Induced pluripotent stem cell

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Exosomes Secreted from Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Prevent Osteonecrosis of the Femoral Head by Promoting Angiogenesis

Exosomes Secreted from Human-Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Prevent Osteonecrosis of the Femoral Head by Promoting Angiogenesis

Our previous studies found that transplantation of exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells (hiPS-MSC-Exos) could promote angiogenesis of ischemic tissue in limb ischemia and skin defects [17, 18]. These satisfactory results suggest that transplantation of hiPS-MSC-Exos might be useful for other ischemic diseases including ONFH. Despite the promising effects of hiPS-MSC-Exos in ischemic diseases, the potential mechanism which regulates angiogenesis remains unclear. Several studies have demonstrated the potential relationship of the PI3K/Akt pathway and stem cells in angiogenesis [5]. Piao et al. [19] found that transplanting MSCs with increased expression levels of pAkt could increase angiogenesis in the ischemic limb of rats. Culture medium from MSCs has been reported to increase the level of angiogenesis by increasing the level of pAkt, an effect which could be inhibited by a PI3K/Akt inhibitor [20]. These results suggest that stem cells can increase the angiogenic ability of endothelial cells via the PI3K/Akt pathway. Since exosomes are important functional products of host cells, the angiogenic effect of exosomes secreted by stem cells might also be associated with the PI3K/Akt pathway. Based on these studies, we hypothesize that transplantation of hiPS-MSC-Exos might prevent the progression of ONFH, and the PI3K/Akt pathway might be involved in the angiogenic effects triggered by hiPS-MSC-Exos.
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Transplantation of induced pluripotent stem cell-derived mesenchymal stem cells improved erectile dysfunction induced by cavernous nerve injury

Transplantation of induced pluripotent stem cell-derived mesenchymal stem cells improved erectile dysfunction induced by cavernous nerve injury

Induced pluripotent stem cells (iPSC) are pluripotent stem cells generated by reprogramming somatic cells [22]. iPSC can differentiate into MSC (induced pluripotent stem cell-derived mesenchymal stem cells, iMSC), providing a new source of MSC [23]. The characters of iMSC includes non-invasive obtaining, easy to amplify and better homogeneity, which would be promising for circumventing the MSC drawbacks mentioned above. The optimized characteristics indicated that it could be a better idea to use iMSC rather than traditional MSC in cell therapy. Previous studies have explored the potential therapeutic effects of iMSC on some type of diseases [23, 24]. For example, researchers used iMSC on chronic mouse asthma model and found that iMSC therapy exerted a long-term effect on alleviating chronic allergic airway inflammation [25]. Soontararak and colleagues applied iMSC on mouse inflammatory bowel disease model and demonstrated that transplantation of iMSC helped improve intestinal health and microbiome normalization [26]. However, to our knowledge, no studies have explored the effects of iMSC on CNI ED and its underlying mechanisms. In this study, we established a CNI ED model to evaluate the related therapeutic functions of iMSC. Moreover, we compared the therapeutic effects between iMSC and adipose-derived mesenchymal stem cells transplantation (adMSC). We also explored the underlying therapeutic mechanisms that iMSC might exert, hoping to have a more comprehensive understanding of its effects.
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Cardiotoxicity evaluation using human embryonic stem cells and induced pluripotent stem cell-derived cardiomyocytes

Cardiotoxicity evaluation using human embryonic stem cells and induced pluripotent stem cell-derived cardiomyocytes

