Stem Cells International

Stem Cells International / 2020 / Article
Special Issue

Mesenchymal Stem Cells and Regenerative Medicine 2020

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Review Article | Open Access

Volume 2020 |Article ID 3763069 | 12 pages | https://doi.org/10.1155/2020/3763069

Functions of Circular RNAs in Regulating Adipogenesis of Mesenchymal Stem Cells

Academic Editor: Huseyin Sumer
Received26 Mar 2020
Revised07 Jul 2020
Accepted08 Jul 2020
Published01 Aug 2020

Abstract

The mesenchymal stem cells (MSCs) are known as highly plastic stem cells and can differentiate into specialized tissues such as adipose tissue, osseous tissue, muscle tissue, and nervous tissue. The differentiation of mesenchymal stem cells is very important in regenerative medicine. Their differentiation process is regulated by signaling pathways of epigenetic, transcriptional, and posttranscriptional levels. Circular RNA (circRNA), a class of noncoding RNAs generated from protein-coding genes, plays a pivotal regulatory role in many biological processes. Accumulated studies have demonstrated that several circRNAs participate in the cell differentiation process of mesenchymal stem cells in vitro and in vivo. In the current review, characteristics and functions of circRNAs in stem cell differentiation will be discussed. The mechanism and key role of circRNAs in regulating mesenchymal stem cell differentiation, especially adipogenesis, will be reviewed and discussed. Understanding the roles of these circRNAs will present us with a more comprehensive signal path network of modulating stem cell differentiation and help us discover potential biomarkers and therapeutic targets in clinic.

1. Introduction

Circular RNAs are a new and intriguing class of noncoding RNA, produced from precursor mRNA (pre-mRNA), single-stranded, and covalently closed. circRNAs have been discovered for more than 40 years [1], once were described as the by-products of aberrant splicing with functional proteins [24]. This cognition has been changed in recent years, with the development of high-throughput sequencing technology and novel bioinformatics algorithms [5]. Thus, backspliced junctions of circRNAs can be reliably identified, through short-read paired-end RNA sequencing (RNA-seq) technology [6, 7]. By sequencing nonpolyadenylated transcriptomes, researchers find that circRNAs are generally expressed in eukaryotes. Their expression has characteristics of cell type-specific and tissue-specific [5, 8]. Although the functions of thousands of described circRNAs remain unknown, accumulated studies have already shown that circRNAs can participate in cellular activities, embryonic development, neural development, and the development of a variety of human diseases [9, 10]. With the regulatory role of circRNAs, the researchers try to find out the potential functions of circRNAs in cell differentiation of mesenchymal stem cells.

The mesenchymal stem cells can be isolated from adult tissues, including bone marrow, adipose tissue, and umbilical cord, and other sources [11]. MSCs are multipotent stromal cells with low immunogenic potential that can differentiate into a variety of unique mesenchymal cell types, such as osteoblasts, chondrocytes, and adipocytes. With the development of regenerative medicine, MSCs have been widely applied in effective cell-based therapy for tissue regeneration and repair [1214].

This review is aimed at presenting and discussing the mechanism on how circRNAs affect adipogenic differentiation of MSCs based on existing literature. Moreover, we propose to summarize the signal path network and figure out the direction to be studied.

2. Adipogenic Differentiation of MSCs

Mesenchymal stem cells are a heterogeneous population of multipotent elements resident in tissues such as bone marrow, muscle, and adipose tissue, which are primarily involved in developmental and regeneration processes [15]. MSCs participate in the repair/remodeling of many tissues. They have an ability termed “plasticity” in which they differentiate into specific cell-matured phenotypes under defined conditions [16]. The control of stem cell fate has been primarily attributed to the regulation of genetic and molecular mediators which are critical determinants for the lineage decision of stem cells. Though complex signaling pathways that drive commitment and differentiation, MSCs can differentiate into the osteogenic, chondrogenic, adipogenic, or myogenic lineage.

Adipogenesis is one of the significant differentiation directions of mesenchymal stem cells, which can be regulated by transcription factors [17]. In this process, MSCs restrict their fate to the adipogenic lineage, accumulate nutrients, and become triglyceride-filled mature adipocytes. This process can be divided into two steps. In the first step, ADSCs restrict themselves to the adipocyte lineage without any morphological changes, forming a preadipocyte (commitment step). Following this commitment is the terminal differentiation step, during which specified preadipocytes undergo growth arrest, accumulating lipids and forming functional, insulin-responsive mature adipocytes [18].

