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STEM CELL BIOLOGY AND STRATEGIES FOR THERAPEUTIC DEVELOPMENT IN DEGENERATIVE DISEASES AND CANCER
Title
STEM CELL BIOLOGY AND STRATEGIES FOR THERAPEUTIC DEVELOPMENT IN DEGENERATIVE DISEASES AND CANCER.
Creator
Alvarez, Angel, Sugaya, Kiminobu, University of Central Florida
Abstract / Description
Stem cell biology is an exciting field that will lead to significant advancements in science and medicine. We hypothesize that inducing the expression of stem cell genes, using the embryonic stem cell gene nanog, will reprogram cells and dedifferentiate human mesenchymal stem cells into pluripotent stem cells capable of neural differentiation. The aims of initial studies are as follows: Aim 1: Demonstrate that forced expression of the embryonic stem cell gene nanog induces changes in human...
Show moreStem cell biology is an exciting field that will lead to significant advancements in science and medicine. We hypothesize that inducing the expression of stem cell genes, using the embryonic stem cell gene nanog, will reprogram cells and dedifferentiate human mesenchymal stem cells into pluripotent stem cells capable of neural differentiation. The aims of initial studies are as follows: Aim 1: Demonstrate that forced expression of the embryonic stem cell gene nanog induces changes in human mesenchymal stem cells to an embryonic stem cell-like phenotype. Aim 2: Demonstrate that induced expression of nanog up-regulates the expression of multiple embryonic stem cell markers and expands the differentiation potential of the stem cells. Aim 3: Demonstrate that these nanog-expressing stem cells have the ability to differentiate along neural lineages in vitro and in vivo, while mock-transfected cells have an extremely limited capacity for transdifferentiation. Alternatively, we hypothesize that embryonic stem cell genes can become activated in malignant gliomas and differentially regulate the subpopulation of cancer stem cells. This study examines the role of embryonic stem cell genes in transformed cells, particularly cancer stem cells. These studies explore has the following objectives: Aim 1: Isolate different sub-populations of cells from tumors and characterize cells with stem cell-like properties. Aim 2: Characterize the expression of embryonic stem cell markers in the sub-population of cancer stem cells. Aim 3: Examine the effects of histone deacetylase inhibitors at inhibiting the growth and reducing the expression of stem cell markers. Our research has demonstrated the potential of the embryonic transcription factor, nanog, at inducing dedifferentiation of human bone marrow mesenchymal stem cells and allowing their recommitment to a neural lineage. Specifically, we used viral and non-viral vectors to induce expression of NANOG, which produced an embryonic stem cell-like morphology in transduced cells. We characterized these cells using real-time PCR and immunohistochemical staining and find an up-regulation of genes responsible for pluripotency and self-renewal. Embryonic stem cell markers including Sox2, Oct4 and TERT were up-regulated following delivery of nanog. The role of nanog in the expression of these markers was further demonstrated in our induced-differentiation method where we transfected embryonic stem cell-like cells, that have been transduced with nanog flanked by two loxP sites, with a vector containing Cre-recominase. We tested the ability of these nanog-transfected cells to undergo neural differentiation in vitro using a neural co-culture system or in vivo following intracranial transplantation. Our next study characterized patient-derived glioblastoma cancer stem cells. We found that cells isolated from serum-free stem cell cultures were enriched for stem cell markers and were more proliferative than the bulk population of cells grown in convention serum-supplemented media. These cancer stem cells expressed embryonic stem cell markers NANOG and OCT4 whereas non-tumor-derived neural stem cells do not. Moreover, the expression of stem cell markers was correlated with enhanced proliferation and could serve as a measure of drug effectiveness. We tested two different histone deacetylase inhibitors, trichostatin A and valproic acid, and found that both inhibited proliferation and significantly reduced expression of stem cell markers in our cancer stem cell lines. These data demonstrate the potential use of stem cell genes as therapeutic markers and supports the hypothesis that cancer stem cells are a major contributor to brain tumor malignancy.
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Date Issued
2011
Identifier
CFE0003641, ucf:48845
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0003641
Investigating changes in quiescence in oral and esophageal epithelium in response to injury
Title
Investigating changes in quiescence in oral and esophageal epithelium in response to injury.
Creator
Rothaus, Alexandra, Andl, Claudia, Chakrabarti, Ratna, Singla, Dinender, University of Central Florida
Abstract / Description
More than 570,000 new cases of esophageal cancer are estimated to be diagnosed annually worldwide. Risk factors include gender, age, tobacco use and dietary habits leading to tissue injury and ultimately cancer. While prognoses for other cancers have improved, the 5-year survival for patients with esophageal cancer is only 20%. During the repair process, cell proliferation is increased and is associated with inflammation. Slow-cycling lifetime residential stem cells, called quiescent cells,...
Show moreMore than 570,000 new cases of esophageal cancer are estimated to be diagnosed annually worldwide. Risk factors include gender, age, tobacco use and dietary habits leading to tissue injury and ultimately cancer. While prognoses for other cancers have improved, the 5-year survival for patients with esophageal cancer is only 20%. During the repair process, cell proliferation is increased and is associated with inflammation. Slow-cycling lifetime residential stem cells, called quiescent cells, facilitate repair but are thought to accumulate mutations during DNA replication eventually giving rise to cancer. We hypothesize that esophageal stem cells become activated upon injury and are regulated by Transforming Growth Factor beta 1 (TGF?1), a known regulator of cell proliferation and differentiation. We established an in vitro model of quiescence using normal esophageal epithelial (STR) and oral (OKF6) cells treated with recombinant human TGF?1. Flow cytometry showed increases in cells arrested in G1/G0 phase of the cell cycle in TGF?1 treated cells for both cell lines (STR p(<)0.01, OKF6 p(<)0.05). EdU (5-ethynyl-2'-deoxyuridine) positive recovery cells indicated quiescence in both cell lines (p(<)0.01). Analysis of TGF?1 regulation of putative stem cell markers via western blot and qRT-PCR showed increases in ITGB1, PDPN and K15 as well as XPC, and MeCP2 in treated cells. To apply our in vitro findings, we performed immunohistochemistry staining on tissue microarrays. Proliferation marker Ki67 increased in disease progression from normal to inflammation to hyperplasia (p(<)0.001) while TGF?1 target markers decrease. Our data indicate that the onset of cancer-associated inflammation correlates with the loss of TGF?1 mediated stemness markers and increased basal proliferation suggesting cancer is a stem cell disease.
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Date Issued
2019
Identifier
CFE0007903, ucf:52754
Format
Document (PDF)
PURL
http://purl.flvc.org/ucf/fd/CFE0007903