| 1. |
- Pozzobon, M, et al.
(författare)
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General consensus on multimodal functions and validation analysis of perinatal derivatives for regenerative medicine applications
- 2022
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Ingår i: Frontiers in bioengineering and biotechnology. - : Frontiers Media SA. - 2296-4185. ; 10, s. 961987-
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Tidskriftsartikel (refereegranskat)abstract
- Perinatal tissues, such as placenta and umbilical cord contain a variety of somatic stem cell types, spanning from the largely used hematopoietic stem and progenitor cells to the most recently described broadly multipotent epithelial and stromal cells. As perinatal derivatives (PnD), several of these cell types and related products provide an interesting regenerative potential for a variety of diseases. Within COST SPRINT Action, we continue our review series, revising and summarizing the modalities of action and proposed medical approaches using PnD products: cells, secretome, extracellular vesicles, and decellularized tissues. Focusing on the brain, bone, skeletal muscle, heart, intestinal, liver, and lung pathologies, we discuss the importance of potency testing in validating PnD therapeutics, and critically evaluate the concept of PnD application in the field of tissue regeneration. Hereby we aim to shed light on the actual therapeutic properties of PnD, with an open eye for future clinical application. This review is part of a quadrinomial series on functional/potency assays for validation of PnD, spanning biological functions, such as immunomodulation, anti-microbial/anti-cancer, anti-inflammation, wound healing, angiogenesis, and regeneration.
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| 2. |
- Casiraghi, F, et al.
(författare)
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Amnion epithelial cells are an effective source of factor H and prevent kidney complement deposition in factor H-deficient mice
- 2021
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Ingår i: Stem cell research & therapy. - : Springer Science and Business Media LLC. - 1757-6512. ; 12:1, s. 332-
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Tidskriftsartikel (refereegranskat)abstract
- Complement factor H (FH) is the main plasma regulator of the alternative pathway of complement. Genetic and acquired abnormalities in FH cause uncontrolled complement activation amplifying, with the consequent accumulation of complement components on the renal glomeruli. This leads to conditions such as C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS). There is no effective therapy for these diseases. Half of the patients progress to end-stage renal disease and the condition recurs frequently in transplanted kidneys. Combined liver/kidney transplantation is a valid option for these patients, but the risks of the procedure and donor organ shortages hamper its clinical application. Therefore, there is an urgent need for alternative strategies for providing a normal FH supply. Human amnion epithelial cells (hAEC) have stem cell characteristics, including the capability to differentiate into hepatocyte-like cells in vivo.Here, we administered hAEC into the livers of newborn Cfh−/− mice, which spontaneously developed glomerular complement deposition and renal lesions resembling human C3G. hAEC engrafted at low levels in the livers of Cfh−/− mice and produced sufficient human FH to prevent complement activation and glomerular C3 and C9 deposition. However, long-term engraftment was not achieved, and eventually hAEC elicited a humoral immune response in immunocompetent Cfh−/− mice.hAEC cell therapy could be a valuable therapeutic option for patients undergoing kidney transplantation in whom post-transplant immunosuppression may protect allogeneic hAEC from rejection, while allogeneic cells provide normal FH to prevent disease recurrence.
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| 3. |
- Gindraux, F, et al.
(författare)
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Perinatal derivatives application: Identifying possibilities for clinical use
- 2022
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Ingår i: Frontiers in bioengineering and biotechnology. - : Frontiers Media SA. - 2296-4185. ; 10, s. 977590-
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Tidskriftsartikel (refereegranskat)abstract
- Perinatal derivatives are drawing growing interest among the scientific community as an unrestricted source of multipotent stromal cells, stem cells, cellular soluble mediators, and biological matrices. They are useful for the treatment of diseases that currently have limited or no effective therapeutic options by means of developing regenerative approaches. In this paper, to generate a complete view of the state of the art, a comprehensive 10-years compilation of clinical-trial data with the common denominator of PnD usage has been discussed, including commercialized products. A set of criteria was delineated to challenge the 10-years compilation of clinical trials data. We focused our attention on several aspects including, but not limited to, treated disorders, minimal or substantial manipulation, route of administration, dosage, and frequency of application. Interestingly, a clear correlation of PnD products was observed within conditions, way of administration or dosage, suggesting there is a consolidated clinical practice approach for the use of PnD in medicine. No regulatory aspects could be read from the database since this information is not mandatory for registration. The database will be publicly available for consultation. In summary, the main aims of this position paper are to show possibilities for clinical application of PnD and propose an approach for clinical trial preparation and registration in a uniform and standardized way. For this purpose, a questionnaire was created compiling different sections that are relevant when starting a new clinical trial using PnD. More importantly, we want to bring the attention of the medical community to the perinatal products as a consolidated and efficient alternative for their use as a new standard of care in the clinical practice.
