bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stem cell contributions to cementoblast differentiation in healthy periodontal ligament and periodontitis
Authors: Zhao Jing , Faure Louis , Adameyko Igor , Sharpe Paul T. 
Published: November 2021

AbstractLoss of tissue attachment as a consequence of bacterial infection and inflammation represents the main therapeutic target for the treatment of periodontitis. Cementoblasts, the cells that produce the mineralized tissue, cementum, that is responsible for connecting the soft periodontal tissue to the tooth, are a key cell type for maintaining/restoring tissue attachment following disease. Here, we identify two distinct stem cell populations that contribute to cementoblast differentiation at different times. During postnatal development, cementoblasts are formed from perivascular-derived cells expressing CD90 and perivascular-associated cells that express Axin2. During adult homeostasis, only Wnt-responsive Axin2+ cells form cementoblasts but following experimental induction of periodontal disease, CD90+ cells become the main source of cementoblasts. We thus show that different populations of resident stem cells are mobilized at different times and during disease to generate precursors for cementoblast differentiation and thus provide an insight into the targeting cells resident cells for novel therapeutic approaches. The differentiation of these stem cells into cementoblasts is however inhibited by bacterial products such as lipopolysaccharides, emphasizing that regeneration of periodontal ligament soft tissue and restoration of attachment will require a multipronged approach.
GATA6 regulates aging of human mesenchymal stem/stromal cells
Authors: Jiao Hongli , Walczak Brian E. , Lee Ming-Song , Lemieux Madeleine E. , Li Wan-Ju 
Published: November 2021

Abstract
Cellular reprogramming forcing the expression of pluripotency markers can reverse aging of cells, but how molecular mechanisms through which reprogrammed cells alter aging-related cellular activities still remains largely unclear. In this study, we reprogrammed human synovial fluid-derived mesenchymal stem cells (MSCs) into induced pluripotent stem cells (iPSCs) using six reprogramming factors and reverted the iPSCs back to MSCs, as an approach to cell rejuvenation. Using the parental and reprogrammed MSCs as control nonrejuvenated and rejuvenated cells, respectively, for comparative analysis, we found that aging-related activities were greatly reduced in reprogrammed MSCs compared with those in their parental lines, indicating reversal of cell aging. Global transcriptome analysis revealed differences in activities of regulatory networks associated with inflammation and proliferation. Mechanistically, we demonstrated that, compared with control cells, the expression of GATA binding protein 6 (GATA6) in reprogrammed cells was attenuated, resulting in an increase in the activity of sonic hedgehog signaling and the expression level of downstream forkhead box P1 (FOXP1), in turn ameliorating cellular hallmarks of aging. Lower levels of GATA6 expression were also found in cells harvested from younger mice or lower passage cultures. Our findings suggest that GATA6 is a critical regulator increased in aged MSCs that controls the downstream sonic hedgehog signaling and FOXP1 pathway to modulate cellular senescence and aging-related activities.
Cell therapy in Huntington's disease: Taking stock of past studies to move the field forward
Authors: Bachoud-Lévi Anne-Catherine , Massart Renaud , Rosser Anne 
Published: November 2021

Abstract
Huntington's disease (HD) is a rare inherited neurodegenerative disease that manifests mostly in adulthood with progressive cognitive, behavioral, and motor dysfunction. Neuronal loss occurs predominantly in the striatum but also extends to other brain regions, notably the cortex. Most patients die around 20 years after motor onset, although there is variability in the rate of progression and some phenotypic heterogeneity. The most advanced experimental therapies currently are huntingtin-lowering strategies, some of which are in stage 3 clinical trials. However, even if these approaches are successful, it is unlikely that they will be applicable to all patients or will completely halt continued loss of neural cells in all cases. On the other hand, cellular therapies have the potential to restore atrophied tissues and may therefore provide an important complementary therapeutic avenue. Pilot studies of fetal cell grafts in the 2000s reported the most dramatic clinical improvements yet achieved for this disease, but subsequent studies have so far failed to identify methodology to reliably reproduce these results. Moving forward, a major challenge will be to generate suitable donor cells from (nonfetal) cell sources, but in parallel there are a host of procedural and trial design issues that will be important for improving reliability of transplants and so urgently need attention. Here, we consider findings that have emerged from clinical transplant studies in HD to date, in particular new findings emerging from the recent multicenter intracerebral transplant HD study, and consider how these data may be used to inform future cell therapy trials.
SMAD-specific E3 ubiquitin ligase 2 promotes angiogenesis by facilitating PTX3 degradation in MSCs from patients with ankylosing spondylitis
Authors: Ma Mengjun , Yang Wen , Cai Zhaopeng , Wang Peng , Li Hongyu , Mi Rujia , Jiang Yuhang , Xie Zhongyu , Sui Pengfei , Wu Yanfeng , Shen Huiyong 
Published: November 2021