The discovery of hPSC-CMs, including hPSC-CMs and hESC-CMs, has been an attractive in vitro model to study cardiotoxicity. Many researchers have used hiPSC- CMs and hESC-CMs as screening models for pro- arrhythmic compounds during drug development to circumvent the lack of sufficient and healthy human car- diac tissue [11–15]. Here we reported the combination of an RTCA Cardio system and hPSC-CMs as a high- throughput platform, enabling unbiased real-time kinetic data acquisition for a more accurate evaluation of the cardiotoxicity of various compounds. This system can continuously monitor the contractility of cardiomyocytes by using noninvasive impedance readout and obtain quantitative data by converting impedance into cell index values [16]. In the current study, hESC-and hiPSC-CMs illustrated comparable baseline parameters before being subjected to different compounds. How- ever, while the beating rate of the commercially avail- able hiPSC-CMs was similar to the native human heart rate, the beating rate of the homemade hESC- CMs used in this study was much lower. The spon- taneous rhythm of hiPSC-CMs tended to be more consistent and less irregular along with cultivation, compared with hESC-CMs.
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Ex Vivo Gene Therapy for Lysosomal Storage Disease Using Ipsc-Derived Neural Stem Cells

Ex Vivo Gene Therapy for Lysosomal Storage Disease Using Ipsc-Derived Neural Stem Cells

Diseases affecting the central nervous system (CNS) pose a formidable obstacle to the delivery of effective therapeutics. A tight-knit collection of cells and macromolecules known as the blood- brain-barrier (BBB) prevents most substances from entering the brain. One intriguing approach to overcoming this obstacle involves transplanting neural stem cells (NSCs), the precursor cells to neurons and glia in the brain, as vehicles for the delivery of therapeutic proteins in their native environment. Notably, this strategy has already been successfully applied to several lysosomal storage diseases caused by genetic deficiencies in one of the many lysosomal hydrolases expressed throughout the body. A major drawback to this approach is that foreign NSCs, e.g. immortalized cell lines and primary fetal NSCs can be tumorigenic and immunogenic. Recently developed induced pluripotent stem cell (iPSC) technologies, combined with pluripotent stem cell differentiation techniques, have the potential to overcome these obstacles. This approach was evaluated using a comprehensive strategy targeting a prototypical lysosomal storage disease, Sly disease (MPS VII). MPS VII patient fibroblasts were transduced with retroviral vectors expressing the transcription factors Oct4, Sox2, Klf4, and c-Myc. Patient fibroblasts were reprogrammed into embryonic stem cell-like iPSCs that demonstrated hallmarks of pluripotency. Patient iPSCs, alongside iPSCs derived from an unaffected individual, were subjected to a stepwise
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Cancer cell reprogramming: a promising therapy converting malignancy to benignity

Cancer cell reprogramming: a promising therapy converting malignancy to benignity

CSC: cancer stem cell; ESC: embryonic stem cell; iPSC: induced pluripotent stem cell; KLF4: Kruppel-like factor 4; Oct-3/4: Octamer-binding transcrip- tion factor 3/4; SOX2: sex-determining region Y-box 2; SSEA-1: stage-specific embryonic antigen-1; TRA-1–60: T cell receptor alpha-1–60; TRA-1–81: T cell receptor alpha-1–81; ROCK: Rho-associated protein kinase; VPA: valproic acid; RepSOX2: 2-[3-(6-methyl-2-pyridinyl)-1H-pyrazol-4-yl]-1,5-naphthyridine; OAC1: Oct4-activating compound 1; MET: mesenchymal–epithelial transition; 5-Fu: 5-fluorouracil; LIN28: Lin-28 homolog; BCR: breakpoint cluster region; ABL1: Abelson murine leukemia viral oncogene homolog 1; B-ALL: B cell acute lymphoblastic leukemia; C/EBPα: CCAAT/enhancer-binding protein alpha; HCC: hepatocellular carcinoma; HNF1A: hepatocyte nuclear factor 1 alpha; HNF3A: hepatocyte nuclear factor 3 alpha; FOXA3: forkhead box protein A3; ALB: albumin; AFP: alpha-fetoprotein; EpCAM: epithelial cell adhesion mol- ecule; FLT3L: FMS-like tyrosine kinase ligand; IL-7: interleukin 7; IL-3: interleukin 3; GM-CSF: granulocyte-macrophage colony stimulating factor; MCSF: mac- rophage colony-stimulating factor; EMT: epithelial–mesenchymal transition; TGF-β: transforming growth factor beta; BMP2: bone morphogenetic protein 2; C/EBPβ: CCAAT/enhancer-binding protein beta; SOX9: sex determining region Y-box 9; FDA: Food and Drug Administration; ZEB1: zinc finger E-box- binding homeobox 1; Osterix: transcription factor Sp7.
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Histone Variant Macroh2a In The Gut And Beyond: A Study Of Intestinal Fortitude

