydrochloride (Y15). Following FAK inhibition, cell survival and proliferation decreased significantly and cell cycle arrest was seen in both cell lines. Migration and invasion assays were used to determine the effect of FAK inhibition on cell motility, which decreased significantly in both cell lines in the presence of either inhibitor. Finally, tumor cell stemness following FAK inhibition was evaluated with extreme limiting dilution assays as well as with immunoblotting and quantitative real-time PCR for the expression of stem cell markers. FAK inhibition decreased formation of tumorspheres and resulted in a corresponding decrease in established stem cell markers. FAK inhibition decreased many characteristics of the malignant phenotype, including cancer stem cell like features in neuroblastoma PDXs, making FAK a candidate for further investigation as a potential target for neuroblastoma therapy.

scholarly journals Human Fetal Bone Marrow-Derived Mesenchymal Stem Cells Promote the Proliferation and Differentiation of Pancreatic Progenitor Cells and the Engraftment Function of Islet-Like Cell Clusters

2019 ◽  
Vol 20 (17) ◽  
pp. 4083
Author(s):  
Xing Yu Li ◽  
Shang Ying Wu ◽  
Po Sing Leung
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Progenitor Cells ◽  
Pancreatic Progenitor ◽  
Pancreatic Progenitor Cells ◽  
Proliferation And Differentiation ◽  
Differentiation And Proliferation

Pancreatic progenitor cells (PPCs) are the primary source for all pancreatic cells, including beta-cells, and thus the proliferation and differentiation of PPCs into islet-like cell clusters (ICCs) opens an avenue to providing transplantable islets for diabetic patients. Meanwhile, mesenchymal stem cells (MSCs) can enhance the development and function of different cell types of interest, but their role on PPCs remains unknown. We aimed to explore the mechanism-of-action whereby MSCs induce the in vitro and in vivo PPC/ICC development by means of our established co-culture system of human PPCs with human fetal bone marrow-derived MSCs. We examined the effect of MSC-conditioned medium on PPC proliferation and survival. Meanwhile, we studied the effect of MSC co-culture enhanced PPC/ICC function in vitro and in vivo co-/transplantation. Furthermore, we identified IGF1 as a critical factor responsible for the MSC effects on PPC differentiation and proliferation via IGF1-PI3K/Akt and IGF1-MEK/ERK1/2, respectively. In conclusion, our data indicate that MSCs stimulated the differentiation and proliferation of human PPCs via IGF1 signaling, and more importantly, promoted the in vivo engraftment function of ICCs. Taken together, our protocol may provide a mechanism-driven basis for the proliferation and differentiation of PPCs into clinically transplantable islets.

scholarly journals Genetic Modification of Primate Amniotic Fluid-Derived Stem Cells Produces Pancreatic Progenitor Cells in vitro

2013 ◽  
Vol 197 (4) ◽  
pp. 269-282 ◽  
Author(s):  
Yu Zhou ◽  
David L. Mack ◽  
J. Koudy Williams ◽  
Sayed-Hadi Mirmalek-Sani ◽  
Emily Moorefield ◽  
...  
Keyword(s):  
Stem Cells ◽  
Amniotic Fluid ◽  
Progenitor Cells ◽  
Genetic Modification ◽  
Pancreatic Progenitor ◽  
Pancreatic Progenitor Cells

Modeling Bone Marrow Failure and MDS in Shwachman Diamond Syndrome Using Induced Pluripotent Stem Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1496-1496 ◽  
Author(s):  
Melisa Ruiz-Gutierrez ◽  
Ozge Vargel Bolukbasi ◽  
Linda Vo ◽  
Ryohichi Sugimura ◽  
Marilyn Sanchez Bonilla ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Chromosome 7 ◽  
Stem Cell Markers ◽  
Hematopoietic Stem ◽  
Monosomy 7