Abstract
Dysregulated angiogenesis of mesenchymal stem cells (MSCs) is closely related to inflammation and disrupted bone metabolism in patients with various autoimmune diseases. However, the role of MSCs in the development of abnormal angiogenesis in patients with ankylosing spondylitis (AS) remains unclear. In this study, we cultured human umbilical vein endothelial cells (HUVECs) with bone marrow-derived MSCs from patients with AS (ASMSCs) or healthy donors (HDMSCs) in vitro. Then, the cocultured HUVECs were assayed using a cell counting kit-8 (CCK-8) to evaluate the cell proliferation. A wound healing assay was performed to investigate cell migration, and a tube formation assay was conducted to determine the angiogenesis efficiency. ASMSCs exhibited increased angiogenesis, and increased expression of SMAD-specific E3 ubiquitin ligase 2 (Smurf2) in MSCs was the main cause of abnormal angiogenesis in patients with AS. Downregulation of Smurf2 in ASMSCs blocked angiogenesis, whereas overexpression of Smurf2 in HDMSCs promoted angiogenesis. The pro-angiogenic effect of Smurf2 was confirmed by the results of a Matrigel plug assay in vivo. By functioning as an E3 ubiquitin ligase in MSCs, Smurf2 regulated the levels of pentraxin 3 (PTX3), which has been shown to suppress angiogenesis through the PTX3-fibroblast growth factor 2 pathway. Moreover, Smurf2 transcription was regulated by activating transcription factor 4-induced endoplasmic reticulum stress. In conclusion, these results identify novel roles of Smurf2 in negatively regulating PTX3 stability and promoting angiogenesis in ASMSCs.
ThemiR-200family is required for ectodermal organ development through the regulation of the epithelial stem cell niche
Authors: Sweat Mason , Sweat Yan , Yu Wenjie , Su Dan , Leonard Riley J. , Eliason Steven L. , Amendt Brad A. 
Published: November 2021

AbstractThe murine lower incisor ectodermal organ contains a single epithelial stem cell (SC) niche that provides epithelial progenitor cells to the continuously growing rodent incisor. The dental stem cell niche gives rise to several cell types and we demonstrate that the miR-200 family regulates these cell fates. The miR-200 family is highly enriched in the differentiated dental epithelium and absent in the stem cell niche. In this study, we inhibited the miR-200 family in developing murine embryos using new technology, resulting in an expanded epithelial stem cell niche and lack of cell differentiation. Inhibition of individual miRs within the miR-200 cluster resulted in differential developmental and cell morphology defects. miR-200 inhibition increased the expression of dental epithelial stem cell markers, expanded the stem cell niche and decreased progenitor cell differentiation. RNA-seq. identified miR-200 regulatory pathways involved in cell differentiation and compartmentalization of the stem cell niche. The miR-200 family regulates signaling pathways required for cell differentiation and cell cycle progression. The inhibition of miR-200 decreased the size of the lower incisor due to increased autophagy and cell death. New miR-200 targets demonstrate gene networks and pathways controlling cell differentiation and maintenance of the stem cell niche. This is the first report demonstrating how the miR-200 family is required for in vivo progenitor cell proliferation and differentiation.
LIF maintains mouse embryonic stem cells pluripotency by modulating TET1 and JMJD2 activity in a JAK2-dependent manner
Authors: Wulansari Noviana , Sulistio Yanuar Alan , Darsono Wahyu Handoko Wibowo , Kim Chang-Hoon , Lee Sang-Hun 
Published: November 2021

