| 1. |
- Abomaray, F, et al.
(författare)
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Mesenchymal Stromal Cells Are More Immunosuppressive In Vitro If They Are Derived from Endometriotic Lesions than from Eutopic Endometrium
- 2017
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Ingår i: Stem cells international. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2017, s. 3215962-
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Tidskriftsartikel (refereegranskat)abstract
- Endometriosis is an inflammatory disease with predominance of immunosuppressive M2 macrophages in the pelvic cavity that could be involved in the pathology through support and immune escape of ectopic lesions. Mesenchymal stromal cells (MSC) are found in ectopic lesions, and MSC from nonendometriosis sources are known to induce M2 macrophages. Therefore, MSC were hypothesized to play a role in the pathology of endometriosis. The aim was to characterize the functional phenotype of MSC in ectopic and eutopic endometrium from women with endometriosis. Stromal cells from endometriotic ovarian cysts (ESCcyst) and endometrium (ESCendo) were examined if they exhibited a MSC phenotype. Then, ESC were phenotypically examined for protein and gene expression of immunosuppressive and immunostimulatory molecules. Finally, ESC were functionally examined for their effects on monocyte differentiation into macrophages. ESCcystand ESCendoexpressed MSC markers, formed colonies, and differentiated into osteoblasts and adipocytes. Phenotypically, ESCcystwere more immunosuppressive, with significantly higher expression of immunosuppressive molecules. Functionally, ESCcystinduced more spindle-shaped macrophages, with significantly higher expression of CD14 and CD163, both features of M2 macrophages. The results suggest that ESCcystmay be more immunosuppressive than ESCendoand may promote immunosuppressive M2 macrophages that may support growth and reduce immunosurveillance of ectopic lesions.
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| 2. |
- Abomaray, F, et al.
(författare)
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Mesenchymal Stromal Cells Support Endometriotic Stromal Cells In Vitro
- 2018
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Ingår i: Stem cells international. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2018, s. 7318513-
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Tidskriftsartikel (refereegranskat)abstract
- Endometriosis is an inflammatory disease marked by ectopic growth of endometrial cells. Mesenchymal stromal cells (MSC) have immunosuppressive properties that have been suggested as a treatment for inflammatory diseases. Therefore, the aim herein was to examine effects of allogeneic MSC on endometriosis-derived cellsin vitroas a potential therapy for endometriosis. MSC from allogeneic adipose tissue (Ad-MSC) and stromal cells from endometrium (ESCendo) and endometriotic ovarian cysts (ESCcyst) from women with endometriosis were isolated. The effects of Ad-MSC on ESCendoand ESCcystwere investigated usingin vitroproliferation, apoptosis, adhesion, tube formation, migration, and invasion assays. Ad-MSC significantly increased proliferation of ESC compared to untreated controls. Moreover, Ad-MSC significantly decreased apoptosis and increased survival of ESC. Ad-MSC significantly increased adhesion of ESCendoand not ESCcyston fibronectin. Conditioned medium from cocultures of Ad-MSC and ESC significantly increased tube formation of human umbilical vein endothelial cells on matrigel. Ad-MSC may significantly increase migration of ESCcystand did not increase invasion of both cell types. The data suggest that allogeneic Ad-MSC should not be considered as a potential therapy for endometriosis, because they may support the pathology by maintaining and increasing growth of ectopic endometrial tissue.
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| 3. |
- Abomaray, FM, et al.
(författare)
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Phenotypic and Functional Characterization of Mesenchymal Stem/Multipotent Stromal Cells from Decidua Basalis of Human Term Placenta
- 2016
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Ingår i: Stem cells international. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2016, s. 5184601-
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Tidskriftsartikel (refereegranskat)abstract
- Mesenchymal stem cell (MSC) therapies for the treatment of diseases associated with inflammation and oxidative stress employ primarily bone marrow MSCs (BMMSCs) and other MSC types such as MSC from the chorionic villi of human term placentae (pMSCs). These MSCs are not derived from microenvironments associated with inflammation and oxidative stress, unlike MSCs from thedecidua basalisof the human term placenta (DBMSCs). DBMSCs were isolated and then extensively characterized. Differentiation of DBMSCs into three mesenchymal lineages (adipocytes, osteocytes, and chondrocytes) was performed. Real-time polymerase chain reaction (PCR) and flow cytometry techniques were also used to characterize the gene and protein expression profiles of DBMSCs, respectively. In addition, sandwich enzyme-linked immunosorbent assay (ELISA) was performed to detect proteins secreted by DBMSCs. Finally, the migration and proliferation abilities of DBMSCs were also determined. DBMSCs were positive for MSC markers and HLA-ABC. DBMSCs were negative for hematopoietic and endothelial markers, costimulatory molecules, and HLA-DR. Functionally, DBMSCs differentiated into three mesenchymal lineages, proliferated, and migrated in response to a number of stimuli. Most importantly, these cells express and secrete a distinct combination of cytokines, growth factors, and immune molecules that reflect their unique microenvironment. Therefore, DBMSCs could be attractive, alternative candidates for MSC-based therapies that treat diseases associated with inflammation and oxidative stress.
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| 4. |
- Aguila, JC, et al.
(författare)
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Cellular programming and reprogramming: sculpting cell fate for the production of dopamine neurons for cell therapy
- 2012
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Ingår i: Stem cells international. - : Hindawi Limited. - 1687-9678 .- 1687-966X. ; 2012, s. 412040-
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Tidskriftsartikel (refereegranskat)abstract
- Pluripotent stem cells are regarded as a promising cell source to obtain human dopamine neurons in sufficient amounts and purity for cell replacement therapy. Importantly, the success of clinical applications depends on our ability to steer pluripotent stem cells towards the right neuronal identity. In Parkinson disease, the loss of dopamine neurons is more pronounced in the ventrolateral population that projects to the sensorimotor striatum. Because synapses are highly specific, only neurons with this precise identity will contribute, upon transplantation, to the synaptic reconstruction of the dorsal striatum. Thus, understanding the developmental cell program of the mesostriatal dopamine neurons is critical for the identification of the extrinsic signals and cell-intrinsic factors that instruct and, ultimately, determine cell identity. Here, we review how extrinsic signals and transcription factors act together during development to shape midbrain cell fates. Further, we discuss how these same factors can be appliedin vitroto induce, select, and reprogram cells to the mesostriatal dopamine fate.
