CDKN2B upregulation prevents teratoma formation in multipotent fibromodulin-reprogrammed cells

Zheng, Zhong; Li, Chenshuang; Ha, Pin; Chang, Grace; Yang, Pu; Zhang, Xinli; Kim, Jong Kil; Jiang, Wenlu; Pang, Xiaoyan; Berthiaume, Emily A.; Mills, Zane; Haveles, Christos S; Chen, Eric; Ting, Kang

doi:10.1172/jci125015

Cited by 16 publications

(19 citation statements)

References 92 publications

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“…This suggests that the major epigenetic changes acquired during replication can be reset to some extent. While reprogramming represents an exciting regenerative prospect in the aging field, some issues remain-namely the propensity for incidence of teratomas when reprogramming is conducted in vivo [56,57]. However, partial reprogramming without dedifferentiation may provide a path forward and it will be important to determine whether resetting of the replication signature also occurs under those circumstances.…”

Section: Discussionmentioning

confidence: 99%

Cellular aging in vitro recapitulates multi-tissue epigenetic aging in vivo

Minteer

Morselli

Meer

et al. 2020

Preprint

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Aging is known to elicit dramatic changes to DNA methylation (DNAm). However, the causes and consequences of such alterations to the epigenome remain unclear. Therefore, the utility of biomarkers of aging based on DNAm patterns will depend on our ability to link them to cellular features, such as proliferation, differentiation, transcriptional repression/activation, senescence, and transformation. Using DNAm from serially passaged mouse embryonic fibroblasts (MEFs), we developed a predictor of replication that is able to accurately predict passage number in independent sample. Our measure, termed DNAmRep, was shown to strongly increase with age when examined in multiple tissues (blood, liver, kidney, lung and adipose). Furthermore, we observed replicative deceleration in animal undergoing caloric restriction. Upon reprogramming to iPSCs, cells derived from both lung and kidney fibroblasts exhibited resetting of our DNAmRep measure. This measure also increased in response to differentiation among B-cell populations. Enrichment analysis implicated CBX7, RNF2 and HDAC2 as potentially important transcription factors and chromatin regulators in the DNAm replication signature. Finally, DNAmRep correlated with beta-galactosidase activity in replicative senescent MEFs, but not in radiation or drug induced senescent MEFs, and was partially separated by immortalization with Large T antigen K1 mutant (LTK1), suggesting that it reflects mitotic history, rather than senescent state. Overall, this study identifies mitotically-derived alterations to the methylome, which partially underlie known epigenetic aging phenomena.

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Section: Discussionmentioning

confidence: 99%

Cellular aging in vitro recapitulates multi-tissue epigenetic aging in vivo

Minteer

Morselli

Meer

et al. 2020

Preprint

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“…GO and KEGG pathway enrichment analyses demonstrated that these DEmRNAs mainly serve as regulators of porcine GC states and functions. For instance, CDK6 , CDK18 , CDKN2B , CDKN2C , CCNB1 , CCNJ , and CCNK are associated with cell cycle [43–45]. BMP2 , GDF15 , TGF-β1 , SMAD5 , and PCNA are involved in cell proliferation [46, 47].…”

Section: Discussionmentioning

confidence: 99%

Integrated Analysis of miRNA-mRNA Interaction Network in Porcine Granulosa Cells Undergoing Oxidative Stress

