β-Catenin Preserves the Stem State of Murine Bone Marrow Stromal Cells Through Activation of EZH2

Sen, Buer; Paradise, Christopher R.; Xie, Zhihui; Sankaran, Jeyantt Srinivas; Uzer, Gunes; Styner, Martin; Meyer, Mark B.; Dudakovic, Amel; Wijnen, André J. van; Rubin, Janet

doi:10.1002/jbmr.3975

Cited by 50 publications

(44 citation statements)

References 94 publications

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“…Findings from several teams revealed that regulating the repressive mark H3K27me3 represents an important step during the differentiation of MSCs toward osteoblasts. It was demonstrated that the activity of the H3K27 demethylases Utx/Kdm6a and Jmjd3/Kdm6b is critical for erasing this mark from the promoter of the Runx2 and Sp7 genes ( Figure 1 ) and hence to induce their expression during osteogenesis ( Ye et al, 2012 ; Hemming et al, 2014 ; Rojas et al, 2015 ; Park-Min, 2016 ; Sepulveda et al, 2017b ; Cakouros and Gronthos, 2020 ; Sen et al, 2020 ). Additionally, an increased activity of the PRC2 complex that “writes” the H3K27me3 mark, can significantly limit the ability of MSCs to engage osteogenic differentiation ( Wei et al, 2010 ).…”

Section: Epigenetic Control Of the Expression Of Master Regulators Ofmentioning

confidence: 99%

Epigenetic Control of Osteogenic Lineage Commitment

Montecino

Carrasco

Nardocci

2021

Front. Cell Dev. Biol.

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Within the eukaryotic nucleus the genomic DNA is organized into chromatin by stably interacting with the histone proteins as well as with several other nuclear components including non-histone proteins and non-coding RNAs. Together these interactions distribute the genetic material into chromatin subdomains which can exhibit higher and lower compaction levels. This organization contributes to differentially control the access to genomic sequences encoding key regulatory genetic information. In this context, epigenetic mechanisms play a critical role in the regulation of gene expression as they modify the degree of chromatin compaction to facilitate both activation and repression of transcription. Among the most studied epigenetic mechanisms we find the methylation of DNA, ATP-dependent chromatin remodeling, and enzyme-mediated deposition and elimination of post-translational modifications at histone and non-histone proteins. In this mini review, we discuss evidence that supports the role of these epigenetic mechanisms during transcriptional control of osteoblast-related genes. Special attention is dedicated to mechanisms of epigenetic control operating at the Runx2 and Sp7 genes coding for the two principal master regulators of the osteogenic lineage during mesenchymal stem cell commitment.

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Section: Epigenetic Control Of the Expression Of Master Regulators Ofmentioning

confidence: 99%

Epigenetic Control of Osteogenic Lineage Commitment

Montecino

Carrasco

Nardocci

2021

Front. Cell Dev. Biol.

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“…Ezh2 activity has been implicated in cell fate determination and differentiation (36), as well as maintenance of the stem cell state in the mesenchymal linages (37).The complexity of these functions of Ezh2 was uncovered in studies of the skeletal tissues. Loss of Ezh2 in the osteogenic lineage resulted in reduced bone formation, but conditional loss of Ezh2 in uncommitted mesenchymal cells yields skeletal patterning defects, including shortened forelimbs, craniosynostosis and clinodactyly (17).…”

Section: Discussionmentioning

confidence: 99%

Enhancer of Zeste Homolog 2 (Ezh2) is essential for patterning of multiple musculoskeletal tissues but dispensable for tendon differentiation

Pal

Riester

Hasan

et al. 2020

Preprint

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An efficient musculoskeletal system depends on the precise assembly and coordinated growth and function of muscles, skeleton and tendons. However, the mechanisms that drive integrated musculoskeletal development and coordinated growth and differentiation of each of these tissues are still being uncovered. Epigenetic modifiers have emerged as critical regulators of cell fate differentiation, but so far almost nothing is known about their roles in tendon biology. Previous studies have shown that epigenetic modifications driven by Enhancer of zeste homolog 2 (EZH2), a major histone methyltransferase, have significant roles in vertebrate development including skeletal patterning and bone formation. We now find that targeting Ezh2 through the limb mesenchyme also has significant effects on tendon and muscle patterning, likely reflecting the essential roles of early mesenchymal cues mediated by Ezh2 for coordinated patterning and development of all tissues of the musculoskeletal system. Conversely, loss of Ezh2 in the tendon cells did not disrupt the tendon cell fate suggesting that tenocyte differentiation and tendon maturation are independent of Ezh2 signaling.

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“…To understand what preserved proliferative ability means for MSC fate, we quantified the osteogenic and the adipogenic capacity of EP, EP + LIV, LP and LP + LIV groups. We have previously established the multipotentiality of MSCs at EP timepoints 23,27,[34][35][36][37][38][39] . In order to check the potential changes in basal mRNA expression at LP Figure 1.…”

Section: Improves Msc Differentiation Potential Into Osteogenic Amentioning

confidence: 99%

Low Intensity Vibrations Augment Mesenchymal Stem Cell Proliferation and Differentiation Capacity during in vitro Expansion

Bas

Loisate

Hudon

et al. 2020

Sci Rep

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A primary component of exercise, mechanical signals, when applied in the form of low intensity vibration (LiV), increases mesenchymal stem cell (MSc) osteogenesis and proliferation. While it is generally accepted that exercise effectively combats the deleterious effects of aging in the musculoskeletal system, how long-term exercise affects stem cell aging, which is typified by reduced proliferative and differentiative capacity, is not well explored. As a first step in understanding the effect of long-term application of mechanical signals on stem cell function, we investigated the effect of LIV during in vitro expansion of MScs. primary MScs were subjected to either a control or to a twice-daily LiV regimen for up to sixty cell passages (P60) under in vitro cell expansion conditions. LIV effects were assessed at both early passage (EP) and late passage (LP). At the end of the experiment, P60 cultures exposed to LIV maintained a 28% increase of cell doubling and a 39% reduction in senescence-associated β-galactosidase activity (p < 0.01) but no changes in telomere lengths and p16 INK4a levels were observed. prolonged culture-associated decreases in osteogenic and adipogenic capacity were partially protected by LiV in both ep and Lp groups (p < 0.05). Mass spectroscopy of late passage MSC indicated a synergistic decrease of actin and microtubule cytoskeleton-associated proteins in both control and LiV groups while LiV induced a recovery of proteins associated with oxidative reductase activity. in summary, our findings show that the application of long-term mechanical challenge (+LiV) during in vitro expansion of MSCs for sixty passages significantly alters MSC proliferation, differentiation and structure. this suggests LiV as a potential tool to investigate the role of physical activity during aging.

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β-Catenin Preserves the Stem State of Murine Bone Marrow Stromal Cells Through Activation of EZH2

Cited by 50 publications

References 94 publications

Epigenetic Control of Osteogenic Lineage Commitment

Epigenetic Control of Osteogenic Lineage Commitment

Enhancer of Zeste Homolog 2 (Ezh2) is essential for patterning of multiple musculoskeletal tissues but dispensable for tendon differentiation

Low Intensity Vibrations Augment Mesenchymal Stem Cell Proliferation and Differentiation Capacity during in vitro Expansion

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