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| 5. |
- Akhmanova, M, et al.
(författare)
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Physical, Spatial, and Molecular Aspects of Extracellular Matrix of In Vivo Niches and Artificial Scaffolds Relevant to Stem Cells Research
- 2015
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Ingår i: Stem cells international. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2015, s. 167025-
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular matrix can influence stem cell choices, such as self-renewal, quiescence, migration, proliferation, phenotype maintenance, differentiation, or apoptosis. Three aspects of extracellular matrix were extensively studied during the last decade: physical properties, spatial presentation of adhesive epitopes, and molecular complexity. Over 15 different parameters have been shown to influence stem cell choices. Physical aspects include stiffness (or elasticity), viscoelasticity, pore size, porosity, amplitude and frequency of static and dynamic deformations applied to the matrix. Spatial aspects include scaffold dimensionality (2D or 3D) and thickness; cell polarity; area, shape, and microscale topography of cell adhesion surface; epitope concentration, epitope clustering characteristics (number of epitopes per cluster, spacing between epitopes within cluster, spacing between separate clusters, cluster patterns, and level of disorder in epitope arrangement), and nanotopography. Biochemical characteristics of natural extracellular matrix molecules regard diversity and structural complexity of matrix molecules, affinity and specificity of epitope interaction with cell receptors, role of non-affinity domains, complexity of supramolecular organization, and co-signaling by growth factors or matrix epitopes. Synergy between several matrix aspects enables stem cells to retain their function in vivo and may be a key to generation of long-term, robust, and effective in vitro stem cell culture systems.
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| 6. |
- Albalushi, H, et al.
(författare)
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Laminin 521 Stabilizes the Pluripotency Expression Pattern of Human Embryonic Stem Cells Initially Derived on Feeder Cells
- 2018
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Ingår i: Stem cells international. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2018, s. 7127042-
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Tidskriftsartikel (refereegranskat)abstract
- Human embryonic stem (hES) cells represent an important tool to study early cell development. The previously described use of human recombinant laminin (LN) 521 represented a step forward in generating clinically safe culture conditions. To test the short-term effect of LN521 on cultured hES cells, five male hES cell lines were cultured on human foreskin fibroblasts (hFFs), Matrigel, LN521, and LN121 and characterized by qPCR, immunofluorescence analysis, as well as their potential for three-germ layer differentiation. Variations in gene expression related to pluripotency, stemness, and testicular cells at different passages and culture conditions were evaluated by qPCR. All cell lines expressed pluripotency markers at protein and RNA level and were able to differentiate into cell types of the three germ layers after being cultured on LN521 for nine passages. Reduction in variation of pluripotency marker expression could be observed after culturing the cells on LN521 for nine passages. hES cells cultured on LN521 exhibited less differentiation, faster cell growth, and attachment when compared to hES cells cultured on LN121 or Matrigel. Our results indicate a positive effect of LN521 in stabilizing pluripotency gene expression and might be the first step towards more controllable and robust culture conditions for hES cells.
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| 7. |
- Avaliani, Natalia, et al.
(författare)
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Directly Converted Human Fibroblasts Mature to Neurons and Show Long-Term Survival in Adult Rodent Hippocampus
- 2017
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Ingår i: Stem Cells International. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2017
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Tidskriftsartikel (refereegranskat)abstract
- Direct conversion of human somatic cells to induced neurons (iNs), using lineage-specific transcription factors has opened new opportunities for cell therapy in a number of neurological diseases, including epilepsy. In most severe cases of epilepsy, seizures often originate in the hippocampus, where populations of inhibitory interneurons degenerate. Thus, iNs could be of potential use to replace these lost interneurons. It is not known, however, if iNs survive and maintain functional neuronal properties for prolonged time periods in in vivo. We transplanted human fibroblast-derived iNs into the adult rat hippocampus and observed a progressive morphological differentiation, with more developed dendritic arborisation at six months as compared to one month. This was accompanied by mature electrophysiological properties and fast high amplitude action potentials at six months after transplantation. This proof-of-principle study suggests that human iNs can be developed as a candidate source for cell replacement therapy in temporal lobe epilepsy.
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| 8. |
- Basit, Farhan, et al.
(författare)
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The MYC/Max/MxD network is a target of mutated FLT3 signaling in hematopoietic stem cells in FLT3-ITD-induced myeloproliferative disease
- 2018
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Ingår i: Stem Cells International. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2018
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Tidskriftsartikel (refereegranskat)abstract
- Acute myeloid leukemia (AML) has poor prognosis due to various mutations, e.g., in the FLT3 gene. Therefore, it is important to identify pathways regulated by the activated Flt3 receptor for the discovery of new therapeutic targets. The Myc network of oncogenes and tumor suppressor genes is involved in mechanisms regulating proliferation and survival of cells, including that of the hematopoietic system. In this study, we evaluated the expression of the Myc oncogenes and Mxd antagonists in hematopoietic stem cell and myeloid progenitor populations in the Flt3-ITD-knockin myeloproliferative mouse model. Our data shows that the expression of Myc network genes is changed in Flt3-ITD mice compared with the wild type. Mycn is increased in multipotent progenitors and in the pre-GM compartment of myeloid progenitors in the ITD mice while the expression of several genes in the tumor suppressor Mxd family, including Mxd1, Mxd2, and Mxd4, is concomitantly downregulated, as well as the expression of the Mxd-related gene Mnt and the transcriptional activator Miz-1. LSKCD150 + CD48 − hematopoietic long-term stem cells are decreased in the Flt3-ITD cells while multipotent progenitors are increased. Of note, PKC412-mediated inhibition of Flt3-ITD signaling results in downregulation of cMyc and upregulation of the Myc antagonists Mxd1, Mxd2, and Mxd4. Our data provides new mechanistic insights into downstream alterations upon aberrant Flt3 signaling and rationale for combination therapies for tyrosine kinase inhibitors with Myc antagonists in treating AML.