Cao

Wang

et al. 2019

Oxidative Medicine and Cellular Longevity

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Oxidative stress (OS), a common intracellular phenomenon induced by excess reactive oxygen species (ROS) generation, has been shown to be associated with mammalian ovarian follicular development blockage and granulosa cell (GC) impairment. However, the mechanism involved in these effects remains unknown, and the effect of OS on the transcriptome profiles in porcine GCs has not been fully characterized. In this study, we found that hydrogen peroxide-mediated oxidative stress induced porcine GC apoptosis and impaired cell viability. Moreover, RNA-seq analysis showed that oxidative stress induced dramatic changes in gene expression in porcine GCs. A total of 2025 differentially expressed genes (DEGs) were identified, including 1940 DEmRNAs and 55 DEmiRNAs. Functional annotation showed that the DEGs were mainly associated with cell states and function regulation. In addition, multiple hub genes (FOXO1, SOD2, BMP2, DICER1, BCL2L11, FZD4, ssc-miR-424, and ssc-miR-27b) were identified by constructing protein-protein interaction and DEmiRNA-DEmRNA regulatory networks. Furthermore, a gene-pathway-function coregulatory network was established and demonstrated that these hub genes were enriched in FoxO, TGF-β, Wnt, PIK3-Akt, MAPK, and cAMP signaling pathways, which play important roles in regulating cell apoptosis, cell proliferation, stress responses, and hormone secretion. The current research provides a comprehensive perspective of the effects of oxidative stress on porcine GCs and also identifies potential therapeutic targets for oxidative stress-induced female infertility.

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“…Taken together, FMOD administration in adult wound models elicits a similar phenotype to fetal wounds at the molecular, cellular, and gross morphological levels (Zheng et al, 2017). Moreover, recent studies demonstrate that FMOD can directly reprogram human dermal fibroblasts into a multipotent stage, indicating its ability to regulate the intracellular signaling cascade and determine the cell fate (Zheng et al, 2012;Li et al, 2016;Zheng et al, 2019). Furthermore, from a translational aspect, recent studies have confirmed the biopotency of FMOD in reducing scar formation, accelerating wound tensile strength reestablishment, and improving dermal collagen architecture organization as well as gross wound appearance in multiple small and large preclinical animal models, and even within an excessive-mechanical-loading model (Zheng et al, 2017;Jiang et al, 2018), highlighting the enormous potentials of FMOD as a regenerative medicine for wound and scar therapies.…”

Section: Fibroblast Activitiesmentioning

confidence: 95%

Small Leucine-Rich Proteoglycans in Skin Wound Healing

2020

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Healing of cutaneous wounds is a complex and well-coordinated process requiring cooperation among multiple cells from different lineages and delicately orchestrated signaling transduction of a diversity of growth factors, cytokines, and extracellular matrix (ECM) at the wound site. Most skin wound healing in adults is imperfect, characterized by scar formation which results in significant functional and psychological sequelae. Thus, the reconstruction of the damaged skin to its original state is of concern to doctors and scientists. Beyond the traditional treatments such as corticosteroid injection and radiation therapy, several growth factors or cytokines-based anti-scarring products are being or have been tested in clinical trials to optimize skin wound healing. Unfortunately, all have been unsatisfactory to date. Currently, accumulating evidence suggests that the ECM not only functions as the structural component of the tissue but also actively modulates signal transduction and regulates cellular behaviors, and thus, ECM should be considered as an alternative target for wound management pharmacotherapy. Of particular interest are small leucine-rich proteoglycans (SLRPs), a group of the ECM, which exist in a wide range of connecting tissues, including the skin. This manuscript summarizes the most current knowledge of SLRPs regarding their spatial-temporal expression in the skin, as well as lessons learned from the genetically modified animal models simulating human skin pathologies. In this review, particular focus is given on the diverse roles of SLRP in skin wound healing, such as anti-inflammation, pro-angiogenesis, pro-migration, pro-contraction, and orchestrate transforming growth factor (TGF)b signal transduction, since cumulative investigations have indicated their therapeutic potential on reducing scar formation in cutaneous wounds. By conducting this review, we intend to gain insight into the potential application of SLRPs in cutaneous wound healing management which may pave the way for the development of a new generation of pharmaceuticals to benefit the patients suffering from skin wounds and their sequelae.

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CDKN2B upregulation prevents teratoma formation in multipotent fibromodulin-reprogrammed cells

Cited by 16 publications

References 92 publications

Cellular aging in vitro recapitulates multi-tissue epigenetic aging in vivo

Cellular aging in vitro recapitulates multi-tissue epigenetic aging in vivo

Integrated Analysis of miRNA-mRNA Interaction Network in Porcine Granulosa Cells Undergoing Oxidative Stress

Small Leucine-Rich Proteoglycans in Skin Wound Healing

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