Histone Variant Macroh2a In The Gut And Beyond: A Study Of Intestinal Fortitude

developmental potency and less still is known about macroH2A’s contributions to adult stem cell identity and function in vivo. In this work, we use induced pluripotent stem cell (iPSC) reprogramming and the murine intestinal stem cell (ISC) system to model macroH2A’s overall impact on cell epigenetic identity from embryo to adult. We manipulated macroH2A content during iPSC reprogramming and concluded that macroH2A removal from somatic chromatin constitutes a mild, but present epigenetic bottleneck to pluripotency acquisition. Using epitope-tagged-macroH2A-expressing cells, we demonstrated that embryonic stem cells (ESCs) display significantly more dynamic macroH2A incorporation and turnover than fibroblasts, particularly proximal to the promoters of highly transcribed genes, concluding that macroH2A is less stably associated with ESC chromatin. In a separate study, we bred macroH2A double germline knockout (DKO) and strain-matched wildtype (WT) mice into reporter strains for ISC subpopulations, enabling us to functionally test active and reserve ISCs during homeostasis and following γ-irradiation injury. We showed that macroH2A DKO intestine is host to elevated numbers of putative reserve ISCs, suggesting that macroH2A may normally limit the size of the reserve ISC pool. We further determined that although macroH2A is unnecessary for intestinal homeostasis, macroH2A strongly bolsters the intestinal regeneration response following irradiative injury by promoting reserve ISC radioresistance. We thus conclude overall that macroH2A imposes a minor resistance to induced pluripotency, limits the size of the reserve ISC pool in adult mice and finally upholds genomic stability by providing resistance to genotoxic stress in vivo.
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Induced pluripotent stem cells: advances to applications

Induced pluripotent stem cells: advances to applications

Abstract: Induced pluripotent stem cell (iPS) technology has enriched the armamentarium of regenerative medicine by introducing autologous pluripotent progenitor pools bioengineered from ordinary somatic tissue. Through nuclear reprogramming, patient-specific iPS cells have been derived and validated. Optimizing iPS-based methodology will ensure robust applications across discovery science, offering opportunities for the development of personalized diagnostics and targeted therapeutics. Here, we highlight the process of nuclear reprogramming of somatic tissues that, when forced to ectopically express stemness factors, are converted into bona fide pluripotent stem cells. Bioengineered stem cells acquire the genuine ability to generate replacement tissues for a wide-spectrum of diseased conditions, and have so far demonstrated therapeutic benefit upon transplantation in model systems of sickle cell anemia, Parkinson’s disease, hemophilia A, and ischemic heart disease. The field of regenerative medicine is therefore primed to adopt and incorporate iPS cell-based advancements as a next generation stem cell platforms. Keywords: iPS, regenerative medicine, individualized medicine, stem cell therapy
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Fast Adipogenesis Tracking System (FATS)—a robust, high-throughput, automation-ready adipogenesis quantification technique

Fast Adipogenesis Tracking System (FATS)—a robust, high-throughput, automation-ready adipogenesis quantification technique