Abstract Myelodysplastic syndrome (MDS) caused by monosomy 7 or del(7q) is a frequent clonal abnormality that arises in the context of inherited bone marrow failure syndromes, such as Shwachman Diamond Syndrome (SDS). Monosomy 7/del(7q) also develops in a subset of patients with acquired aplastic anemia or de novo MDS in the general population. Monosomy 7/del(7q) is associated with high grade MDS and a high risk of malignant transformation, most frequently to acute myelogenous leukemia (AML). Bone marrow failure and clonal evolution to MDS and AML remain major causes of morbidity and mortality for individuals with SDS. Currently, the only curative therapy for these hematological complications is a hematopoietic stem cell transplant. Prognosis is extremely poor once SDS patients develop leukemia. The basis for this propensity to develop monosomy 7 clones remains unclear. The longterm aim of this study is to understand the molecular mechanisms underlying leukemia predisposition and develop more effective treatments. Whether monosomy 7/del(7q) functions as a driver of MDS, or is merely an associated marker of clonal progression in bone marrow failure remains a critical question. The lack of synteny between murine versus human chromosome 7 has posed a major barrier to the development of mouse models of monosomy 7/del(7q). To study the biological and molecular consequences of monosomy 7/del(7q) in SDS, induced pluripotent stem cells (iPSCs) were generated from bone marrow mononuclear cells of two patients with SDS. Each patient harbored homozygous c.258+2 T>C mutations in the canonical splice donor site of intron 2 in the SBDS gene. The SDS-iPSCs retained the pathogenic homozygous IVS2+2 T>C SBDS mutations, expressed stem cell markers, formed teratomas, and expressed reduced levels of SBDS protein similar to levels noted in the primary patient samples. Proliferation of 4 distinct SDS-iPSC clones derived from two different patients was reduced relative to wild type controls without an increase in cell death. SDS-iPSC formed smaller embryoid bodies with reduced production of CD34+ hematopoietic stem/progenitor cells. Hematopoietic differentiation from CD34+ to CD45+ cells was also impaired. Preliminary data suggest that SDS-iPSCs retain the capacity to give rise to hematopoietic stem/progenitor cells and early myeloid progenitor cells in vitro. These populations were also observed in primary SDS patient-derived bone marrow samples. Because the number of CD34+ cells derived from SDS-iPSCs are limiting, a previously reported 5 transcrition factor re-specification system was used to expand multilineage hematopietic progenitors for further characterization. SDS iPSCs were able to differentiate into an expandable CD34+ population in vitro. Further studies to characterize the hematopoietic impairment in SDS iPSC and primary marrow samples are ongoing. To model del(7q) in SDS iPSCs, a deletion of the MDS-associated long arm of chromosome 7 was genomically engineered using a previously published modified Cre-Lox approach. The deletion of 7q at locus (11.2) was confirmed by karyotyping and by qPCR across chromosome 7. The SDS (del7q) iPSCs retained the SBDS pathogenic mutations, expressed stem cell markers, and formed teratomas. Proliferation of the SDS del(7q) iPSC was markedly impaired compared to isogenic SDS iPSCs. No increase in cell death was observed in the SDS del7q iPSCs. Studies are in progress to determine the effects of del7q on hematopoiesis. Investigation is ongoing to determine the molecular consequences of deleting 7q. These isogenic SDS+/- del(7q) iPS models provide a platform to study the role of 7q loss in clonal evolution from bone marrow failure and to screen for novel therapeutic compounds or pathways to treat bone marrow failure and MDS. Disclosures No relevant conflicts of interest to declare.

scholarly journals Molecular Characterization of c-Abl/c-Src Kinase Inhibitors Targeted against Murine Tumour Progenitor Cells that Express Stem Cell Markers

PLoS ONE ◽  
2010 ◽  
Vol 5 (11) ◽  
pp. e14143 ◽  
Author(s):  
Thomas Kruewel ◽  
Silvia Schenone ◽  
Marco Radi ◽  
Giovanni Maga ◽  
Astrid Rohrbeck ◽  
...  
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Molecular Characterization ◽  
Kinase Inhibitors ◽  
Src Kinase ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Murine Tumour
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