Abstract
The LIF-JAK2-STAT3 pathway is the central signal transducer that maintains undifferentiated mouse embryonic stem cells (mESCs), which is achieved by the recruitment of activated STAT3 to the master pluripotency genes and activation of the gene transcriptions. It remains unclear, however, how the epigenetic status required for the master gene transcriptions is built into LIF-treated mESC cultures. In this study, Jak2, but not Stat3, in the LIF canonical pathway, establishes an open epigenetic status in the pluripotency gene promoter regions. Upon LIF activation, cytosolic JAK2 was translocalized into the nucleus of mESCs, and reduced DNA methylation (5mC levels) along with increasing DNA hydroxymethylation (5hmC) in the pluripotent gene (Nanog/Pou5f1) promoter regions. In addition, the repressive histone codes H3K9m3/H3K27m3 were reduced by JAK2. Activated JAK2 directly interacted with the core epigenetic enzymes TET1 and JMJD2, modulating its activity and promotes the DNA and histone demethylation, respectively. The JAK2 effects were attained by tyrosine phosphorylation on the epigenetic enzymes. The effects of JAK2 phosphorylation on the enzymes were diverse, but all were merged to the epigenetic signatures associated with open DNA/chromatin structures. Taken together, these results reveal a previously unrecognized epigenetic regulatory role of JAK2 as an important mediator of mESC maintenance.
Autonomous TGFβ signaling induces phenotypic variation in human acute myeloid leukemia
Authors: Shingai Yasuhiro , Yokota Takafumi , Okuzaki Daisuke , Sudo Takao , Ishibashi Tomohiko , Doi Yukiko , Ueda Tomoaki , Ozawa Takayuki , Nakai Ritsuko , Tanimura Akira , Ichii Michiko , Shibayama Hirohiko , Kanakura Yuzuru , Hosen Naoki 
Published: November 2021

Abstract
Heterogeneity of leukemia stem cells (LSCs) is involved in their collective chemoresistance. To eradicate LSCs, it is necessary to understand the mechanisms underlying their heterogeneity. Here, we aimed to identify signals responsible for heterogeneity and variation of LSCs in human acute myeloid leukemia (AML). Monitoring expression levels of endothelial cell-selective adhesion molecule (ESAM), a hematopoietic stem cell-related marker, was useful to detect the plasticity of AML cells. While healthy human hematopoietic stem/progenitor cells robustly expressed ESAM, AML cells exhibited heterogeneous ESAM expression. Interestingly, ESAM− and ESAM+ leukemia cells obtained from AML patients were mutually interconvertible in culture. KG1a and CMK, human AML clones, also represented the heterogeneity in terms of ESAM expression. Single cell culture with ESAM− or ESAM+ AML clones recapitulated the phenotypic interconversion. The phenotypic alteration was regulated at the gene expression level, and RNA sequencing revealed activation of TGFβ signaling in these cells. AML cells secreted TGFβ1, which autonomously activated TGFβ pathway and induced their phenotypic variation. Surprisingly, TGFβ signaling blockade inhibited not only the variation but also the proliferation of AML cells. Therefore, autonomous activation of TGFβ signaling underlies the LSC heterogeneity, which may be a promising therapeutic target for AML.
Metabolic sensor O-GlcNAcylation regulates megakaryopoiesis and thrombopoiesis through c-Myc stabilization and integrin perturbation
Authors: Luanpitpong Sudjit , Poohadsuan Jirarat , Klaihmon Phatchanat , Kang Xing , Tangkiettrakul Kantpitchar , Issaragrisil Surapol 
Published: November 2021