Adipogenesis is essential in in vitro experimentation to assess differentiation capability of stem cells, and therefore, its accurate measurement is important. Quantitative analysis of adipogenic levels, however, is challenging and often susceptible to errors due to non-specific reading or manual estimation by observers. To this end, we developed a novel adipocyte quantification algorithm, named Fast Adipogenesis Tracking System (FATS), based on computer vision libraries. The FATS algorithm is versatile and capable of accurately detecting and quantifying percentage of cells undergoing adipogenic and browning differentiation even under difficult conditions such as the presence of large cell clumps or high cell densities. The algorithm was tested on various cell lines including 3T3-L1 cells, adipose- derived mesenchymal stem cells (ASCs), and induced pluripotent stem cell (iPSC)-derived cells. The FATS algorithm is particularly useful for adipogenic measurement of embryoid bodies derived from pluripotent stem cells and was capable of accurately distinguishing adipogenic cells from false-positive stains. We then demonstrate the effectiveness of the FATS algorithm for screening of nuclear receptor ligands that affect adipogenesis in the high-throughput manner. Together, the FATS offer a universal and automated image-based method to quantify adipocyte differentiation of different cell lines in both standard and high-throughput workflows.
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Understanding Megakaryopoiesis And Thrombopoiesis Using Human Stem Cells Models

Understanding Megakaryopoiesis And Thrombopoiesis Using Human Stem Cells Models

Human stem cell models (CD34+ hematopoietic progenitors, embryonic stem cells and induced pluripotent stem cells (iPSCs)) are powerful tools for the study of megakaryopoiesis and thrombopoiesis, particularly in situations where mouse models are unavailable or do not accurately recapitulate human physiology or development. In the first part of this thesis, we identified and characterized novel megakaryocyte (MK) maturation stages in MK cultures derived from human stem cells. An immature, low granular (LG) MK pool (defined by side scatter on flow cytometry) gives rise to a mature high granular (HG) pool, which then becomes damaged by apoptosis and GPIbα (CD42b) shedding. We define an undamaged HG/CD42b+ MK subpopulation, which endocytoses fluorescently-labeled coagulation factor V (FV) from the medium into alpha-granules and releases functional FV+CD42b+ platelet-like particles in vitro and when infused into immunodeficient mice. Importantly, these FV+ platelets have the same size distribution as infused human donor platelets and are preferentially incorporated into clots after laser injury. Using drugs to protect HG MKs from apoptosis and CD42b shedding, we also demonstrate that apoptosis precedes CD42b shedding and that apoptosis inhibition enriches the FV+ HG/CD42b+ MKs, leading to increased platelet yield in vivo, but not in vitro. These studies identify a transition between distinct MK populations in vitro, including one that is primed for platelet release. Technologies to optimize and select these platelet-ready MKs may be important to efficiently generate functional platelets from in vitro-grown MKs. In the second part of this thesis, we used patient-specific iPSCs to model Thrombocytopenia Absent Radius (TAR) syndrome, a rare congenital disorder characterized by low platelet counts and bilateral absence of the radius. We generated several iPSC lines from patients and controls and confirmed that the patient lines had decreased expression of RBM8A, the candidate disease gene for TAR syndrome. We differentiated patient and control iPSCs to hematopoietic progenitor cells (HPCs) and MKs and showed that HPCs derived from TAR iPSCs exhibited decreased MK colony-forming potential but differentiated normally into MKs in liquid culture. When we restored RBM8A expression in TAR iPSCs using a doxycycline inducible system, we saw no effect on megakaryopoiesis. We then knocked out RBM8A in TAR iPSCs and found that a complete deficiency in RBM8A expression was lethal for iPSCs, HPCs, MKs and erythrocytes. These studies suggest that we were unable to determine a specific role for RBM8A in primitive (embryonic) megakaryopoiesis and perhaps future studies to direct iPSCs towards the definitive (adult) MK lineage may better elucidate RBM8A’s role in TAR syndrome.
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The potential and limitations of induced pluripotent stem cells to achieve wound healing

The potential and limitations of induced pluripotent stem cells to achieve wound healing