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| 4. |
- Gramignoli, R, et al.
(författare)
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Effects of Pro-Inflammatory Cytokines on Hepatic Metabolism in Primary Human Hepatocytes
- 2022
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 23:23
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Tidskriftsartikel (refereegranskat)abstract
- Three decades of hepatocyte transplantation have confirmed such a cell-based approach as an adjunct or alternative treatment to solid organ transplantation. Donor cell survival and engraftment were indirectly measured by hepatospecific secretive or released metabolites, such as ammonia metabolism in urea cycle defects. In cases of sepsis or viral infection, ammonia levels can significantly and abruptly increase in these recipients, erroneously implying rejection. Pro-inflammatory cytokines associated with viral or bacterial infections are known to affect many liver functions, including drug-metabolizing enzymes and hepatic transport activities. We examined the influence of pro-inflammatory cytokines in primary human hepatocytes, isolated from both normal donors or patients with metabolic liver diseases. Different measures of hepatocyte functions, including ammonia metabolism and phase 1–3 metabolism, were performed. All the hepatic functions were profoundly and significantly suppressed after exposure to concentrations of from 0.1 to 10 ng/mL of different inflammatory cytokines, alone and in combination. Our data indicate that, like phase I metabolism, suppression of phase II/III and ammonia metabolism occurs in hepatocytes exposed to pro-inflammatory cytokines in the absence of cell death. Such inflammatory events do not necessarily indicate a rejection response or loss of the cell graft, and these systemic inflammatory signals should be carefully considered when the immunosuppressant regiment is reduced or relieved in a hepatocyte transplantation recipient in response to such alleged rejection.
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| 5. |
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| 6. |
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| 7. |
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| 8. |
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| 9. |
- Selvam, AK, et al.
(författare)
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A Novel mRNA-Mediated and MicroRNA-Guided Approach to Specifically Eradicate Drug-Resistant Hepatocellular Carcinoma Cell Lines by Se-Methylselenocysteine
- 2021
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Ingår i: Antioxidants (Basel, Switzerland). - : MDPI AG. - 2076-3921. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- Despite progress in the treatment of non-visceral malignancies, the prognosis remains poor for malignancies of visceral organs and novel therapeutic approaches are urgently required. We evaluated a novel therapeutic regimen based on treatment with Se-methylselenocysteine (MSC) and concomitant tumor-specific induction of Kynurenine aminotransferase 1 (KYAT1) in hepatocellular carcinoma (HCC) cell lines, using either vector-based and/or lipid nanoparticle-mediated delivery of mRNA. Supplementation of MSC in KYAT1 overexpressed cells resulted in significantly increased cytotoxicity, due to ROS formation, as compared to MSC alone. Furthermore, microRNA antisense-targeted sites for miR122, known to be widely expressed in normal hepatocytes while downregulated in hepatocellular carcinoma, were added to specifically limit cytotoxicity in HCC cells, thereby limiting the off-target effects. KYAT1 expression was significantly reduced in cells with high levels of miR122 supporting the concept of miR-guided induction of tumor-specific cytotoxicity. The addition of alpha-ketoacid favored the production of methylselenol, enhancing the cytotoxic efficacy of MSC in HCC cells, with no effects on primary human hepatocytes. Altogether, the proposed regimen offers great potential to safely and specifically target hepatic tumors that are currently untreatable.
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| 10. |
- Solhi, R, et al.
(författare)
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Metabolic hallmarks of liver regeneration
- 2021
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Ingår i: Trends in endocrinology and metabolism: TEM. - : Elsevier BV. - 1879-3061 .- 1043-2760. ; 32:9, s. 731-745
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Tidskriftsartikel (refereegranskat)
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| 11. |
- Teixo, R, et al.
