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Control of Mesenchymal Stem Cell Biology by Histone Modifications

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Control of Mesenchymal Stem Cell Biology by Histone Modifications Ren et al. Cell Biosci (2020) 10:11 https://doi.org/10.1186/s13578-020-0378-8 Cell & Bioscience REVIEW Open Access Control of mesenchymal stem cell biology by histone modifcations Jianhan Ren, Delan Huang, Runze Li, Weicai Wang* and Chen Zhou* Abstract Mesenchymal stem cells (MSCs) are considered the most promising seed cells for regenerative medicine because of their considerable therapeutic properties and accessibility. Fine-tuning of cell biological processes, including diferen- tiation and senescence, is essential for achievement of the expected regenerative efcacy. Researchers have recently made great advances in understanding the spatiotemporal gene expression dynamics that occur during osteogenic, adipogenic and chondrogenic diferentiation of MSCs and the intrinsic and environmental factors that afect these processes. In this context, histone modifcations have been intensively studied in recent years and have already been indicated to play signifcant and universal roles in MSC fate determination and diferentiation. In this review, we sum- marize recent discoveries regarding the efects of histone modifcations on MSC biology. Moreover, we also provide our insights and perspectives for future applications. Keywords: Epigenetics, Histone modifcations, Mesenchymal stem cells, Cell diferentiation, Cellular senescence, Cell biology Background or CD11b, CD79α or CD19, and HLA class II. In addi- Mesenchymal stem cells are multipotent cells that can tion, MSCs must be able to diferentiate into osteocytes, diferentiate into various lineages whose nomenclature chondrocytes and adipocytes in vitro under diferentiat- remains inconsistent. Apart from “mesenchymal stem ing conditions [5]. MSCs can also transdiferentiate into cells”, MSCs are also called “mesenchymal stromal cells”, diferent types of cells from other germ layers, including “bone marrow stromal cells” (BMSCs) and “multipo- neurons, epithelial cells, cardiomyocytes, hepatic cells tent stromal cells” [1]. Friedenstein originally discovered and islet cells [6–10], meaning that they can be used to MSCs in mouse bone marrow [2]. Since then, MSCs have repair or regenerate various tissues, such as cartilage, been isolated from most types of mesenchymal tissue, bone, and adipose tissue [11]. Moreover, MSCs possess including skeletal muscle tissue, adipose tissue, umbilical anti-infammatory and proinfammatory capabilities, cord tissue, placenta tissue, liver tissue, skin tissue, syno- enabling them to regulate the immune response [12–14]. vial membranes, dental pulp, periodontal ligaments, cer- MSCs are regarded as immune-privileged because they vical tissue, amniotic fuid, lung tissue, and dermal tissue express MHC-I at low levels and are negative for MHC II [3]. and T-cell costimulatory molecules. Compared to embry- According to the International Society for Cellular onic stem cells (ESCs) and induced pluripotent stem Terapy (ISCT) [4], MSCs must be positive for CD105, cells (iPSCs), MSCs have low tumorigenicity [15]. Tese CD90, and CD73 while negative for CD45, CD34, CD14 advantages make them promising candidates for the treatment of a wide range of diseases, including myocar- dial infarction, graft-versus-host disease (GvHD), acute *Correspondence: [email protected]; [email protected] respiratory distress syndrome (ARDS), amyotrophic lat- Guanghua School of Stomatology, Hospital of Stomatology, and Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen eral sclerosis, and chronic kidney disease, among others University, 56 Lingyuanxi Road, Guangzhou 510055, China [16–20]. © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea- tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo- main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ren et al. Cell Biosci (2020) 10:11 Page 2 of 15 Given the great clinical and scientifc signifcance of changes gene expression and thus strongly infuences the MSCs, understanding of their biological characteristics fate commitment of MSCs. Te roles of histone-modify- in vivo and in vitro, including their proliferation, difer- ing enzymes are described below and are summarized in entiation, cellular senescence and responses to abnormal Fig. 2. microenvironments, is urgently