Prion Protein in Stem Cells: A Lipid Raft Component Involved in the Cellular Differentiation Process

The prion protein (PrP) is an enigmatic molecule with a pleiotropic effect on different cell types; it is localized stably in lipid raft microdomains and it is able to recruit downstream signal transduction pathways by its interaction with various biochemical partners. Since its discovery, this lipid raft component has been involved in several functions, although most of the publications focused on the pathological role of the protein. Recent studies report a key role of cellular prion protein (PrPC) in physiological processes, including cellular differentiation. Indeed, the PrPC, whose expression is modulated according to the cell differentiation degree, appears to be part of the multimolecular signaling pathways of the neuronal differentiation process. In this review, we aim to summarize the main findings that report the link between PrPC and stem cells.

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The Role of Cellular Prion Protein in Cancer Biology: A Potential Therapeutic Target

Frontiers in Oncology ◽

10.3389/fonc.2021.742949 ◽

2021 ◽

Vol 11 ◽

Author(s):

Manqiu Ding ◽

Yongqiang Chen ◽

Yue Lang ◽

Li Cui

Keyword(s):

Stem Cells ◽

Nervous System ◽

Cell Survival ◽

Cancer Cells ◽

Prion Protein ◽

Therapeutic Target ◽

Cancer Biology ◽

Cellular Prion Protein ◽

Potential Therapeutic Target

Prion protein has two isoforms including cellular prion protein (PrPC) and scrapie prion protein (PrPSc). PrPSc is the pathological aggregated form of prion protein and it plays an important role in neurodegenerative diseases. PrPC is a glycosylphosphatidylinositol (GPI)-anchored protein that can attach to a membrane. Its expression begins at embryogenesis and reaches the highest level in adulthood. PrPC is expressed in the neurons of the nervous system as well as other peripheral organs. Studies in recent years have disclosed the involvement of PrPC in various aspects of cancer biology. In this review, we provide an overview of the current understanding of the roles of PrPC in proliferation, cell survival, invasion/metastasis, and stem cells of cancer cells, as well as its role as a potential therapeutic target.

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Role of hypoxia-mediated cellular prion protein functional change in stem cells and potential application in angiogenesis

Molecular Medicine Reports ◽

10.3892/mmr.2017.7387 ◽

2017 ◽

Vol 16 (5) ◽

pp. 5747-5751 ◽

Cited By ~ 2

Author(s):

Seung Pil Yun ◽

Yong-Seok Han ◽

Jun Hee Lee ◽

Yeo Min Yoon ◽

Chul Won Yun ◽

...

Keyword(s):

Stem Cells ◽

Prion Protein ◽

Potential Application ◽

Functional Change ◽

Cellular Prion Protein

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The role of prion protein in stem cell regulation

Reproduction ◽

10.1530/rep-13-0100 ◽

2013 ◽

Vol 146 (3) ◽

pp. R91-R99 ◽

Cited By ~ 12

Author(s):

A Miranda ◽

P Ramos-Ibeas ◽

E Pericuesta ◽

M A Ramirez ◽

A Gutierrez-Adan

Keyword(s):

Stem Cells ◽

Prion Protein ◽

Prion Diseases ◽

Cellular Prion Protein ◽

Important Advance ◽

Self Renewal ◽

Stem Cell Regulation ◽

Pluripotency Gene ◽

New Strategies

Cellular prion protein (PrPC) has been well described as an essential partner of prion diseases due to the existence of a pathological conformation (PrPSc). Recently, it has also been demonstrated that PrPCis an important element of the pluripotency and self-renewal matrix, with an increasing amount of evidence pointing in this direction. Here, we review the data that demonstrate its role in the transcriptional regulation of pluripotency, in the differentiation of stem cells into different lineages (e.g. muscle and neurons), in embryonic development, and its involvement in reproductive cells. Also highlighted are recent results from our laboratory that describe an important regulation by PrPCof the major pluripotency geneNanog. Together, these data support the appearance of new strategies to control stemness, which could represent an important advance in the field of regenerative medicine.

