Histone Changes Control Mesenchymal Stem Cell Ageing Epigenetically

Bin Yu^*
*Correspondence: Bin Yu, Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China, Email:

Introduction

Mesenchymal stem cell ageing

A trustworthy source for cell-based regenerative therapy, mesenchymal stem cells (MSCs) are known for their multipotency and biological capabilities. However, systemic homeostasis issues brought on by ageing in vivo and cell culture passaging in vitro cause a reduction in MSC function, causing MSCs to enter a senescent state with impaired capacity for self-renewal and biassed differentiation propensity. In addition to explaining the pathophysiology of numerous diseases, MSC functional decline also restricts the widespread use of MSCs in regenerative therapy. Growing data suggests that ageing causes alterations in epigenetic pathways, which are a major regulator of differentiation programmes for cell destiny. As a result, we will now discuss the epigenetic dysregulations that cause osteoporosis and MSC ageing. Understanding specific epigenetic processes could provide up new possibilities for analysing MSC-related.

Description

We examine the significance of epigenetics as a contributing factor for ageing adult stem cells in this review. With a focus on adult stem cells in the bone marrow, we discuss the most recent research on how epigenetic variables become dysregulated as adult stem cells age and how this affects stem cell self-renewal and differentiation. We are able to understand an emerging pattern similar to adult stem cells in the bone marrow niche and how this can link to epigenetic enzymes altered with ageing using the most recent whole genome bisulphite sequencing and chromatin immunoprecipitations. We start by quickly going over the early findings in yeast, drosophila, and Caenorhabditis elegans (C. elegans) that sparked the groundbreaking studies that revealed the significance of epigenetic modifications related to longevity and ageing [1].

Widespread active chromatin marks, including histone acetylation and H3K4me3 together with hypomethylated DNA, are revealed by genome-wide maps of epigenetic alterations from mouse and human ESC. These marks ensure that the developmental genes have an open chromatin configuration to maintain an activated condition and that the genes linked with stem cells are active because they contribute to the open chromatin configuration. However, lineage genes must be suppressed to keep stem cells young and open to activation, which explains the presence of the bivalent mark, which combines the active H3K4me3 and the repressive H3K27me3. Some adult stem cells, including HSC, exhibit this as well. This prevents differentiated cells from differentiating into other cell types and ensures that they continue along the lineage for which they are intended. It is also strongly related to the bivalent histone mark resolving to become univalent. H3K9me2 levels significantly increased and chromosomes spread during differentiation, according to a genome-wide analysis. The same is true for H3K27me3, which reduces plasticity and forces adherence to the desired lineage.

Epigenetic control, which is characterised by heredity, reversibility, and no gene alterations, refers to changing phenotype through gene differential expression without changing DNA sequence. To maintain cell and niche homeostasis, epigenetic changes in cells occur in response to external environmental stimuli and cellular intrinsic heredity. In light of this, MSC ageing or senescence in vivo or in vitro is additionally influenced by its own intrinsic dysregulation and microenvironmental stimuli from the MSC niche, in the course of which typical epigenetic marks might be discovered. The key epigenetic mechanisms include DNA methylation, histone alterations, and chromatin remodelling. In MSCs, the epigenetic profile reflects constantly changing chromatin structure and associated gene transcriptional activity. Additionally, noncoding RNAs (ncRNAs) and mRNA participate in posttranscriptional processing [2].

It is well known that each of these epigenetic markers has a significant impact on the destiny of MSCs on several levels. In order to assess the pathophysiology of aged and sick tissue problems and explore more efficient therapeutic or regenerative techniques, it is important to better rationalise and understand the function mechanism of various epigenetic marks and modifiers happening in MSC ageing. Only a few researches have looked at how MSCs' mRNA changes with age. However, RNA N6-methyladenosine (m6A) alteration is intimately related to the biological activity of MSCs in a normal bone. Demethyltransferase fat mass and obesity-associated protein (FTO) enhance lipogenesis, which balances out the osteogenesis caused by methyltransferase like 3 (METTL3). The GDF11-FTO-PPAR axis promotes lipogenesis as we age because Fto gene expression rises and prevents the production of m6A on Ppar mRNA. However, application of METTL3 could stop the processes of adipogenesis and osteoporosis [3].

MiRNAs that are involved in regulating the proteins that cause senescence are downregulated in response to the replicative pressure brought on by serial passages. The global gene regulatory network is first dysregulated as a result of the downregulation of these miRNAs, which ultimately accelerates ageing. For instance, downregulation of miR-10a is inadequate to stop Krüppel-like factor 4 (KLF4) from causing senescence. Intriguingly, downregulation of the miR-17 family (which includes miR-17, miR-20b-5p, and miR-106a-5p) affects how many genes, including the aging-related Smad ubiquitination regulatory factor-1 (Smurf1), p21, CCND1, and E2F1 genes, function. Additionally, it has been found that other downregulated miRNAs, such as miR-543, miR-590-3p, and miR-24a, individually regulate p18/p21 and p16 activity [4].

Exogenous inhibitors are a typical way to stop illnesses and ageing caused by epigenetic factors in MSCs. A combination of collagen sponge and the HDAC1/4 inhibitor MS-275 promotes the healing of a critical-sized calvarial lesion in rats in non-aging animal models of bone tissue regeneration. Additionally, MS-275 administered intraperitoneally prevents Runx2-null animals from developing delayed cranial suture closure. The number of osteoblasts in endocortical bone increased and the blood level of OCN increased when mice were intraperitoneally treated with vorinostat, another HDAC1 inhibitor. With the exception of this, miRNA-mediated bone repair typically uses particular biomaterials. For instance, ectopic bone formation on complex scaffolds rises when hMSCs transfected with anti-miR-34a, antimiR- 138, or anti-miR-222 by lipofectamine are loaded on a hydroxyapatite/ tricalcium phosphate ceramic powder [5].

Conclusion

Lentiviruses expressing the CBX4 protein can be injected into joint capsules to treat illnesses by upregulating genes linked with bone formation and downregulating genes associated with inflammation and cell death. Similar to this, the ATPase-active mammalian brahma (BRM) protein is a part of the SWI/SNF complex. Mice with the Brm gene knocked down are less likely to develop osteoporosis as they age and have less fat in their bone marrow. In osteoporosis, lentivirus is also employed to change the degree of histone acetylation and methylation. By elevating H3K9ac on the promoters of Wnt genes, injection of lentiviruses expressing the Gcn5 gene in OVX mice restores endogenous BMSC osteogenic potential. Except for that, the aberrant MSC adipogenic lineage commitment is reversed when the Ezh2 gene is knocked down by lentivirus-expressing shRNA, which lowers the H3K27me3 on Wnt genes.

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