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| 9. |
- Berglund, Sofia, et al.
(författare)
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Expansion of Gammadelta T Cells from Cord Blood : A Therapeutical Possibility
- 2018
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Ingår i: STEM CELLS INTERNATIONAL. - : HINDAWI LTD. - 1687-966X .- 1687-9678.
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Tidskriftsartikel (refereegranskat)abstract
- Gammadelta (gamma delta) T cells are found in both blood and tissues and have antiviral and antitumor properties. The frequency of gamma delta T cells in umbilical cord blood (UCB) is low, and the majority express delta 1, in contrast to blood, whereas the main subset is delta 2 gamma 9 T cells. UCB gamma delta T cells are functionally immature, which together with their scarcity complicates the development of UCB gamma delta T cell therapies. We aimed to develop an effective expansion protocol for UCB gamma delta T cells based on zoledronate and IL-2. We found that culture with 5 mu M zoledronate and 200 IU IL-2/ml medium for 14 days promoted extensive proliferation. The majority of the cultured cells were gamma 9 delta 2 T cells. The fold expansion of this, originally infrequent, subset was impressive (median and maximum fold change 253 and 1085, resp.). After culture, the cells had a polyclonal gamma delta T cell repertoire and the main memory subset was central memory (CD45RO(+) CD27(+)). The cells produced cytokines such as IL-1B, IL-2, and IL-8 and displayed significant tumor-killing capacity. These results show that development of in vitro expanded UCB gamma delta T cell therapies is feasible. It could prove a valuable treatment modality for patients after umbilical cord blood transplantation.
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| 10. |
- Bergström, Tomas F.
(författare)
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Assessment of Hereditary Retinal Degeneration in the English Springer Spaniel Dog and Disease Relationship to an RPGRIP1 Mutation
- 2012
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Ingår i: Stem Cells International. - : Hindawi Limited. - 1687-966X .- 1687-9678.
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Tidskriftsartikel (refereegranskat)abstract
- Intensive breeding and selection on desired traits have produced high rates of inherited diseases in dogs. Hereditary retinal degeneration, often called progressive retinal atrophy (PRA), is prevalent in dogs with disease entities comparable to human retinitis pigmentosa (RP) and Leber's congenital amaurosis (LCA). Recent molecular studies in the English Springer Spaniel (ESS) dog have shown that PRA cases are often homozygous for a mutation in the RPGRIP1 gene, the defect also causing human RP, LCA, and cone rod dystrophies. The present study characterizes the disease in a group of affected ESS in USA, using clinical, functional, and morphological studies. An objective evaluation of retinal function using electroretinography (ERG) is further performed in a masked fashion in a group of American ESS dogs, with the examiner masked to the genetic status of the dogs. Only 4 of 6 homozygous animals showed clinical signs of disease, emphasizing the need and importance for more precise studies on the clinical expression of molecular defects before utilizing animal models for translational research, such as when using stem cells for therapeutic intervention.
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| 11. |
- Chen, Liangliang, et al.
(författare)
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User-Friendly Genetic Conditional Knockout Strategies by CRISPR/Cas9
- 2018
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Ingår i: STEM CELLS INTERNATIONAL. - : HINDAWI LTD. - 1687-966X .- 1687-9678.
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Tidskriftsartikel (refereegranskat)abstract
- Loss-of-function studies are critically important in gene functional analysis of model organisms and cells. However, conditional gene inactivation in diploid cells is difficult to achieve, as it involves laborious vector construction, multifold electroporation, and complicated genotyping. Here, a strategy is presented for generating biallelic conditional gene and DNA regulatory region knockouts in mouse embryonic stem cells by codelivery of CRISPR-Cas9 and short-homology-arm targeting vectors sequentially or simultaneously. Collectively, a simple and rapid method was presented to knock out any DNA element conditionally. This approach will facilitate the functional studies of essential genes and regulatory regions during development.
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| 12. |
- Dottori, Mirella, et al.
(författare)
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Stem Cells as In Vitro Models of Disease
- 2012
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Ingår i: Stem Cells International. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2012
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 13. |
- Ekblad, A, et al.
(författare)
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Soft Tissue Repair with Easy-Accessible Autologous Newborn Placenta or Umbilical Cord Blood in Severe Malformations: A Primary Evaluation
- 2017
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Ingår i: Stem cells international. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2017, s. 1626741-
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Tidskriftsartikel (refereegranskat)abstract
- Disrupted organogenesis leads to permanent malformations that may require surgical correction. Autologous tissue grafts may be needed in severe lack of orthotopic tissue but include donor site morbidity. The placenta is commonly discarded after birth and has a therapeutic potential. The aim of this study was to determine if the amnion from placenta or plasma rich of growth factors (PRGF) with mononuclear cells (MNC) from umbilical cord blood (UCB), collected noninvasively, could be used as bio-constructs for autologous transplantation as an easy-accessible no cell culture-required method. Human amnion and PRGF gel were isolated and kept in culture for up to 21 days with or without small intestine submucosa (SIS). The cells in the constructs showed a robust phenotype without induced increased proliferation (Ki67) or apoptosis (caspase 3), but the constructs showed decreased integrity of the amnion-epithelial layer at the end of culture. Amnion-residing cells in the SIS constructs expressed CD73 or pan-cytokeratin, and cells in the PRGF-SIS constructs expressed CD45 and CD34. This study shows that amnion and UCB are potential sources for production of autologous grafts in the correction of congenital soft tissue defects. The constructs can be made promptly after birth with minimal handling or cell expansion needed.