Abstract
Metabolic state of hematopoietic stem cells (HSCs) is an important regulator of self-renewal and lineage-specific differentiation. Posttranslational modification of proteins via O-GlcNAcylation is an ideal metabolic sensor, but how it contributes to megakaryopoiesis and thrombopoiesis remains unknown. Here, we reveal for the first time that cellular O-GlcNAcylation levels decline along the course of megakaryocyte (MK) differentiation from human-derived hematopoietic stem and progenitor cells (HSPCs). Inhibition of O-GlcNAc transferase (OGT) that catalyzes O-GlcNAcylation prolongedly decreases O-GlcNAcylation and induces the acquisition of CD34+CD41a+ MK-like progenitors and its progeny CD34−CD41a+/CD42b+ megakaryoblasts (MBs)/MKs from HSPCs, consequently resulting in increased CD41a+ and CD42b+ platelets. Using correlation and co-immunoprecipitation analyses, we further identify c-Myc as a direct downstream target of O-GlcNAcylation in MBs/MKs and provide compelling evidence on the regulation of platelets by novel O-GlcNAc/c-Myc axis. Our data indicate that O-GlcNAcylation posttranslationally regulates c-Myc stability by interfering with its ubiquitin-mediated proteasomal degradation. Depletion of c-Myc upon inhibition of OGT promotes platelet formation in part through the perturbation of cell adhesion molecules, that is, integrin-α4 and integrin-β7, as advised by gene ontology and enrichment analysis for RNA sequencing and validated herein. Together, our findings provide a novel basic knowledge on the regulatory role of O-GlcNAcylation in megakaryopoiesis and thrombopoiesis that could be important in understanding hematologic disorders whose etiology are related to impaired platelet production and may have clinical applications toward an ex vivo platelet production for transfusion.
Protein kinase C-β-dependent changes in the glucose metabolism of bone marrow stromal cells of chronic lymphocytic leukemia
Authors: von Heydebrand Franziska , Fuchs Maximilian , Kunz Meik , Voelkl Simon , Kremer Anita N. , Oostendorp Robert A. J. , Wilke Jochen , Leitges Michael , Egle Alexander , Mackensen Andreas , Lutzny-Geier Gloria 
Published: November 2021

Abstract
Survival of chronic lymphocytic leukemia (CLL) cells critically depends on the support of an adapted and therefore appropriate tumor microenvironment. Increasing evidence suggests that B-cell receptor-associated kinases such as protein kinase C-β (PKCβ) or Lyn kinase are essential for the formation of a microenvironment supporting leukemic growth. Here, we describe the impact of PKCβ on the glucose metabolism in bone marrow stromal cells (BMSC) upon CLL contact. BMSC get activated by CLL contact expressing stromal PKCβ that diminishes mitochondrial stress and apoptosis in CLL cells by stimulating glucose uptake. In BMSC, the upregulation of PKCβ results in increased mitochondrial depolarization and leads to a metabolic switch toward oxidative phosphorylation. In addition, PKCβ-deficient BMSC regulates the expression of Hnf1 promoting stromal insulin signaling after CLL contact. Our data suggest that targeting PKCβ and the glucose metabolism of the leukemic niche could be a potential therapeutic strategy to overcome stroma-mediated drug resistance.
Human induced pluripotent stem cells and CRISPR/Cas-mediated targeted genome editing: Platforms to tackle sensorineural hearing loss
Authors: Stojkovic Miodrag , Han Dongjun , Jeong Minjin , Stojkovic Petra , Stankovic Konstantina M. 
Published: November 2021

Abstract
Hearing loss (HL) is a major global health problem of pandemic proportions. The most common type of HL is sensorineural hearing loss (SNHL) which typically occurs when cells within the inner ear are damaged. Human induced pluripotent stem cells (hiPSCs) can be generated from any individual including those who suffer from different types of HL. The development of new differentiation protocols to obtain cells of the inner ear including hair cells (HCs) and spiral ganglion neurons (SGNs) promises to expedite cell-based therapy and screening of potential pharmacologic and genetic therapies using human models. Considering age-related, acoustic, ototoxic, and genetic insults which are the most frequent causes of irreversible damage of HCs and SGNs, new methods of genome editing (GE), especially the CRISPR/Cas9 technology, could bring additional opportunities to understand the pathogenesis of human SNHL and identify novel therapies. However, important challenges associated with both hiPSCs and GE need to be overcome before scientific discoveries are correctly translated to effective and patient-safe applications. The purpose of the present review is (a) to summarize the findings from published reports utilizing hiPSCs for studies of SNHL, hence complementing recent reviews focused on animal studies, and (b) to outline promising future directions for deciphering SNHL using disruptive molecular and genomic technologies.
Mesenchymal stem cell immunomodulation: In pursuit of controlling COVID-19 related cytokine storm
Authors: Song Na , Wakimoto Hiroaki , Rossignoli Filippo , Bhere Deepak , Ciccocioppo Rachele , Chen Kok-Siong , Khalsa Jasneet Kaur , Mastrolia Ilenia , Samarelli Anna Valeria , Dominici Massimo , Shah Khalid 
Published: November 2021