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Cellular and Molecular Mechanisms Mediated by recPrPC Involved in the Neuronal Differentiation Process of Mesenchymal Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20020345 ◽

2019 ◽

Vol 20 (2) ◽

pp. 345 ◽

Cited By ~ 8

Author(s):

Stefano Martellucci ◽

Costantino Santacroce ◽

Francesca Santilli ◽

Luca Piccoli ◽

Simona Delle Monache ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Neuronal Differentiation ◽

Lipid Rafts ◽

Prion Protein ◽

Signal Pathway ◽

Differentiation Process ◽

Akt Phosphorylation ◽

Intracellular Signal

Human Dental Pulp Stem Cells (hDPSCs) represent a type of adult mesenchymal stem cells that have the ability to differentiate in vitro in several lineages such as odontoblasts, osteoblasts, chondrocytes, adipocytes and neurons. In the current work, we used hDPSCs as the experimental model to study the role of recombinant prion protein 23–231 (recPrPC) in the neuronal differentiation process, and in the signal pathway activation of ERK 1/2 and Akt. We demonstrated that recPrPC was able to activate an intracellular signal pathway mediated by extracellular-signal-regulated kinase 1 and 2 (ERK 1/2) and protein kinase B (Akt). Moreover, in order to understand whether endogenous prion protein (PrPC) was necessary to mediate the signaling induced by recPrPC, we silenced PrPC, demonstrating that the presence of endogenous PrPC was essential for ERK 1/2 and Akt phosphorylation. Since endogenous PrPC is a well-known lipid rafts component, we evaluated the role of these structures in the signal pathway induced by recPrPC. Our results suggest that lipid rafts integrity play a key role in recPrPC activity. In fact, lipid rafts inhibitors, such as fumonisin B1 and MβCD, significantly prevented ERK 1/2 and Akt phosphorylation induced by recPrPC. In addition, we investigated the capacity of recPrPC to induce hDPSCs neuronal differentiation process after long-term stimulation through the evaluation of typical neuronal markers expression such as B3-Tubulin, neurofilament-H (NFH) and growth associated protein 43 (GAP43). Accordingly, when we silenced endogenous PrPC, we observed the inhibition of neuronal differentiation induced by recPrPC. The combined data suggest that recPrPC plays a key role in the neuronal differentiation process and in the activation of specific intracellular signal pathways in hDPSCs.

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Emerging Role of Cellular Prion Protein in the Maintenance and Expansion of Glioma Stem Cells

Cells ◽

10.3390/cells8111458 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1458

Author(s):

Stefano Thellung ◽

Alessandro Corsaro ◽

Alessia Bosio ◽

Martina Zambito ◽

Federica Barbieri ◽

...

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Prion Protein ◽

Cellular Prion Protein ◽

Membrane Receptors ◽

Cell Proliferation And Migration ◽

And Migration ◽

Stress Dependent ◽

Proliferation And Migration

Cellular prion protein (PrPC) is a membrane-anchored glycoprotein representing the physiological counterpart of PrP scrapie (PrPSc), which plays a pathogenetic role in prion diseases. Relatively little information is however available about physiological role of PrPC. Although PrPC ablation in mice does not induce lethal phenotypes, impairment of neuronal and bone marrow plasticity was reported in embryos and adult animals. In neurons, PrPC stimulates neurite growth, prevents oxidative stress-dependent cell death, and favors antiapoptotic signaling. However, PrPC activity is not restricted to post-mitotic neurons, but promotes cell proliferation and migration during embryogenesis and tissue regeneration in adult. PrPC acts as scaffold to stabilize the binding between different membrane receptors, growth factors, and basement proteins, contributing to tumorigenesis. Indeed, ablation of PrPC expression reduces cancer cell proliferation and migration and restores cell sensitivity to chemotherapy. Conversely, PrPC overexpression in cancer stem cells (CSCs) from different tumors, including gliomas—the most malignant brain tumors—is predictive for poor prognosis, and correlates with relapses. The mechanisms of the PrPC role in tumorigenesis and its molecular partners in this activity are the topic of the present review, with a particular focus on PrPC contribution to glioma CSCs multipotency, invasiveness, and tumorigenicity.