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| 14. |
- Erkers, T, et al.
(författare)
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Lymphocytes in Placental Tissues: Immune Regulation and Translational Possibilities for Immunotherapy
- 2017
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Ingår i: Stem cells international. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2017, s. 5738371-
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Tidskriftsartikel (refereegranskat)abstract
- Immune modulation at the fetomaternal interface is crucial to ensure that the fetal allograft is not rejected. In the present review, the focus is to describe basic functions of lymphocyte populations and how they may contribute to fetomaternal immune regulation, as well as determining what proportions and effector functions of these cells are reported to be present in placental tissues in humans. Also explored is the possibility that unique cell populations at the fetomaternal interface may be targets for adoptive cell therapy. Increasing the understanding of immune modulation during pregnancy can give valuable insight into other established fields such as allogeneic hematopoietic stem cell transplantation and solid organ transplantation. In these settings, lymphocytes are key components that contribute to inflammation and rejection of either patient or donor tissues following transplantation. In contrast, an allogeneic fetus eludes rejection by the maternal immune system.
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| 15. |
- Gaballa, Ahmed, et al.
(författare)
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CD8(+)gamma delta T Cells Are More Frequent in CMV Seropositive Bone Marrow Grafts and Display Phenotype of an Adaptive Immune Response
- 2019
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Ingår i: STEM CELLS INTERNATIONAL. - : HINDAWI LTD. - 1687-966X .- 1687-9678. ; 2019
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Tidskriftsartikel (refereegranskat)abstract
- The role of gamma delta (gamma delta) T cells in human cytomegalovirus (HCMV) immune surveillance has been the focus of research interest for years. Recent reports have shown a substantial clonal proliferation of gamma delta T cells in response to HCMV, shedding light on the adaptive immune response of gamma delta T cells. Nevertheless, most efforts have focused on V delta 2(neg)gamma delta T cell subset while less attention has been given to investigate other less common gamma delta T cell subsets. In this regard, a distinct subpopulation of gamma delta T cells that expresses the CD8 coreceptor (CD8(+)gamma delta T cells) has not been thoroughly explored. Whether it is implicated in HCMV response and its ability to generate adaptive response has not been thoroughly investigated. In this study, we combined flow cytometry and immune sequencing of the TCR gamma-chain (TRG) to analyze in-depth bone marrow (BM) graft gamma delta T cells from CMV seropositive (CMV+) and CMV seronegative (CMV-) donors. We showed that the frequency of CD8(+)gamma delta T cells was significantly higher in CMV+ grafts compared to CMV- grafts (P<0.001). Further characterization revealed that CD8(+)gamma delta T cells from CMV+ grafts express V gamma 9(-) and preferentially differentiated from a naive to terminal effector memory phenotype (CD27(low/-)CD45RO(-)). In line with these findings, TRG immune sequencing revealed clonal focusing and reduced usage of the V gamma 9/JP gene segment in a CMV+ graft. Furthermore, CD8(+)gamma delta T cells showed an enhanced response to TCR/CD3 and cytokine stimulation in contrast to CD8(-)gamma delta T cells. We conclude that gamma delta T cells in BM grafts are reshaped by donor CMV serostatus and highlight the potential adaptive role of CD8(+)gamma delta T cells in HCMV immune response.
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| 16. |
- Ghosheh, Nidal, et al.
(författare)
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Highly Synchronized Expression of Lineage-Specific Genes during In Vitro Hepatic Differentiation of Human Pluripotent Stem Cell Lines
- 2016
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Ingår i: Stem Cells International. - : Hindawi Limited. - 1687-966X .- 1687-9678.
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Tidskriftsartikel (refereegranskat)abstract
- Human pluripotent stem cells- (hPSCs-) derived hepatocytes have the potential to replace many hepatic models in drug discovery and provide a cell source for regenerative medicine applications. However, the generation of fully functional hPSC-derived hepatocytes is still a challenge. Towards gaining better understanding of the differentiation and maturation process, we employed a standardized protocol to differentiate six hPSC lines into hepatocytes and investigated the synchronicity of the hPSC lines by applying RT-qPCR to assess the expression of lineage-specific genes (OCT4, NANOG, T, SOX17, CXCR4, CER1, HHEX, TBX3, PROX1, HNF6, AFP, HNF4a, KRT18, ALB, AAT, and CYP3A4) which serve as markers for different stages during liver development. The data was evaluated using correlation and clustering analysis, demonstrating that the expression of these markers is highly synchronized and correlated well across all cell lines. The analysis also revealed a distribution of the markers in groups reflecting the developmental stages of hepatocytes. Functional analysis of the differentiated cells further confirmed their hepatic phenotype. Taken together, these results demonstrate, on the molecular level, the highly synchronized differentiation pattern across multiple hPSC lines. Moreover, this study provides additional understanding for future efforts to improve the functionality of hPSC-derived hepatocytes and thereby increase the value of related models.
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| 17. |
- Hosseini, Kimia, et al.
