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Buzhor E.,LifeMap science Ltd. | Leshansky L.,LifeMap science Ltd. | Blumenthal J.,LifeMap science Ltd. | Barash H.,LifeMap science Ltd. | And 4 more authors.
Regenerative Medicine

Cell therapies aim to repair the mechanisms underlying disease initiation and progression, achieved through trophic effect or by cell replacement. Multiple cell types can be utilized in such therapies, including stem, progenitor or primary cells. This review covers the current state of cell therapies designed for the prominent disorders, including cardiovascular, neurological (Parkinson's disease, amyotrophic lateral sclerosis, stroke, spinal cord injury), autoimmune (Type 1 diabetes, multiple sclerosis, Crohn's disease), ophthalmologic, renal, liver and skeletal (osteoarthritis) diseases. Various cell therapies have reached advanced clinical trial phases with potential marketing approvals in the near future, many of which are based on mesenchymal stem cells. Advances in pluripotent stem cell research hold great promise for regenerative medicine. The information presented in this review is based on the analysis of the cell therapy collection detailed in LifeMap Discovery® (LifeMap Sciences Inc., USA) the database of embryonic development, stem cell research and regenerative medicine. © 2014 Future Medicine Ltd. Source

Meivar-Levy I.,Stem Cells and Tissue Engineering Center | Ferber S.,Stem Cells and Tissue Engineering Center | Ferber S.,Tel Aviv University
Best Practice and Research: Clinical Endocrinology and Metabolism

Tissue replacement is a promising direction for the treatment of diabetes, which will become widely available only when islets or insulin-producing cells that will not be rejected by the diabetic recipients are available in unlimited amounts. The present review addresses the research in the field of generating functional insulin-producing cells by transdifferentiation of adult liver cells both in vitro and in vivo. It presents recent knowledge of the mechanisms which underlie the process and assesses the challenges which should be addressed for its efficient implementation as a cell based replacement therapy for diabetics. © 2015 Published by Elsevier Ltd. Source

Berneman-Zeitouni D.,Stem Cells and Tissue Engineering Center | Berneman-Zeitouni D.,Tel Aviv University | Molakandov K.,Stem Cells and Tissue Engineering Center | Molakandov K.,Tel Aviv University | And 11 more authors.

Lineage-specific transcription factors (TFs) display instructive roles in directly reprogramming adult cells into alternate developmental fates, in a process known as transdifferentiation. The present study analyses the hypothesis that despite being fast, transdifferentiation does not occur in one step but is rather a consecutive and hierarchical process. Using ectopic expression of Pdx1 in human liver cells, we demonstrate that while glugacon and somatostatin expression initiates within a day, insulin gene expression becomes evident only 2-3 days later. To both increase transdifferentiation efficiency and analyze whether the process indeed display consecutive and hierarchical characteristics, adult human liver cells were treated by three pancreatic transcription factors, Pdx1, Pax4 and Mafa (3pTFs) that control distinct hierarchical stages of pancreatic development in the embryo. Ectopic expression of the 3pTFs in human liver cells, increased the transdifferentiation yield, manifested by 300% increase in the number of insulin positive cells, compared to each of the ectopic factors alone. However, only when the 3pTFs were sequentially supplemented one day apart from each other in a direct hierarchical manner, the transdifferentiated cells displayed increased mature β-cell-like characteristics. Ectopic expression of Pdx1 followed by Pax4 on the 2 nd day and concluded by Mafa on the 3rd day resulted in increased yield of transdifferentiation that was associated by increased glucose regulated c-peptide secretion. By contrast, concerted or sequential administration of the ectopic 3pTFs in an indirect hierarchical mode resulted in the generation of insulin and somatostatin co-producing cells and diminished glucose regulated processed insulin secretion. In conclusion transcription factors induced liver to pancreas transdifferentiation is a progressive and hierarchical process. It is reasonable to assume that this characteristic is general to wide ranges of tissues. Therefore, our findings could facilitate the development of cell replacement therapy modalities for many degenerative diseases including diabetes. © 2014 Berneman-Zeitouni et al. Source