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The Post-Transfusion Recovery and Survival of Red Blood Cells in Mice Is Affected by the Expression of Cellular Prion Protein.

Blood ◽

10.1182/blood.v108.11.959.959 ◽

2006 ◽

Vol 108 (11) ◽

pp. 959-959

Author(s):

Karel Holada ◽

Jan Simak ◽

Jaroslav G. Vostal

Keyword(s):

Stem Cells ◽

Flow Cytometry ◽

Red Blood Cells ◽

Prion Protein ◽

Blood Cells ◽

Survival Curve ◽

Protective Role ◽

Cellular Prion Protein ◽

Hematopoietic Stem

Abstract Three documented transfusion cases of vCJD underline the need of better insight in blood prion protein biology. Cellular prion protein (PrPc) plays key role in the pathophysiology of prion diseases. Its expression by cells is necessary for amplification of infectious prions and the disease process itself. Physiological function of PrPc remains obscure. Its clarification may provide important clues for the development of urgently needed blood test and effective disease treatment. PrPc is expressed on CD34+ hematopoietic stem cells and its expression is regulated during blood cell differentiation. Recently the importance of PrPc for self-renewal of long-term repopulating hematopoietic stem cells was suggested and other studies reported the protective function of PrPc against oxidative stress and apoptosis in various cell cultures. We previously demonstrated that human as well as mouse red blood cells (RBC) express approximately 200 PrPc molecules / cell (Holada et al., BJH 2000, 110, 472–80). To test if the PrPc expression plays a role in the post-transfusion recovery and survival of RBC we carried out transfusion study in mice. RBC isolated from blood of wild type (WT) and PrP knockout (KO) FVB mice were labeled “in vitro” by different levels of NHS-biotin. The labeling was optimized to allow simultaneous detection of both populations of RBC in mouse blood using flow cytometry. To exclude the influence of different level of cell biotinylation on the experiment outcome two mixtures of RBC were prepared. The first contained KO RBC labeled with high and WT RBC with low level of biotin and the second mixture contained cells labeled “vice versa”. Each mixture was injected via tail vein in a group of WT mice (n=5) and the survival of RBCs was followed. Samples were analyzed on day 1, 2, 3, 6, 9, 15, 21 and 29. The count of biotinylated RBC was measured in comparison to 100 000 nonlabeled recipient RBC. Simultaneously the expression of PrPc on RBC was monitored using flow cytometry with MAb 6H4. KO RBC displayed significantly higher first day post-transfusion recovery compared to WT RBC in both groups of mice (81 ± 3 % vs. 74 ± 3 %, P<0.005 and 90 ± 4 % vs. 80 ± 4 %, P<0.005). The slope of the RBC survival curve in all individual mice during the initial 15 days was steeper for KO RBC (mavg = − 3.44) than for WT RBC (mavg = − 2.37) suggesting the protective role of PrPc in circulating RBC. The difference in the slope diminished during the 15 to 29 day period which was accompanied by a 50% decrease of PrPc surface expression on transfused WT RBC. To confirm our data the identical experiment was carried out in a group of KO mice (n=5) transfused with a mixture containing KO RBC labeled with low and WT RBC with high level of biotin. Again the first day post-transfusion recovery was higher for KO RBC (80 ± 6 % vs. 75 ± 6 %, P<0.05) and the initial slope of the KO RBC survival curve was steeper in all mice in the group. Our data suggest that PrPc expression plays role in the post-transfusion recovery and survival of RBC. The observation that WT RBC disappear from the circulation at lower rate than KO RBC until their level of surface PrPc reaches 50% is compatible with the protective role of PrPc expression on cells. Taken together our study demonstrates that physiological role of PrPc expression on RBC may lay in facilitating their longer survival in circulation. (GACR 310/04/0419, MSMT 0021620806).