Abstract
The coronavirus disease 2019 (COVID-19) pandemic has grown to be a global public health crisis with no safe and effective treatments available yet. Recent findings suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus pathogen that causes COVID-19, could elicit a cytokine storm that drives edema, dysfunction of the airway exchange, and acute respiratory distress syndrome in the lung, followed by acute cardiac injury and thromboembolic events leading to multiorgan failure and death. Mesenchymal stem cells (MSCs), owing to their powerful immunomodulatory abilities, have the potential to attenuate the cytokine storm and have therefore been proposed as a potential therapeutic approach for which several clinical trials are underway. Given that intravenous infusion of MSCs results in a significant trapping in the lung, MSC therapy could directly mitigate inflammation, protect alveolar epithelial cells, and reverse lung dysfunction by normalizing the pulmonary microenvironment and preventing pulmonary fibrosis. In this review, we present an overview and perspectives of the SARS-CoV-2 induced inflammatory dysfunction and the potential of MSC immunomodulation for the prevention and treatment of COVID-19 related pulmonary disease.
Compressive behavior of precast concrete sandwich panels containing recycled tyre crumb rubber core
Authors: Awan Abdul Basir , Shaikh Faiz Uddin Ahmed 
Published: November 2021

AbstractThis paper presents the structural behavior of precast concrete sandwich panels (PCSPs) containing recycled tyre crumb rubber core under uni‐axial compression and compared with that containing commonly used expanded polystyrene (EPS) foam. A total of six panels were cast and tested. Two for each category of precast concrete panels that is, solid concrete panel, crumb rubber sandwich panel and foam sandwich panel. Results showed that the ultimate axial load of crumb rubber sandwich panel was found to be 91% of solid concrete panel and also exhibited higher structural response in comparison to foam sandwich panel. It was observed that all panels failed in a similar manner by crushing of concrete at ultimate load. Moreover, a finite element model was developed in ABAQUS using in‐built model of concrete plasticity damage to simulate the ultimate axial capacity of recycled tyre crumb rubber concrete sandwich panel and its failure in uniaxial compression. Analysis showed that the finite element modeling slightly overestimated the experimental results. Furthermore, the experimental test results showed that the recycled tyre crumb rubber can be utilized as an alternate core material in PCSPs without substantially compromising the ultimate strength or any change in structural response.
Investigation of the relationships among science teachers' epistemic orientations, epistemic understanding, and implementation of Next Generation Science Standards science practices
Authors: Park Soonhye , Kite Vance , Suh Jee Kyung , Jung Jinhong , Rachmatullah Arif 
Published: November 2021

AbstractEngaging students in the essential practices of science has been forwarded as an effective means to achieve scientific literacy for all students by promoting the learning of content, procedures, and the epistemology of science concurrently. However, the emphasis on science practices requires teachers not only to develop skills and knowledge specific to the science practices, but also to adopt epistemic orientations congruent with student‐centered, knowledge generation science teaching approaches. This exploratory quantitative study examined the relationships between secondary science teachers' epistemic orientations and their understanding and self‐reported implementation of the science practices described in the US Next Generation Science Standards (NGSS). This study also identified teacher‐level variables that predict teachers' epistemic orientations, their understanding and implementation of the science practices. Data were collected from 128 secondary science teachers in a southeastern state of the US using three instruments: epistemic orientation survey with demographic questions, epistemic nature of science practice survey, and science practice implementation survey. One‐way analysis of variance, correlation analyses, multiple linear regression, and path analyses were used to examine the relationship among these three variables and the influence of teacher‐level variables on each of the three variables. Our results indicated that teachers' participation in NGSS PD programs significantly predicted their self‐reported implementation of science practices. In addition, teachers' lateral entry was the only significant predictor of teachers' epistemic understanding of science practices. Concerning the relationship among the three variables, the path analysis revealed that teachers' epistemic orientations significantly mediated the relationship between their epistemic understanding and implementation of science practices (χ2/df = 1.530,p = 0.216, comparative fit index = 0.980, Tucker–Lewis index = 0.940, root‐mean‐square error of approximation = 0.065). This study highlights a close relationship between teachers' epistemic orientations and enactment of science practices, which suggests prioritizing epistemic orientations in supporting teachers to implement the science‐as‐practice approach.