Gefen-Halevi S.,Stem Cells and Tissue Engineering Center | Gefen-Halevi S.,Bar - Ilan University | Rachmut I.H.,Stem Cells and Tissue Engineering Center | Rachmut I.H.,Bar - Ilan University | And 8 more authors.
Cellular Reprogramming

Reprogramming adult mammalian cells is an attractive approach for generating cell-based therapies for degenerative diseases, such as diabetes. Adult human liver cells exhibit a high level of developmental plasticity and have been suggested as a potential source of pancreatic progenitor tissue. An instructive role for dominant pancreatic transcription factors in altering the hepatic developmental fate along the pancreatic lineage and function has been demonstrated. Here we analyze whether transcription factors expressed in mature pancreatic β-cells preferentially activate β-cell lineage differentiation in liver. NKX6.1 is a transcription factor uniquely expressed in β-cells of the adult pancreas, its potential role in reprogramming liver cells to pancreatic lineages has never been analyzed. Our results suggest that NKX6.1 activates immature pancreatic markers such as NGN-3 and ISL-1 but not pancreatic hormones gene expression in human liver cells. We hypothesized that its restricted capacity to activate a wide pancreatic repertoire in liver could be related to its incapacity to activate endogenous PDX-1 expression in liver cells. Indeed, the complementation of NKX6.1 by ectopic PDX-1 expression substantially and specifically promoted insulin expression and glucose regulated processed hormone secretion to a higher extent than that of PDX-1 alone, without increasing the reprogrammed cells. This may suggest a potential role for NKX6.1 in promoting PDX-1 reprogrammed cells maturation along the β-cell-like lineage. By contrast, NKX6.1 repressed PDX-1 induced proglucagon gene expression. The individual and concerted effects of pancreatic transcription factors in adult extra-pancreatic cells, is expected to facilitate developing regenerative medicine approaches for cell replacement therapy in diabetics. © 2010 Mary Ann Liebert, Inc. Source

Mauda-Havakuk M.,Stem Cells and Tissue Engineering Center | Mauda-Havakuk M.,Tel Aviv University | Litichever N.,Stem Cells and Tissue Engineering Center | Litichever N.,Tel Aviv University | And 12 more authors.

Background: Cellular differentiation and lineage commitment have previously been considered irreversible processes. However, recent studies have indicated that differentiated adult cells can be reprogrammed to pluripotency and, in some cases, directly into alternate committed lineages. However, although pluripotent cells can be induced in numerous somatic cell sources, it was thought that inducing alternate committed lineages is primarily only possible in cells of developmentally related tissues. Here, we challenge this view and analyze whether direct adult cell reprogramming to alternate committed lineages can cross the boundaries of distinct developmental germ layers. Methodology/Principal Findings: We ectopically expressed non-integrating pancreatic differentiation factors in ectoderm-derived human keratinocytes to determine whether these factors could directly induce endoderm-derived pancreatic lineage and β-cell-like function. We found that PDX-1 and to a lesser extent other pancreatic transcription factors, could rapidly and specifically activate pancreatic lineage and β-cell-like functional characteristics in ectoderm-derived human keratinocytes. Human keratinocytes transdifferentiated along the β cell lineage produced processed and secreted insulin in response to elevated glucose concentrations. Using irreversible lineage tracing for KRT-5 promoter activity, we present supporting evidence that insulin-positive cells induced by ectopic PDX-1 expression are generated in ectoderm derived keratinocytes. Conclusions/Significance: These findings constitute the first demonstration of human ectoderm cells to endoderm derived pancreatic cells transdifferentiation. The study represents a proof of concept which suggests that transcription factors induced reprogramming is wider and more general developmental process than initially considered. These results expanded the arsenal of adult cells that can be used as a cell source for generating functional endocrine pancreatic cells. Directly reprogramming somatic cells into alternate desired tissues has important implications in developing patient-specific, regenerative medicine approaches. © 2011 Mauda-Havakuk et al. Source

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