(författare)
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Application of Perinatal Derivatives on Oncological Preclinical Models: A Review of Animal Studies
- 2022
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 23:15
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Tidskriftsartikel (refereegranskat)abstract
- The increasing cancer incidence has certified oncological management as one of the most critical challenges for the coming decades. New anticancer strategies are still needed, despite the significant advances brought to the forefront in the last decades. The most recent, promising therapeutic approaches have benefitted from the application of human perinatal derivatives (PnD), biological mediators with proven benefits in several fields beyond oncology. To elucidate preclinical results and clinic outcomes achieved in the oncological field, we present a narrative review of the studies resorting to animal models to assess specific outcomes of PnD products. Recent preclinical evidence points to promising anticancer effects offered by PnD mediators isolated from the placenta, amniotic membrane, amniotic fluid, and umbilical cord. Described effects include tumorigenesis prevention, uncontrolled growth or regrowth inhibition, tumor homing ability, and adequate cell-based delivery capacity. Furthermore, PnD treatments have been described as supportive of chemotherapy and radiological therapies, particularly when resistance has been reported. However, opposite effects of PnD products have also been observed, offering support and trophic effect to malignant cells. Such paradoxical and dichotomous roles need to be intensively investigated. Current hypotheses identify as explanatory some critical factors, such as the type of the PnD biological products used or the manufacturing procedure to prepare the tissue/cellular treatment, the experimental design (including human-relevant animal models), and intrinsic pathophysiological characteristics. The effective and safe translation of PnD treatments to clinical practice relies on the collaborative efforts of all researchers working with human-relevant oncological preclinical models. However, it requires proper guidelines and consensus compiled by experts and health workers who accurately describe the methodology of tissue collection, PnD isolation, manufacturing, preservation, and delivery to the final user.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Bluhme, E, et al.
(författare)
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Procurement and Evaluation of Hepatocytes for Transplantation From Neonatal Donors After Circulatory Death
- 2022
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Ingår i: Cell transplantation. - : SAGE Publications. - 1555-3892 .- 0963-6897. ; 31, s. 9636897211069900-
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocyte transplantation is a promising treatment for liver failure and inborn metabolic liver diseases, but progress has been hampered by a scarcity of available organs. Here, hepatocytes isolated from livers procured for a neonatal hepatocyte donation program within a research setting were assessed for metabolic function and suitability for transplantation. Organ donation was considered for infants who died in neonatal intensive care in the Stockholm region during 2015–2021. Inclusion was assessed when a decision to discontinue life-sustaining treatment had been made and hepatectomy performed after declaration of death. Hepatocyte isolation was performed by three-step collagenase perfusion. Hepatocyte viability, yield, and function were assessed using fresh and cryopreserved cells. Engraftment and maturation of cryopreserved neonatal hepatocytes were assessed by transplantation into an immunodeficient mouse model and analysis of the gene expression of phase I, phase II, and liver-specific enzymes and proteins. Twelve livers were procured. Median warm ischemia time (WIT) was 190 [interquartile range (IQR): 80–210] minutes. Median viability was 86% (IQR: 71%–91%). Median yield was 6.9 (IQR: 3.4–12.8) x106 viable hepatocytes/g. Transplantation into immunodeficient mice resulted in good engraftment and maturation of hepatocyte-specific proteins and enzymes. A neonatal organ donation program including preterm born infants was found to be feasible. Hepatocytes isolated from neonatal donors had good viability, function, and engraftment despite prolonged WIT. Therefore, neonatal livers should be considered as a donor source for clinical hepatocyte transplantation, even in cases with extended WIT.
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| 18. |
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| 19. |
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| 20. |
- Gensous, N, et al.