needed. In this review, we systemically summarize the most recent progress in the feld of histone modifcation-mediated control of Roles of histone modifcations in MSC osteogenic, MSC biological processes and our perspectives on the adipogenic and chondrogenic diferentiation latest advancements. Bone formation involves proliferation of MSCs, difer- Histone modifcation refers to posttranslational modi- entiation of MSCs into progenitor cells and eventually fcation of histones. Most histone modifcations involve osteoblasts, and secretion of bone matrix by osteoblasts. sites within the frst 30 amino acids of the N-terminal MSC osteogenic diferentiation is critical to bone forma- domains of histones (also known as histone tails), such tion [38], and impairment of the osteoblast diferentia- as H3K4, H3K9 and H3K27 [21]. Tere are many difer- tion potential of MSCs can lead to various diseases, such ent kinds of histone modifcations, including acetylation, as osteoporosis, osteopetrosis, osteopenia, and oculo- methylation, phosphorylation, ubiquitylation, SUMOyla- faciocardiodental (OFCD) syndrome [39–41]. Recent tion, and proline isomerization [22]. studies profling the genome-wide patterns of difer- Histone methylation, which is mediated by histone ent histone marks have revealed relationships between methyltransferases (HMTs) and histone demethylases histone modifcations and osteogenic diferentiation of (HDMs), mainly infuences lysine and arginine residues MSCs. For example, Meyer and colleagues found that the on the histone side chains; through this process, lysine histone patterns of osteogenic diferentiated MSCs are can be mono-, di- or trimethylated. Diferent histone similar to those of undiferentiated MSCs by ChIP-seq methylations afect gene transcription in diferent ways and RNA-seq analyses, suggesting an intrinsic prefer- in cooperation with other identifying proteins [23–25]. ence of MSCs for osteogenic diferentiation [36]. Tan and Histone acetyltransferases (HATs) and histone deacety- colleagues noted that H3K9ac marks on gene promoter lases (HDACs) are both enzymes that regulate histone regions globally decrease but that H3K9me2 marks glob- acetylation on lysine residues, but they produce opposite ally increase during osteogenic diferentiation through results [26, 27]. In addition, proteins that contain special- ChIP-on-chip and expression microarray analyses [42]. ized binding regions, such as bromodomains, are termed Adipogenesis is another important process of MSCs. readers [28]; these proteins can recognize and bind to Adipogenic diferentiation correlates with the formation acetylated lysine residues, thus interacting with specifc of adipose tissue, which is a critical regulator of energy histone modifcations [29]. homeostasis, metabolism and immunity [37]. Tere- As mentioned above, many types of histone modifca- fore, disruption of MSC diferentiation potential results tions exist apart from methylation and acetylation. Te in abnormal accumulation of adipose tissue [43]. Unlike major enzymes and efector molecules corresponding to osteogenic diferentiated MSCs, adipogenic diferenti- these modifcations are summarized in Table 1. ated MSCs have a signifcantly diferent histone pattern than undiferentiated MSCs [36]. Regulatory roles of histone modifcations in MSC Chondrogenesis is a critical physiological process for diferentiation cartilage formation. Cartilage formation is essential not MSC diferentiation is a complex process regulated by only during embryogenesis but also during bone tissue various signaling pathways with intricate crosstalk [30– repair or the pathological processes of diseases such as 33] in which all types of epigenetic and transcriptional osteoarthritis (OA) [44]. A previous study used genome- regulation are involved [34]. Early studies focused on wide ChIP and deep sequencing analyses to examine his- how external stimuli and internal transcription factors tone mark changes in specifc genes during chondrogenic modulate the diferentiation of MSCs; however, recent diferentiation [45]. Te active marks H3K4me3, H3K9ac studies have revealed the roles of histone modifcations and H3K36me3 were enriched on upregulated chondro- in this process [35]. For example, it has been well estab- genic signature genes, including COL2A1, COL9A2, and lished that histones on the promoter regions of master ACAN, among others, whereas the levels of
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