(författare)
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Differentiation of Human Embryonic Stem Cells into Neuron, Cholinergic, and Glial Cells
- 2020
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Ingår i: Stem Cells International. - : HINDAWI LTD. - 1687-9678 .- 1687-966X. ; 2020
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Tidskriftsartikel (refereegranskat)abstract
- Human embryonic stem cells (hESCs) are pluripotent cells, capable of differentiation into different cellular lineages given the opportunity. Derived from the inner cell mass of blastocysts in early embryonic development, the cell self-renewal ability makes them a great tool for regenerative medicine, and there are different protocols available for maintaining hESCs in their undifferentiated state. In addition, protocols for differentiation into functional human neural stem cells (hNSCs), which have the potential for further differentiation into various neural cell types, are available. However, many protocols are time-consuming and complex and do not always fit for purpose. In this study, we carefully combined, optimized, and developed protocols for differentiation of hESCs into adherent monolayer hNSCs over a short period of time, with the possibility of both expansion and freezing. Moreover, the method details further differentiation into neurons, cholinergic neurons, and glial cells in a simple, single step by step protocol. We performed immunocytochemistry, qPCR, and electrophysiology to examine the expression profile and characteristics of the cells to verify cell lineage. Using presented protocols, the creation of neuronal cultures, cholinergic neurons, and a mixed culture of astrocytes and oligodendrocytes can be completed within a three-week time period.
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| 18. |
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| 19. |
- Kanayama, Kengo, et al.
(författare)
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Genome-wide mapping of bivalent histone modifications in hepatic stem/progenitor cells
- 2019
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Ingår i: Stem Cells International. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2019
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Tidskriftsartikel (refereegranskat)abstract
- The “bivalent domain,” a distinctive histone modification signature, is characterized by repressive trimethylation of histone H3 at lysine 27 (H3K27me3) and active trimethylation of histone H3 at lysine 4 (H3K4me3) marks. Maintenance and dynamic resolution of these histone marks play important roles in regulating differentiation processes in various stem cell systems. However, little is known regarding their roles in hepatic stem/progenitor cells. In the present study, we conducted the chromatin immunoprecipitation (ChIP) assay followed by high-throughput DNA sequencing (ChIP-seq) analyses in purified delta-like 1 protein (Dlk + ) hepatic stem/progenitor cells and successfully identified 562 genes exhibiting bivalent domains within 2 kb of the transcription start site. Gene ontology analysis revealed that these genes were enriched in developmental functions and differentiation processes. Microarray analyses indicated that many of these genes exhibited derepression after differentiation toward hepatocyte and cholangiocyte lineages. Among these, 72 genes, including Cdkn2a and Sox4, were significantly upregulated after differentiation toward hepatocyte or cholangiocyte lineages. Knockdown of Sox4 in Dlk + cells suppressed colony propagation and resulted in increased numbers of albumin + /cytokeratin 7 + progenitor cells in colonies. These findings implicate that derepression of Sox4 expression is required to induce normal differentiation processes. In conclusion, combined ChIP-seq and microarray analyses successfully identified bivalent genes. Functional analyses of these genes will help elucidate the epigenetic machinery underlying the terminal differentiation of hepatic stem/progenitor cells.
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| 20. |
- Khatlani, T, et al.
(författare)
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Preconditioning by Hydrogen Peroxide Enhances Multiple Properties of Human Decidua Basalis Mesenchymal Stem/Multipotent Stromal Cells
- 2018
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Ingår i: Stem cells international. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2018, s. 6480793-
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Tidskriftsartikel (refereegranskat)abstract
- Stem cell-based therapies rely on stem cell ability to repair in an oxidative stress environment. Preconditioning of mesenchymal stem cells (MSCs) to a stress environment has beneficial effects on their ability to repair injured tissues. We previously reported that MSCs from thedecidua basalis(DBMSCs) of human placenta have many important cellular functions that make them potentially useful for cell-based therapies. Here, we studied the effect of DBMSC preconditioning to a stress environment. DBMSCs were exposed to various concentrations of hydrogen peroxide (H2O2), and their functions were then assessed. DBMSC expression of immune molecules after preconditioning was also determined. DBMSC preconditioning with H2O2enhanced their proliferation, colonogenicity, adhesion, and migration. In addition, DBMSCs regardless of H2O2treatment displayed antiangiogenic activity. H2O2preconditioning also increased DBMSC expression of genes that promote cellular functions and decreased the expression of genes, which have opposite effect on their functions. Preconditioning also reduced DBMSC expression of IL-1β, but had no effects on the expression of other immune molecules that promote proliferation, adhesion, and migration. These data show that DBMSCs resist a toxic environment, which adds to their potential as a candidate stem cell type for treating various diseases in hostile environments.
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| 21. |
- Klassen, H., et al.
(författare)
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Photoreceptor Differentiation following Transplantation of Allogeneic Retinal Progenitor Cells to the Dystrophic Rhodopsin Pro347Leu Transgenic Pig
- 2012
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Ingår i: Stem Cells International. - : Hindawi Limited. - 1687-966X .- 1687-9678.
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Tidskriftsartikel (refereegranskat)abstract
- Purpose. Transplantation of stem, progenitor, or precursor cells has resulted in photoreceptor replacement and evidence of functional efficacy in rodent models of retinal degeneration. Ongoing work has been directed toward the replication of these results in a large animal model, namely, the pig. Methods. Retinal progenitor cells were derived from the neural retina of GFP-transgenic pigs and transplanted to the subretinal space of rhodopsin Pro347Leu-transgenic allorecipients, in the early stage of the degeneration and the absence of immune suppression. Results. Results confirm the survival of allogeneic porcine RPCs without immune suppression in the setting of photoreceptor dystrophy. The expression of multiple photoreceptor markers by grafted cells included the rod outer segment-specific marker ROM-1. Further evidence of photoreceptor differentiation included the presence of numerous photoreceptor rosettes within GFP-positive grafts, indicative of the development of cellular polarity and self-assembly into rudiments of outer retinal tissue. Conclusion. Together, these data support the tolerance of RPCs as allografts and demonstrate the high level of rod photoreceptor development that can be obtained from cultured RPCs following transplantation. Strategies for further progress in this area, together with possible functional implications, are discussed.
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| 22. |
- Kok, ZY, et al.