(författare)
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Aging and Caloric Restriction Modulate the DNA Methylation Profile of the Ribosomal RNA Locus in Human and Rat Liver
- 2020
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 12:2
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Tidskriftsartikel (refereegranskat)abstract
- A growing amount of evidence suggests that the downregulation of protein synthesis is an adaptive response during physiological aging, which positively contributes to longevity and can be modulated by nutritional interventions like caloric restriction (CR). The expression of ribosomal RNA (rRNA) is one of the main determinants of translational rate, and epigenetic modifications finely contribute to its regulation. Previous reports suggest that hypermethylation of ribosomal DNA (rDNA) locus occurs with aging, although with some species- and tissue- specificity. In the present study, we experimentally measured DNA methylation of three regions (the promoter, the 5′ of the 18S and the 5′ of 28S sequences) in the rDNA locus in liver tissues from rats at two, four, 10, and 18 months. We confirm previous findings, showing age-related hypermethylation, and describe, for the first time, that this gain in methylation also occurs in human hepatocytes. Furthermore, we show that age-related hypermethylation is enhanced in livers of rat upon CR at two and 10 months, and that at two months a trend towards the reduction of rRNA expression occurs. Collectively, our results suggest that CR modulates age-related regulation of methylation at the rDNA locus, thus providing an epigenetic readout of the pro-longevity effects of CR.
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| 21. |
- Ghasemzad, M, et al.
(författare)
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Novel Gene-Correction-Based Therapeutic Modalities for Monogenic Liver Disorders
- 2022
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Ingår i: Bioengineering (Basel, Switzerland). - : MDPI AG. - 2306-5354. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- The majority of monogenic liver diseases are autosomal recessive disorders, with few being sex-related or co-dominant. Although orthotopic liver transplantation (LT) is currently the sole therapeutic option for end-stage patients, such an invasive surgical approach is severely restricted by the lack of donors and post-transplant complications, mainly associated with life-long immunosuppressive regimens. Therefore, the last decade has witnessed efforts for innovative cellular or gene-based therapeutic strategies. Gene therapy is a promising approach for treatment of many hereditary disorders, such as monogenic inborn errors. The liver is an organ characterized by unique features, making it an attractive target for in vivo and ex vivo gene transfer. The current genetic approaches for hereditary liver diseases are mediated by viral or non-viral vectors, with promising results generated by gene-editing tools, such as CRISPR-Cas9 technology. Despite massive progress in experimental gene-correction technologies, limitations in validated approaches for monogenic liver disorders have encouraged researchers to refine promising gene therapy protocols. Herein, we highlighted the most common monogenetic liver disorders, followed by proposed genetic engineering approaches, offered as promising therapeutic modalities.
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| 22. |
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| 23. |
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| 24. |
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| 25. |
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| 26. |
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| 27. |
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| 28. |
- Heydari, Z, et al.
(författare)
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Tissue Engineering in Liver Regenerative Medicine: Insights into Novel Translational Technologies
- 2020
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:2
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Tidskriftsartikel (refereegranskat)abstract
- Organ and tissue shortage are known as a crucially important public health problem as unfortunately a small percentage of patients receive transplants. In the context of emerging regenerative medicine, researchers are trying to regenerate and replace different organs and tissues such as the liver, heart, skin, and kidney. Liver tissue engineering (TE) enables us to reproduce and restore liver functions, fully or partially, which could be used in the treatment of acute or chronic liver disorders and/or generate an appropriate functional organ which can be transplanted or employed as an extracorporeal device. In this regard, a variety of techniques (e.g., fabrication technologies, cell-based technologies, microfluidic systems and, extracorporeal liver devices) could be applied in tissue engineering in liver regenerative medicine. Common TE techniques are based on allocating stem cell-derived hepatocyte-like cells or primary hepatocytes within a three-dimensional structure which leads to the improvement of their survival rate and functional phenotype. Taken together, new findings indicated that developing liver tissue engineering-based techniques could pave the way for better treatment of liver-related disorders. Herein, we summarized novel technologies used in liver regenerative medicine and their future applications in clinical settings.
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| 29. |
- Morandi, F, et al.