Stem cell therapy has emerged as an exciting po- tential therapy for wound healing. When transplanted into a wound, stem cells act in a direct and paracrine manner to promote cell recruitment, immunomodu- lation, extracellular matrix remodeling, and angiogen- esis by secretion of cytokines and growth factors [17–19]. Adult-derived cells, such as mesenchymal stem cells (MSC), have shown potential in accelerat- ing healing of chronic wounds, particularly in the diabetic population where populations of MSC are deficient [20–24]. MSC have shown efficacy in mul- tiple clinical trials of DFU healing and are currently included in several commercially available topical products including Grafix and Stravix [25–27]. Em- bryonic stem cell (ESC)-derived MSC are superior to adult-derived MSC, as they retain their potency, show a high proliferative ability, and display a con- sistent phenotype [28]. However, use of these cells is limited by the ethical issues associated with the use of embryonic stem cells, need for invasive harvesting techniques, immunogenicity, and limited cell survival in vivo [29].
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Fetal hemoglobin reactivation and cell engineering in the treatment of sickle cell anemia

Fetal hemoglobin reactivation and cell engineering in the treatment of sickle cell anemia

thalassemia, with skin fibroblasts removed, transformed into pluripotent stem cells, and then differentiated into hemopoietic stem cells, capable of producing normal adult hemoglobin. It was even suggested to collect cells from amniotic fluid or chorionic villus sampling, used for prenatal diagnosis, reprogram them into induced pluripotent stem cells, correct the mutation, and reinfuse them during the perinatal period, ie, an option for very early treatment before organ damage takes place. 57

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Pluripotent stem cells for Parkinson's disease: progress and challenges

Pluripotent stem cells for Parkinson's disease: progress and challenges

A number of groups have made considerable progress in demonstrating that authentic A9 DA neurons can be produced in vitro with high effi ciency from hESC and iPSC lines, including lines derived from patients with PD. Several of these groups have also shown survival and engraftment of these cells in the 6-OHDA rat model as well as evidence of dopamine release and correction of behavioral defi cits. Th ese studies, combined with the proof-of-concept provided by human trials using fetus- derived DA neurons, provide compelling evidence to justify the development of these cells for use in human clinical trials. However, there are outstanding issues to be resolved. In many cases, the behavioral improvements observed in animal studies are modest, and there is currently limited evidence that complex motor defi cits can be corrected with engrafted hPSC-derived DA neurons [27]. Th is may be due to the variable or low number of cells in the grafts, limitations of the rodent PD models, or diff erences in the micro environmental signals between human and rat cells in the brain or a result of infl uences from contaminating non-A9 DA cells in the graft. Better animal model systems would facilitate the development of these cells, and predictive long-term effi cacy studies with non-human primate models such as the MPTP monkey model will be of great value. In addition, other issues need to be addressed, including the low survival rate of DA neurons in grafts, diffi culty in integrating transplanted cells into the host brain’s circuitry, defi ning the number of DA neurons needed for a transplant (Freed and colleagues [14] suggested that at least about 20,000 cells are needed for transplantation), site of injection, and graft-induced dyskinesia. Some of these issues, such as cell number or dose, injection site, and cell survival, may not be resolved without information from human clinical studies, but it is certain that addressing these issues will require properly controlled animal and human studies using a well- characterized cell product made with defi ned protocols and reagents.
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Generation of pig induced pluripotent stem cells using an extended pluripotent stem cell culture system

Generation of pig induced pluripotent stem cells using an extended pluripotent stem cell culture system