(författare)
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Dental Pulp Stem Cell Heterogeneity: Finding Superior Quality "Needles" in a Dental Pulpal "Haystack" for Regenerative Medicine-Based Applications
- 2022
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Ingår i: Stem cells international. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2022, s. 9127074-
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Tidskriftsartikel (refereegranskat)abstract
- Human dental pulp stem/stromal cells (hDPSCs) derived from the permanent secondary dentition are recognised to possess certain advantageous traits, which support their potential use as a viable source of mesenchymal stem/stromal cells (MSCs) for regenerative medicine-based applications. However, the well-established heterogeneous nature of hDPSC subpopulations, coupled with their limited numbers within dental pulp tissues, has impeded our understanding of hDPSC biology and the translation of sufficient quantities of these cells from laboratory research, through successful therapy development and clinical applications. This article reviews our current understanding of hDPSC biology and the evidence underpinning the molecular basis of their heterogeneity, which may be exploited to distinguish individual subpopulations with specific or superior characteristics for regenerative medicine applications. Pertinent unanswered questions which still remain, regarding the developmental origins, hierarchical organisation, and stem cell niche locations of hDPSC subpopulations and their roles in hDPSC heterogeneity and functions, will further be explored. Ultimately, a greater understanding of how key features, such as specific cell surface, senescence and other relevant genes, and protein and metabolic markers, delineate between hDPSC subpopulations with contrasting stemness, proliferative, multipotency, immunomodulatory, anti-inflammatory, and other relevant properties is required. Such knowledge advancements will undoubtedly lead to the development of novel screening, isolation, and purification strategies, permitting the routine and effective identification, enrichment, and expansion of more desirable hDPSC subpopulations for regenerative medicine-based applications. Furthermore, such innovative measures could lead to improved cell expansion, manufacture, and banking procedures, thereby supporting the translational development of hDPSC-based therapies in the future.
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| 23. |
- Nawaz, Muhammad, et al.
(författare)
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Extracellular Vesicles: Evolving Factors in Stem Cell Biology
- 2016
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Ingår i: Stem Cells International. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2016:1073140
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Tidskriftsartikel (refereegranskat)abstract
- Stem cells are proposed to continuously secrete trophic factors that potentially serve as mediators of autocrine and paracrine activities, associated with reprogramming of the tumor microenvironment, tissue regeneration, and repair. Hitherto, significant efforts have been made to understand the level of underlying paracrine activities influenced by stem cell secreted trophic factors, as little is known about these interactions. Recent findings, however, elucidate this role by reporting the effects of stem cell derived extracellular vesicles (EVs) that mimic the phenotypes of the cells from which they originate. Exchange of genetic information utilizing persistent bidirectional communication mediated by stem cell-EVs could regulate stemness, self-renewal, and differentiation in stem cells and their subpopulations. This review therefore discusses stem cell-EVs as evolving communication factors in stem cell biology, focusing on how they regulate cell fates by inducing persistent and prolonged genetic reprogramming of resident cells in a paracrine fashion. In addition, we address the role of stem cell-secreted vesicles in shaping the tumor microenvironment and immunomodulation and in their ability to stimulate endogenous repair processes during tissue damage. Collectively, these functions ensure an enormous potential for future therapies.
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| 24. |
- Pastula, Agnieszka, et al.
(författare)
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Three-Dimensional Gastrointestinal Organoid Culture in Combination with Nerves or Fibroblasts : A Method to Characterize the Gastrointestinal Stem Cell Niche
- 2016
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Ingår i: Stem Cells International. - : Hindawi Publishing Corporation. - 1687-9678 .- 1687-966X.
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Tidskriftsartikel (refereegranskat)abstract
- The gastrointestinal epithelium is characterized by a high turnover of cells and intestinal stem cells predominantly reside at the bottom of crypts and their progeny serve to maintain normal intestinal homeostasis. Accumulating evidence demonstrates the pivotal role of a niche surrounding intestinal stem cells in crypts, which consists of cellular and soluble components and creates an environment constantly influencing the fate of stem cells. Here we describe different 3D culture systems to culture gastrointestinal epithelium that should enable us to study the stem cell niche in vitro in the future: organoid culture and multilayered systems such as organotypic cell culture and culture of intestinal tissue fragments ex vivo. These methods mimic the in vivo situation in vitro by creating 3D culture conditions that reflect the physiological situation of intestinal crypts. Modifications of the composition of the culture media as well as coculturing epithelial organoids with previously described cellular components such as myofibroblasts, collagen, and neurons show the impact of the methods applied to investigate niche interactions in vitro. We further present a novel method to isolate labeled nerves from the enteric nervous system using Dclk1-CreGFP mice.
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| 25. |
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| 26. |
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| 27. |
- Pradip, Arvind, et al.
(författare)
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High Content Analysis of Human Pluripotent Stem Cell Derived Hepatocytes Reveals Drug Induced Steatosis and Phospholipidosis
- 2016
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Ingår i: Stem Cells International. - : Hindawi Publishing Corporation. - 1687-9678 .- 1687-966X. ; 2016
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Tidskriftsartikel (refereegranskat)abstract
- Hepatotoxicity is one of the most cited reasons for withdrawal of approved drugs from the market. The use of nonclinically relevant in vitro and in vivo testing systems contributes to the high attrition rates. Recent advances in differentiating human induced pluripotent stem cells (hiPSCs) into pure cultures of hepatocyte-like cells expressing functional drug metabolizing enzymes open up possibilities for novel, more relevant human cell based toxicity models. The present study aimed to investigate the use of hiPSC derived hepatocytes for conducting mechanistic toxicity testing by image based high content analysis (HCA). The hiPSC derived hepatocytes were exposed to drugs known to cause hepatotoxicity through steatosis and phospholipidosis, measuring several endpoints representing different mechanisms involved in drug induced hepatotoxicity. The hiPSC derived hepatocytes were benchmarked to the HepG2 cell line and generated robust HCA data with low imprecision between plates and batches. The different parameters measured were detected at subcytotoxic concentrations and the order of which the compounds were categorized (as severe, moderate, mild, or nontoxic) based on the degree of injury at isomolar concentration corresponded to previously published data. Taken together, the present study shows how hiPSC derived hepatocytes can be used as a platform for screening drug induced hepatotoxicity by HCA.