(författare)
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Human Amnion Epithelial Cells Impair T Cell Proliferation: The Role of HLA-G and HLA-E Molecules
- 2020
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:9
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Tidskriftsartikel (refereegranskat)abstract
- The immunoprivilege status characteristic of human amnion epithelial cells (hAECs) has been recently highlighted in the context of xenogenic transplantation. However, the mechanism(s) involved in such regulatory functions have been so far only partially been clarified. Here, we have analyzed the expression of HLA-Ib molecules in isolated hAEC obtained from full term placentae. Moreover, we asked whether these molecules are involved in the immunoregulatory functions of hAEC. Human amnion-derived cells expressed surface HLA-G and HLA-F at high levels, whereas the commonly expressed HLA-E molecule has been measured at a very low level or null on freshly isolated cells. HLA-Ib molecules can be expressed as membrane-bound and soluble forms, and in all hAEC batches analyzed we measured high levels of sHLA-G and sHLA-E when hAEC were maintained in culture, and such a release was time-dependent. Moreover, HLA-G was present in extracellular vesicles (EVs) released by hAEC. hAEC suppressed T cell proliferation in vitro at different hAEC:T cell ratios, as previously reported. Moreover, inhibition of T cell proliferation was partially reverted by pretreating hAEC with anti-HLA-G, anti-HLA-E and anti-β2 microglobulin, thus suggesting that HLA-G and -E molecules are involved in hAEC-mediated suppression of T cell proliferation. Finally, either large-size EV (lsEV) or small-size EV (ssEV) derived from hAEC significantly modulated T-cell proliferation. In conclusion, we have here characterized one of the mechanism(s) underlying immunomodulatory functions of hAEC, related to the expression and release of HLA-Ib molecules.
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| 30. |
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| 31. |
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| 32. |
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| 33. |
- Picerno, A, et al.
(författare)
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The Icarus Flight of Perinatal Stem and Renal Progenitor Cells Within Immune System
- 2022
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Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 13, s. 840146-
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Tidskriftsartikel (refereegranskat)abstract
- Our immune system actively fights bacteria and viruses, and it must strike a delicate balance between over- and under-reaction, just like Daedalus and Icarus in Greek mythology, who could not escape their imprisonment by flying too high or too low. Both human amniotic epithelial and mesenchymal stromal cells and the conditioned medium generated from their culture exert multiple immunosuppressive activities. They have strong immunomodulatory properties that are influenced by the types and intensity of inflammatory stimuli present in the microenvironment. Notably, very recently, the immunomodulatory activity of human adult renal stem/progenitor cells (ARPCs) has been discovered. ARPCs cause a decrease in Tregs and CD3+ CD4− CD8− (DN) T cells in the early stages of inflammation, encouraging inflammation, and an increase in the late stages of inflammation, favoring inflammation quenching. If the inflammatory trigger continues, however, ARPCs cause a further increase in DN T cells to avoid the development of a harmful inflammatory state. As in the flight of Daedalus and Icarus, who could not fly too high or too low to not destroy their wings by the heat of the sun or the humidity of the sea, in response to an inflammatory environment, stem cells seem to behave by paying attention to regulating T cells in the balance between immune tolerance and autoimmunity. Recognizing the existence of both suppressive and stimulatory properties, and the mechanisms that underpin the duality of immune reaction, will aid in the development of active immunotherapeutic approaches that manipulate the immune system to achieve therapeutic benefit.
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| 34. |
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| 35. |
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| 36. |
- Shahrbaf, MA, et al.
(författare)
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Extraembryonic Mesenchymal Stromal/Stem Cells in Liver Diseases: A Critical Revision of Promising Advanced Therapy Medicinal Products
- 2022
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Liver disorders have been increasing globally in recent years. These diseases are associated with high morbidity and mortality rates and impose high care costs on the health system. Acute liver failure, chronic and congenital liver diseases, as well as hepatocellular carcinoma have been limitedly treated by whole organ transplantation so far. But novel treatments for liver disorders using cell-based approaches have emerged in recent years. Extra-embryonic tissues, including umbilical cord, amnion membrane, and chorion plate, contain multipotent stem cells. The pre-sent manuscript discusses potential application of extraembryonic mesenchymal stromal/stem cells, focusing on the management of liver diseases. Extra-embryonic MSC are characterized by robust and constitutive anti-inflammatory and anti-fibrotic properties, indicating as therapeutic agents for inflammatory conditions such as liver fibrosis or advanced cirrhosis, as well as chronic inflammatory settings or deranged immune responses.
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| 37. |
- Srinivasan, RC, et al.
