Stem Cells
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2022 ◽  
Vol 145 ◽  
pp. 112473
Author(s):  
Aljohra M. Al-Otaibi ◽  
Asma S. Al-Gebaly ◽  
Rafa Almeer ◽  
Gadah Albasher ◽  
Wedad S. Al-Qahtani ◽  
...  

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chet H. Loh ◽  
Siebe van Genesen ◽  
Matteo Perino ◽  
Magnus R. Bark ◽  
Gert Jan C. Veenstra

AbstractPolycomb Repressive Complex 2 (PRC2) is crucial for the coordinated expression of genes during early embryonic development, catalyzing histone H3 lysine 27 trimethylation. Two distinct PRC2 complexes, PRC2.1 and PRC2.2, contain respectively MTF2 and JARID2 in embryonic stem cells (ESCs). In this study, we explored their roles in lineage specification and commitment, using single-cell transcriptomics and mouse embryoid bodies derived from Mtf2 and Jarid2 null ESCs. We observe that the loss of Mtf2 results in enhanced and faster differentiation towards cell fates from all germ layers, while the Jarid2 null cells are predominantly directed towards early differentiating precursors, with reduced efficiency towards mesendodermal lineages. These effects are caused by derepression of developmental regulators that are poised for activation in pluripotent cells and gain H3K4me3 at their promoters in the absence of PRC2 repression. Upon lineage commitment, the differentiation trajectories are relatively similar to those of wild-type cells. Together, our results uncover a major role for MTF2-containing PRC2.1 in balancing poised lineage-specific gene activation, whereas the contribution of JARID2-containing PRC2 is more selective in nature compared to MTF2. These data explain how PRC2 imposes thresholds for lineage choice during the exit of pluripotency.


Cell Research ◽  
2021 ◽  
Author(s):  
Minglei Zhi ◽  
Jinying Zhang ◽  
Qianzi Tang ◽  
Dawei Yu ◽  
Shuai Gao ◽  
...  

AbstractPig epiblast-derived pluripotent stem cells are considered to have great potential and broad prospects for human therapeutic model development and livestock breeding. Despite ongoing attempts since the 1990s, no stably defined pig epiblast-derived stem cell line has been established. Here, guided by insights from a large-scale single-cell transcriptome analysis of pig embryos from embryonic day (E) 0 to E14, specifically, the tracing of pluripotency changes during epiblast development, we developed an in vitro culture medium for establishing and maintaining stable pluripotent stem cell lines from pig E10 pregastrulation epiblasts (pgEpiSCs). Enabled by chemical inhibition of WNT-related signaling in combination with growth factors in the FGF/ERK, JAK/STAT3, and Activin/Nodal pathways, pgEpiSCs maintain their pluripotency transcriptome features, similar to those of E10 epiblast cells, and normal karyotypes after more than 240 passages and have the potential to differentiate into three germ layers. Strikingly, ultradeep in situ Hi-C analysis revealed functional impacts of chromatin 3D-spatial associations on the transcriptional regulation of pluripotency marker genes in pgEpiSCs. In practice, we confirmed that pgEpiSCs readily tolerate at least three rounds of successive gene editing and generated cloned gene-edited live piglets. Our findings deliver on the long-anticipated promise of pig pluripotent stem cells and open new avenues for biological research, animal husbandry, and regenerative biomedicine.


2021 ◽  
Author(s):  
Caixia Jin ◽  
Qingjian Ou ◽  
Jie Chen ◽  
Tao Wang ◽  
Jieping Zhang ◽  
...  

Abstract Purpose: Autophagy is a key regulator of stem cell quiescence and self-renewal, especially in mesenchymal stem cells but related research on neural retinal stem cells is still limited. We are aimed to explore the function and mechanism of autophagy in the neural retinal stem cell.Methods: The published single cell sequencing data was involved to analysis the expression time course of IFITM3 in the mouse neural retinal progenitor cells (mNRPCs). The RNA interference was used to knock down the expression of IFITM3 in the mNRPCs. And the normal mNRPCs and mNRPCs with knockdown of IFITM3 were analysis with the CCK8 for the cell viability, RNA-seq for the mRNA expression, real-time quantitative PCR, immunofluorescence assay for the location of relative proteins, western blot for the levels of relative proteins and autophagy flux assay.Results: This study showed the mNRPCs in vivo and in vitro high expressed IFITM3 which are expressed in the mNRPCs. The proliferation of mNRPCs was greatly inhibited, and cell viability was greatly reduced after IFITM3 knockdown. Moreover, RNA-seq analysis showed that lysosomes were significant changed after IFITM3 knockdown. When cells were treated with rapamycin (RAMP), lysosome activation and agglomeration were evident in all groups. However, there was no significant difference between IFITM3 knockdown groups. The expression of LAMP1 was significantly increased, accompanied by increased lysosome agglomeration, in RAMP-treated cells and especially in IFITM3-knockdown cells. Further detection showed that SQSTM1/p62, HSC70 and LAMP-2A were upregulated, while there was no significant difference in LC3A/B expression, which demonstrated that the MA pathway was not activated but the CMA pathway was activated when knockdown of IFITM3. Conclusion: Our findings indicate that IFITM3 participates in regulating mNRPC viability and proliferation mainly through the CMA pathway, indicating that IFITM3 plays a significant role in maintaining the homeostasis of progenitor cell self-renewal by sustaining low-level activation of the CMA pathway to eliminate factors that are deleterious to cells and acts as a very important protector of RPCs.