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| 28. |
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| 29. |
- Sallustio, F, et al.
(författare)
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Role of Toll-Like Receptors in Actuating Stem/Progenitor Cell Repair Mechanisms: Different Functions in Different Cells
- 2019
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Ingår i: Stem cells international. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2019, s. 6795845-
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Tidskriftsartikel (refereegranskat)abstract
- Toll-like receptors (TLRs) represent one of the bridges that regulate the cross-talk between the innate and adaptive immune systems. TLRs interact with molecules shared and preserved by the pathogens of origin but also with endogenous molecules (damage/danger-associated molecular patterns (DAMPs)) that derive from injured tissues. This is probably why TLRs have been found to be expressed on several kinds of stem/progenitor cells (SCs). In these cells, the role of TLRs in the regulation of the basal motility, proliferation, differentiation processes, self-renewal, and immunomodulation has been demonstrated. In this review, we analyze the many different functions that the TLRs assume in SCs, pointing out that they can have different effects, depending on the background and on the kind of ligands that they recognize. Moreover, we discuss the TLR involvement in the response of SC to specific tissue damage and in the reparative processes, as well as how the identification of molecules mediating the differential function of TLR signaling could be decisive for the development of new therapeutic strategies. Considering the available studies on TLRs in SCs, here we address the importance of TLRs in sensing an injury by stem/progenitor cells and in determining their behavior and reparative activity, which is dependent on the conditions. Therefore, it could be conceivable that SCs employed in therapy could be potentially exposed to TLR ligands, which might modulate their therapeutic potential in vivo. In this context, to modulate SC proliferation, survival, migration, and differentiation in the pathological environment, we need to better understand the mechanisms of action of TLRs on SCs and learn how to control these receptors and their downstream pathways in a precise way. In this manner, in the future, cell therapy could be improved and made safer.
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| 30. |
- Sheng, Renwang, et al.
(författare)
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The Application of Mechanical Stimulations in Tendon Tissue Engineering
- 2020
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Ingår i: Stem Cells International. - : Hindawi Publishing Corporation. - 1687-9678 .- 1687-966X. ; 2020
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Forskningsöversikt (refereegranskat)abstract
- Tendon injury is the most common disease in the musculoskeletal system. The current treatment methods have many limitations, such as poor therapeutic effects, functional loss of donor site, and immune rejection. Tendon tissue engineering provides a new treatment strategy for tendon repair and regeneration. In this review, we made a retrospective analysis of applying mechanical stimulation in tendon tissue engineering, and its potential as a direction of development for future clinical treatment strategies. For this purpose, the following topics are discussed; (1) the context of tendon tissue engineering and mechanical stimulation; (2) the applications of various mechanical stimulations in tendon tissue engineering, as well as their inherent mechanisms; (3) the application of magnetic force and the synergy of mechanical and biochemical stimulation. With this, we aim at clarifying some of the main questions that currently exist in the field of tendon tissue engineering and consequently gain new knowledge that may help in the development of future clinical application of tissue engineering in tendon injury.
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| 31. |
- Solders, Martin, et al.
(författare)
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Maternal Adaptive Immune Cells in Decidua Parietalis Display a More Activated and Coinhibitory Phenotype Compared to Decidua Basalis
- 2017
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Ingår i: Stem Cells International. - : Hindawi Limited. - 1687-9678 .- 1687-966X. ; 2017
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 Martin Solders et al. The maternal part of the placenta, the decidua, consists of maternal immune cells, decidual stromal cells, and extravillous fetal trophoblasts. In a successful pregnancy, these cell compartments interact to provide an intricate balance between fetal tolerance and antimicrobial defense. These processes are still poorly characterized in the two anatomically different decidual tissues, basalis and parietalis. We examined immune cells from decidua basalis and parietalis from term placentas (n=15) with flow cytometry. By using multivariate discriminant analysis, we found a clear separation between the two decidual compartments based on the 81 investigated parameters. Decidua parietalis lymphocytes displayed a more activated phenotype with a higher expression of coinhibitory markers than those isolated from basalis and contained higher frequencies of T regulatory cells. Decidua basalis contained higher proportions of monocytes, B cells, and mucosal-associated invariant T (MAIT) cells. The basalis B cells were more immature, and parietalis MAIT cells showed a more activated phenotype. Conventional T cells, NK cells, and MAIT cells from both compartments potently responded with the production of interferon-γ and/or cytotoxic molecules in response to stimulation. To conclude, leukocytes in decidua basalis and parietalis displayed remarkable phenotypic disparities, indicating that the corresponding stromal microenvironments provide different immunoregulatory signals.
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| 32. |
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| 33. |
- Virant-Klun, I., et al.
(författare)
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MicroRNAs: From Female Fertility, Germ Cells, and Stem Cells to Cancer in Humans
- 2016
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Ingår i: Stem Cells International. - : Hindawi Limited. - 1687-966X .- 1687-9678.
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs are a family of naturally occurring small noncoding RNA molecules that play an important regulatory role in gene expression. They are suggested to regulate a large proportion of protein encoding genes by mediating the translational suppression and posttranscriptional control of gene expression. Recent findings show that microRNAs are emerging as important regulators of cellular differentiation and dedifferentiation, and are deeply involved in developmental processes including human preimplantation development. They keep a balance between pluripotency and differentiation in the embryo and embryonic stem cells. Moreover, it became evident that dysregulation of microRNA expression may play a fundamental role in progression and dissemination of different cancers including ovarian cancer. The interest is still increased by the discovery of exosomes, that is, cell-derived vesicles, which can carry different proteins but also microRNAs between different cells and are involved in cell-to-cell communication. MicroRNAs, together with exosomes, have a great potential to be used for prognosis, therapy, and biomarkers of different diseases including infertility. The aim of this review paper is to summarize the existent knowledge on microRNAs related to female fertility and cancer: from primordial germ cells and ovarian function, germinal stem cells, oocytes, and embryos to embryonic stem cells.