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The Role of Angiogenesis and Pro-Angiogenic Exosomes in Regenerative Dentistry

International Journal of Molecular Sciences ◽

10.3390/ijms20020406 ◽

2019 ◽

Vol 20 (2) ◽

pp. 406 ◽

Cited By ~ 14

Author(s):

Alina-Andreea Zimta ◽

Oana Baru ◽

Mandra Badea ◽

Smaranda Buduru ◽

Ioana Berindan-Neagoe

Keyword(s):

Stem Cells ◽

Vascular Endothelial Cells ◽

Cell Types ◽

Toxic Waste ◽

Vascular Endothelial ◽

Regenerative Dentistry ◽

Oral Tissue ◽

Cellular Components ◽

Stimulation Of

Dental surgeries can result in traumatic wounds that provoke major discomfort and have a high risk of infection. In recent years, density research has taken a keen interest in finding answers to this problem by looking at the latest results made in regenerative medicine and adapting them to the specificities of oral tissue. One of the undertaken directions is the study of angiogenesis as an integrative part of oral tissue regeneration. The stimulation of this process is intended to enhance the local availability of stem cells, oxygen levels, nutrient supply, and evacuation of toxic waste. For a successful stimulation of local angiogenesis, two major cellular components must be considered: the stem cells and the vascular endothelial cells. The exosomes are extracellular vesicles, which mediate the communication between two cell types. In regenerative dentistry, the analysis of exosome miRNA content taps into the extended communication between these cell types with the purpose of improving the regenerative potential of oral tissue. This review analyzes the stem cells available for the dentistry, the molecular cargo of their exosomes, and the possible implications these may have for a future therapeutic induction of angiogenesis in the oral wounds.

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Insulin-Like Growth Factor Binding Protein-6 Promotes the Differentiation of Placental Mesenchymal Stem Cells into Skeletal Muscle Independent of Insulin-Like Growth Factor Receptor-1 and Insulin Receptor

Stem Cells International ◽

10.1155/2019/9245938 ◽

2019 ◽

Vol 2019 ◽

pp. 1-18 ◽

Cited By ~ 2

Author(s):

Doaa Aboalola ◽

Victor K. M. Han

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Growth Factor ◽

Muscle Differentiation ◽

Insulin Like Growth Factor ◽

Differentiation Process ◽

Placental Mesenchymal Stem Cells

As mesenchymal stem cells (MSCs) are being investigated for regenerative therapies to be used in the clinic, delineating the roles of the IGF system in MSC growth and differentiation, in vitro, is vital in developing these cellular therapies to treat degenerative diseases. Muscle differentiation is a multistep process, starting with commitment to the muscle lineage and ending with the formation of multinucleated fibers. Insulin-like growth factor binding protein-6 (IGFBP-6), relative to other IGFBPs, has high affinity for IGF-2. However, the role of IGFBP-6 in muscle development has not been clearly defined. Our previous studies showed that in vitro extracellular IGFBP-6 increased myogenesis in early stages and could enhance the muscle differentiation process in the absence of IGF-2. In this study, we identified the signal transduction mechanisms of IGFBP-6 on muscle differentiation by placental mesenchymal stem cells (PMSCs). We showed that muscle differentiation required activation of both AKT and MAPK pathways. Interestingly, we demonstrated that IGFBP-6 could compensate for IGF-2 loss and help enhance the muscle differentiation process by triggering predominantly the MAPK pathway independent of activating either IGF-1R or the insulin receptor (IR). These findings indicate the complex interactions between IGFBP-6 and IGFs in PMSC differentiation into the skeletal muscle and that the IGF signaling axis, specifically involving IGFBP-6, is important in muscle differentiation. Moreover, although the major role of IGFBP-6 is IGF-2 inhibition, it is not necessarily the case that IGFBP-6 is the main modulator of IGF-2.

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