Human induced pluripotent stem (iPS) cells hold great therapeutic promise for regenerative medicine. Human iPS cells can proliferate indefinitely in culture and differ- entiate into all cell types in an adult body, thereby pro- viding unlimited source material for cell-based therapies to treat numerous disorders. Before translating to the clinic, however, it is imperative to test the safety and effi- cacy of iPS cell-based therapies using animal models. Owing to easy accessibility, low costs, and a range of available genetic and molecular tools, rodents, in par- ticular mice, have been the most popular animal model for pre-clinical trials. However, in many instances, ro- dent models cannot accurately reflect the human condi- tions due to significant differences in development and physiology [1]. Pigs are more similar to humans than the rodents in organ size, physiology, and anatomy, and thus autologous and/or homologous transplantation using pig iPS cell derivatives represents a superior model for re- generative medicine. Moreover, with the development of interspecies blastocyst complementation, human organs generated in pigs may help solve the worldwide shortage of human organs for transplantation in the future [2 – 4]. In this regard, chimeric-competent pig iPS cells can serve as a con-species control, providing invaluable in- formation on the molecular and functional features of derived organs. Despite the potential, however, authentic pig embryonic stem (ES) cells have yet been established, and the maintenance of pig iPS cells still depends on ec- topic expression of exogenous reprogramming factors. Importantly, neither pig ES nor iPS cells so far have met
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Stem Cell Sources for Regenerative Medicine and Cartilage Tissue Engineering.

Stem Cell Sources for Regenerative Medicine and Cartilage Tissue Engineering.

The research described in this dissertation covers both induced pluripotent stem cells and adult tissue progenitors as clinical cell sources for regenerative medicine. We were able to derive canine iPSCs from adult fibroblasts by using four transcription factors. The isolated iPSCs have similar characteristics to ESCs from other species, but the exact cellular mechanisms behind their unique co-dependency on both FGF2 and LIF is still unknown. Additionally, we identified acquired genomic aberrations during extended culture periods of canine iPSCs. During chondrocytes culture, as an example of adult tissue progenitor, our study showed that combined application of defined serum free media and low oxygen provides the optimized chondrocytes expansion method which meets FDA requirements. Low-SFM culture conditions resulted in improved cell growth rate, reduced levels of de- differentiation during expansion, and greater ability to re-differentiate into cartilage upon induction.
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Clinical potentials of human pluripotent stem cells in lung diseases

Clinical potentials of human pluripotent stem cells in lung diseases

As pulmonary epithelia are constantly exposed to in- jurious stimuli from the environment, the lung needs to generate new cells to replenish injured and aged epithe- lial cells for maintaining normal structure and function. It is known that the endogenous repair capacity of the lung is relative low [4-7] and may fail after repeated challenges, leading to development of life-threatening pulmonary diseases such as asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. Due to lung structural complexity with cellular diversity and slow epithelial cell turnover rates, it is still a challenge to isolate and characterize lung stem/progenitor cells for exploring the lung disease processes and endogenous re- pair mechanisms. To date, whether there are undifferenti- ated multipotent stem cells with the ability to self-renew indefinitely in lung is controversial. Injuries to mobilize stem cells for tracking DNA label-retaining cells (LRCs) are a key approach to identifying stem/progenitor cell compartment in distinct lung regions. There is mounting evidence showing that local progenitor cells function to renew injured and aged epithelial cells in anatomically dif- ferent regions [8-11]. In the trachea and larger airways, basal cells have traditionally been considered as progenitor cells, with the capacity for proliferating and differentiating into basal, ciliated, and goblet cells [12,13]. In human, the large airway epithelium is more pseudostratified, and there are parabasal cells located right above the basal cells. Because parabasal cells express high level of proliferation marker MIB-1, they are thought to function as transient amplifying (TA) cells derived from basal cells in the larger airways [14,15]. In addition, subcutaneous transplantation experiments have shown that tracheal grandular cells can repopulate tracheal epithelium. In SO 2 -induced tracheal
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Therapeutic use of stem cells for cardiovascular disease