2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Dongxia Ge ◽  
Michael J. O’Brien ◽  
Felix H. Savoie ◽  
Jeffrey M. Gimble ◽  
Xiying Wu ◽  
...  

AbstractLocalized cartilage lesions in early osteoarthritis and acute joint injuries are usually treated surgically to restore function and relieve pain. However, a persistent clinical challenge remains in how to repair the cartilage lesions. We expressed doublecortin (DCX) in human adipose-derived stromal/stem cells (hASCs) and engineered hASCs into cartilage tissues using an in vitro 96-well pellet culture system. The cartilage tissue constructs with and without DCX expression were implanted in the knee cartilage defects of rabbits (n = 42) and monkeys (n = 12). Cohorts of animals were euthanized at 6, 12, and 24 months after surgery to evaluate the cartilage repair outcomes. We found that DCX expression in hASCs increased expression of growth differentiation factor 5 (GDF5) and matrilin 2 in the engineered cartilage tissues. The cartilage tissues with DCX expression significantly enhanced cartilage repair as assessed macroscopically and histologically at 6, 12, and 24 months after implantation in the rabbits and 24 months after implantation in the monkeys, compared to the cartilage tissues without DCX expression. These findings suggest that hASCs expressing DCX may be engineered into cartilage tissues that can be used to treat localized cartilage lesions.


Author(s):  
Saleheh Shahmoradi ◽  
Fatemeh Yazdian ◽  
Amin Janghorbani ◽  
Leila Satarian ◽  
Farnaz Behroozi ◽  
...  

Introduction: Age-related macular degeneration (AMD) is one of the retina diseases in which retinal pigment epithelium cells are degraded and lead to blindness. Available treatments only slow down the progression of it. In this study, human embryonic stem cells (hESCs) differentiated into retinal pigment epithelium cells were cultured on a polycaprolactone scaffold. Methods: The optimization of the diameter of the produced scaffolds by electrospinning method was done using the fuzzy method for the first time. To improve cell adhesion and proliferation, related parameters to alkaline hydrolysis method were optimized and hydrophobic surface of scaffold was modified. After in vitro analysis, cells were cultured on different groups of scaffolds. In vivo analyses were done and cells culture on scaffolds observed. Results: The optimal parameters for the scaffold based on the fuzzy model were 18.1 kV for voltage, 0.07 g / ml for solution concentration and 115 nm for scaffold diameter, respectively. The immersion time of the scaffold in alkaline solution and concentration of solution were measured 97 min and 3.7 M, respectively. The treated scaffold had a higher degradation rate and water adsorption. MTT-Assay results showed that scaffolds with modified surfaces had a higher amount of cell viability and proliferation after 7 days. SEM image results confirmed this finding after almost two months. Additionally, the results of ICC test showed that after passing this time, cells kept their RPE and epithelium. Conclusion: Based on the results, the hydrolyzed scaffold is a suitable substrate for cell proliferation and can be a good option for AMD treatment.


2021 ◽  
Author(s):  
Kenta Ite ◽  
Masashi Toyoda ◽  
Saeko Yoshioka ◽  
Takaaki Yukitake ◽  
Mayu Yamazaki-Inoue ◽  
...  

Many drugs have the potential to induce the expression of drug-metabolizing enzymes, particularly cytochrome P450 3A4 (CYP3A4). Hepatocytes are often employed to evaluate drug-mediated CYP3A4 induction, but the variation between different cell lots is an issue that needs to be solved. Only a limited number of immortalized hepatocyte cell lines have been reported to date. In this study, we describe the successful generation of hepatocytes from disease-specific induced pluripotent stem cells (iPSCs) derived from a patient with fulminant hepatitis (FH-iPSCs). To examine the CYP3A4 induction potential, FH-iPSCs were induced into hepatocytes. Drug-mediated induction testing revealed that HepaKI exhibited a 57.2-fold increase in CYP3A4 after exposure to rifampicin, relative to control cells. These results suggest that FH-iPSCs are a preferred cell source for in vitro CYP3A4 induction assays.


2021 ◽  
pp. 3056-3064
Author(s):  
Erma Safitri ◽  
Hery Purnobasuki

Background and Aim: Mesenchymal stem cells (MSCs) transplanted into the testes of rats with testicular failure can help rescue fertility. However, the low viability of transplanted MSCs limits the success of this treatment. This study aimed to determine the effectiveness of MSCs cultured under hypoxia to increase the fertility rate in rats (Rattus norvegicus). Materials and Methods: Bone marrow-derived MSCs (200 million cells/rat) were transplanted into male rat models with induced infertility (10 rats/treatment group) after 4 days of culture in 21% O2 (normoxia) and 1% O2 (hypoxia). Ten fertile and 10 untreated infertile rats served as controls. In the infertile male rats that had been fasted from food for 5 days, the fasting condition induced malnutrition and then resulted in testicular failure. Results: The results indicated that the MSCs cultured under hypoxic conditions were more effective than those cultured in normoxic conditions as a treatment for testicular failure in infertile male rats based on the increased number of cells expressing p63 as a quiescent cell marker and ETV5 as a transcription factor expressed in Sertoli and germ cells. Furthermore, the structure of the seminiferous tubules, which contain spermatogonia, primary and secondary spermatocytes, and spermatid, Sertoli, and Leydig cells, was improved in infertile male rats treated with the MSCs cultured under hypoxic conditions. Conclusion: The testicular transplantation of MSCs cultured under hypoxic conditions was an effective treatment for testicular failure in rats.


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