(författare)
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Effects of Cryogenic Storage on Human Amnion Epithelial Cells
- 2020
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:7
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Tidskriftsartikel (refereegranskat)abstract
- Perinatal stem cells and epithelial cells isolated from full term amnion membrane, in particular, have attracted interest over the last decade, as a promising source of multipotent cells for cellular therapies. Human amnion epithelial cells (hAEC) have been used to treat monogenetic liver disease such as maple syrup urine disease or fibrosis of the liver in preclinical studies. In most studies xeno-transplants of hAEC were conducted without providing immunosuppression to recipients, reflecting the tolerogenic properties of hAEC. For many cell types, successful cryopreservation is critical for providing a readily available, off-the-shelf product. In this study, hAEC were isolated from full-term human placenta from 14 different donors, cryopreserved using a protocol and reagents commonly adopted for epithelial cell preservation. The cells were analyzed in terms of survival, recovery, and homogeneity, profiled for surface markers characteristic of epithelial, mesenchymal, endothelial, or hematopoietic cells. There were no significant differences observed in the percentage of cells with epithelial cell markers before and after cryopreservation. The relative proportion of stromal and hematopoietic cells was significantly reduced in hAEC preparations after cryopreservation. The expression of stem cell and immunomodulatory molecules were confirmed in the final product. Since multipotent cells are readily available from full-term placenta, this novel cell source might significantly increase the number of patients eligible to receive cellular therapies for liver and other diseases.
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| 38. |
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| 39. |
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| 40. |
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| 41. |
- Zabulica, M, et al.
(författare)
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Gene Editing Correction of a Urea Cycle Defect in Organoid Stem Cell Derived Hepatocyte-like Cells
- 2021
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 22:3
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Tidskriftsartikel (refereegranskat)abstract
- Urea cycle disorders are enzymopathies resulting from inherited deficiencies in any genes of the cycle. In severe cases, currently available therapies are marginally effective, with liver transplantation being the only definitive treatment. Donor liver availability can limit even this therapy. Identification of novel therapeutics for genetic-based liver diseases requires models that provide measurable hepatic functions and phenotypes. Advances in stem cell and genome editing technologies could provide models for the investigation of cell-based genetic diseases, as well as the platforms for drug discovery. This report demonstrates a practical, and widely applicable, approach that includes the successful reprogramming of somatic cells from a patient with a urea cycle defect, their genetic correction and differentiation into hepatic organoids, and the subsequent demonstration of genetic and phenotypic change in the edited cells consistent with the correction of the defect. While individually rare, there is a large number of other genetic-based liver diseases. The approach described here could be applied to a broad range and a large number of patients with these hepatic diseases where it could serve as an in vitro model, as well as identify successful strategies for corrective cell-based therapy.
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| 42. |
- Zahmatkesh, E, et al.
(författare)
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Tissue-Specific Microparticles Improve Organoid Microenvironment for Efficient Maturation of Pluripotent Stem-Cell-Derived Hepatocytes
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- Liver organoids (LOs) are receiving considerable attention for their potential use in drug screening, disease modeling, and transplantable constructs. Hepatocytes, as the key component of LOs, are isolated from the liver or differentiated from pluripotent stem cells (PSCs). PSC-derived hepatocytes are preferable because of their availability and scalability. However, efficient maturation of the PSC-derived hepatocytes towards functional units in LOs remains a challenging subject. The incorporation of cell-sized microparticles (MPs) derived from liver extracellular matrix (ECM), could provide an enriched tissue-specific microenvironment for further maturation of hepatocytes inside the LOs. In the present study, the MPs were fabricated by chemical cross-linking of a water-in-oil dispersion of digested decellularized sheep liver. These MPs were mixed with human PSC-derived hepatic endoderm, human umbilical vein endothelial cells, and mesenchymal stromal cells to produce homogenous bioengineered LOs (BLOs). This approach led to the improvement of hepatocyte-like cells in terms of gene expression and function, CYP activities, albumin secretion, and metabolism of xenobiotics. The intraperitoneal transplantation of BLOs in an acute liver injury mouse model led to an enhancement in survival rate. Furthermore, efficient hepatic maturation was demonstrated after ex ovo transplantation. In conclusion, the incorporation of cell-sized tissue-specific MPs in BLOs improved the maturation of human PSC-derived hepatocyte-like cells compared to LOs. This approach provides a versatile strategy to produce functional organoids from different tissues and offers a novel tool for biomedical applications.
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