Therapeutic use of stem cells for cardiovascular disease

Induced pluripotent stem cells are attractive because of their ability to differentiate into large numbers of cardio- myocytes. There is better functional integration within host heart cells in comparison to adult cells, specifically in terms of the electromechanical connections with host cardiomyocytes. A limitation to the use of these cells is the associated risk of teratoma formation after trans- plantation of undifferentiated cells into infarcted hearts. In one study, the transplantation of undifferentiated syn- genic iPSs into mice resulted in teratoma formation in 65 % of transplantation sites after 30 days [19, 20]. This result emphasizes the need for a method to control or direct differentiation of iPS towards cardiac progenitor cells before transplantation to avoid the formation of ter- atomas or alternate and undesired cell types [21]. Overall, additional animal studies are needed to ensure the safety and efficacy of these cells.
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Amenable epigenetic traits of dental pulp stem cells underlie high capability of xeno free episomal reprogramming

Amenable epigenetic traits of dental pulp stem cells underlie high capability of xeno free episomal reprogramming

but one piece of evidence suggests that it is also expressed in human trophoblasts and plays an important role in trophoblast cell fusion [49]. Based on the DNA methylation results, we selected PAX9 and HERV-FRD genes due to the presence of multiple differentially methylated regions that are equivalent to iPS/ES cells and examined their effects. Accordingly, PAX9 was over-expressed (PAX9-OE) and HERV-FRD was knocked-down (HERV-FRD-KD) in DPSCs for evaluation of the reprogramming propensity. Consistent with expectation, increases in generation of iPS colonies were observed in both cell lines, indicating that PAX9 serves as an enhancing factor and HERV-FRD as a suppressing factor for iPS reprogramming. An important question remaining to be answered is how the developmen- tal PAX9 and HERV-FRD genes regulate the reprogram- ming process, and this warrants additional study. Although the prime determinants and effects of epigenetic changes during induced pluripotency are not fully understood, it is clearly perceived that dynamic changes in epigenetic signa- tures from the somatic state into the pluripotent state are needed to acquire pluripotency [50]. Our results indicate that DPSCs are advantageous since the cells already possess certain degrees of epigenetic marker similarity to the iPS state, especially regarding developmental genes presumed to play important roles in regulating pluripotency.
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Review Paper: Application of Hair Follicle Bulge Stem Cells in Wound Healing

Review Paper: Application of Hair Follicle Bulge Stem Cells in Wound Healing

Despite the significant advances in regenerative medicine, wound healing has remained a challenging clinical problem. Skin is the largest human organ with many vital functions; therefore, any damage to its normal structure should be treated as soon as possible. Easy access to skin stem cells has created a lot of excitement in therapeutic applications. “Cell therapy” is considered a novel method in regenerative medicine, especially when conventional treatments fail. Candidate cell populations for therapeutic applications include embryonic, induced pluripotent, adult mesenchymal, and hair follicle stem cells. It is possible to differentiate stem cells separated from the bulge area of hair follicle into neurons, melanocytes, keratinocytes, glia and smooth muscle cells that are negative for the keratinocyte marker kr15.
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Directly induced human Schwann cell precursors as a valuable source of Schwann cells

Directly induced human Schwann cell precursors as a valuable source of Schwann cells

Human pluripotent [embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs)] [4, 5] and multi- potent stem cells from adipose [6, 7], bone marrow [7], umbilical cord [8], dental pulp [9, 10], epidermal kerati- nocytes [11], and muscle [12], which have NCC differen- tiation/trans-differentiation capacity, and are capable of differentiating into SCs, have been demonstrated as al- ternative sources of SCs. To date, human pluripotent stem cells (hPSCs) with high expansion and differenti- ation capacity are considered the most ideal renewable sources to generate high numbers of SCs through an intermediary NCC stage, but their wider uses are still limited by long differentiation time and low functionality [4, 5, 13–16]. Although great progress has been made in nerve tissue engineering and biomaterials to aid the process of nerve regeneration, the use of differentiated SCs to support neurons and form myelin sheaths in vitro and in vivo is still unsatisfactory, especially for long-gap nerve injury [13, 17–19].
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