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| 34. |
- Witman, N, et al.
(författare)
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Cardiac Progenitor Cells in Basic Biology and Regenerative Medicine
- 2018
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Ingår i: Stem cells international. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2018, s. 8283648-
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Tidskriftsartikel (refereegranskat)abstract
- Major cardiovascular events including myocardial infarction (MI) continue to dominate morbidity rates in the developed world. Although multiple device therapies and various pharmacological agents have been shown to improve patient care and reduce mortality rates, clinicians and researchers alike still lack a true panacea to regenerate damaged cardiac tissue. Over the previous two to three decades, cardiovascular stem cell therapies have held great promise. Several stem cell-based approaches have now been shown to improve ventricular function and are documented in preclinical animal models as well as phase I and phase II clinical trials. More recently, the cardiac progenitor cell has begun to gain momentum as an ideal candidate for stem cell therapy in heart disease. Here, we will highlight the most recent advances in cardiac stem/progenitor cell biology in regard to both the basics and applied settings.
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| 35. |
- Wu, Ziqian, et al.
(författare)
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Identification of Functional Modules and Key Pathways Associated with Innervation in Graft Bone-CGRP Regulates the Differentiation of Bone Marrow Mesenchymal Stem Cells via p38 MAPK and Wnt6/β-Catenin
- 2023
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Ingår i: Stem cells international. - : Hindawi Publishing Corporation. - 1687-966X .- 1687-9678. ; 2023
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Tidskriftsartikel (refereegranskat)abstract
- Bone resorption occurs after bone grafting, however, contemporaneous reconstruction of the innervation of the bone graft is a potential treatment to maintain the bone mass of the graft. The innervation of bone is an emerging research topic. To understand the potential molecular mechanisms of bone innervation after bone grafting, we collected normal iliac bone tissue as well as bone grafts with or without innervation from nine patients 1 year after surgery and performed RNA sequencing. We identified differentially expressed genes) from these samples and used the gene ontology and Kyoto Encyclopedia of Genes and Genomes databases for functional enrichment and signaling pathway analysis. In parallel, we established protein-protein interaction networks to screen functional modules. Based on bioinformatic results, we validated in vitro the osteogenic differentiation potential of rat bone marrow mesenchymal stem cells (BMMSCs) after calcitonin gene-related peptide (CGRP) stimulation and the expression of p38 MAPK and Wnt6/β-catenin pathways during osteogenesis. Our transcriptome analysis of bone grafts reveals functional modules and signaling pathways of innervation which play a vital role in the structural and functional integration of the bone graft. Simultaneously, we demonstrate that CGRP regulates the differentiation of BMMSCs through p38 MAPK and Wnt6/β-catenin.
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| 36. |
- Zhang, Aini, et al.
(författare)
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Advances in Regulatory Strategies of Differentiating Stem Cells towards Keratocytes
- 2022
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Ingår i: Stem Cells International. - : Hindawi Publishing Corporation. - 1687-9678 .- 1687-966X. ; 2022
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Forskningsöversikt (refereegranskat)abstract
- Corneal injury is a commonly encountered clinical problem which led to vision loss and impairment that affects millions of people worldwide. Currently, the available treatment in clinical practice is corneal transplantation, which is limited by the accessibility of donors. Corneal tissue engineering appears to be a promising alternative for corneal repair. However, current experimental strategies of corneal tissue engineering are insufficient due to inadequate differentiation of stem cell into keratocytes and thus cannot be applied in clinical practice. In this review, we aim to clarify the role and effectiveness of both biochemical factors, physical regulation, and the combination of both to induce stem cells to differentiate into keratocytes. We will also propose novel perspectives of differentiation strategy that may help to improve the efficiency of corneal tissue engineering.
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| 37. |
- Zhou, Y, et al.
(författare)
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Autologous Mesenchymal Stem Cell Transplantation in Multiple Sclerosis: A Meta-Analysis
- 2019
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Ingår i: Stem cells international. - : Hindawi Limited. - 1687-966X .- 1687-9678. ; 2019, s. 8536785-
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is considered to be a central nervous system (CNS) chronic inflammatory demyelinating disease, affecting more than 2 million individuals worldwide. In this meta-analysis, we aimed to assess the safety and efficacy of autologous mesenchymal stem cells (aMSCs) in treating MS patients. The PubMed, Embase, Cochrane, Web of Science, and Clinical Trial databases were searched in September 2019. The analysis was conducted for three endpoints: transplant-related mortality (TRM), rate of disease progression, and no evidence of disease activity (NEDA) status. RevMan and the metaprop command of the meta package in R was used in assessing the efficacy and safety of aMSCs. Subgroup analyses were performed for exploration of heterogeneity regarding outcomes. Nine studies comprising 133 patients were included in the meta-analysis. The pooled estimate of TRM was 0% (95% confidence interval (CI) 0%–0.3%). The rate of progression was 16% at 6 months (95% CI 10%–27%) and 35% at 1 year (95% CI 27%–46%). Lower 6-month and 1-year progression rates were significantly associated with intrathecal injection (p=0.02; p=0.003). The pooled proportion of NEDA patients at 6 months was 72% (95% CI 58%–89%) and at 1 year was 62% (95% CI 42%–81%). Cell transplantation with aMSCs in MS patients is safe, with the largest benefit profile obtained in patients with aMSCs intrathecal injection.
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