2.1. Commitment Step

At the launch stage of adipogenesis, the expression of c-Jun and c-Fos in ADSCs is increased [19]. c-Fos binds to the AP-2 promoter and modulates AP-2 expression [20]. At this moment, binding of AP-2α to CCAAT/enhancer-binding protein (C/EBP) α represses its activity to avoid C/EBPα preventing preadipocytes from entering mitotic clonal expansion. The signal transducers and activators of transcription (STAT) family, especially STAT 5A and 5B, are highly expressed in this stage [21]. The induction of STAT 5A/5B in preadipocytes is accompanied by the ectopic expression of C/EBPβ and δ and is also coordinately regulated with the peroxisome proliferator-activated receptors (PPAR) γ [22]. After 2-6 hours of induction, the expression of c-Jun, c-Fos, etc. disappeared. In this early lineage commitment process, Wnt/β-catenin functions as a critical initiator, suppresses the induction of adipogenesis, and regulates the cell cycle [23, 24]. Reports have shown that Wnt10b appears to have an activating role in commitment and maintains preadipocytes in an undifferentiated state through inhibition of C/EBP-α and PPARγ [25, 26].

Following a delay of about 16–20 hours after induction, preadipocytes synchronously reenter DNA synthesis prophase of the cell cycle [27] and undergo several rounds of mitotic clonal expansion. Along with preadipocytes entering into S phase and mitotic clonal expanding, C/EBPβ gains its DNA-binding activity. C/EBPβ is phosphorylated twice sequentially, leading to the acquisition of DNA-binding function [28]. After 18–24 hours, the C/EBPα and PPARγ genes are transcriptionally activated by C/EBPβ through C/EBP regulatory elements in their proximal promoters [29]. PPARγ2 and C/EBPα coordinately transactivate a large group of genes that produce the adipocyte phenotype. They constituted the most important signal path of adipogenic differentiation, C/EBPβ+δ-PPARγ-C/EBPα [30].

2.2. Terminal Differentiation Step

Preadipocytes have entered the growth inhibition phase; then, the cells immediately return to the cell cycle and enter the asexual amplification stage. While the transcriptional activity of C/EBPβ/δ is enhanced by STAT 5A/5B, C/EBPα is increasingly expressed and achieved the highest concentration in the time of induction for 4 d. [22, 31]. The cells then exit the cell cycle losing their fibroblastic morphology and start accumulating triglyceride in the cytoplasm with the appearance and metabolic features of adipocytes [32]. Lipid accumulation drives the expression of the adipocyte fatty acid-binding protein, AP2, and mediates PPARγ expression. The insulin-sensitive transporter GLUT4 also expressed increasingly, promoting the triglyceride accumulation [18]. In the terminal differentiation, the canonical Wnt signaling pathway can also regulate adipogenesis by attenuating the expression of Wnt10b [25]. Wnt family members can also activate noncanonical pathway antagonizing the canonical pathway [32]. Through Wnt5b, the noncanonical pathway inhibits adipogenesis by decreasing the transcriptional activity of PPARγ and regulates insulin sensitivity of the differentiating adipocytes [33, 34]. Then activated phosphoinositide 3-kinase (PI3K)/serine/threonine protein kinases B (Akt) signaling in mesenchymal cells drives and maintains the adipogenesis around 7-28 d after induction [35]. With such complex factors regulated, adipogenic precursor cells complete triglyceride accumulation after a few days of induction, showing typical adipocyte morphology.

3. Characteristics and Functions of circRNA

circRNAs are generated from pre-mRNAs; most of them are arising from exons. By using the standard splice signals, two-step mechanism, and spliceosome machinery, the 3 tail of one exon is joined to the 5 head of an upstream exon; pre-mRNAs compose into a covalently closed and circular configuration [6, 36, 37]; besides, some circRNAs can also arise from introns [38]. The formation of circRNAs depends on the RNA-editing enzyme ADAR1 and can be facilitated by cis-regulatory elements and trans-acting factors [36, 3942]. According to types of circularization, circRNAs can be classified into exonic circRNAs and intronic circRNAs. They are distinct and independent varieties in a generation. In recent years, researchers focus on clarifying the functions of circRNAs, which are involved in the regulation of multiple biological processes.

3.1. miRNA Sponge

circRNAs are usually considered one class of noncoding RNA, which mainly function as efficient microRNA (miRNA) sponge, which is involved with miRNA inhibition with regulatory potential [9, 43, 44]. Indeed, this phenomenon has been widely reported, circRNA overexpression could alleviate apoptosis and promote anabolism through the miRNA pathway [45, 46]. This route is generally considered endogenous RNA (ceRNA) and constitutes a regulatory network across the transcriptome [47, 48]. In the regulation of MSC differentiation, sponging function of circRNA has been extensively investigated. However, only a few of circRNAs were showed to serve as miRNA sponge [49, 50]. They may play a part in other functions. In addition, some of the circRNAs do not display binding sites for miRNA; future efforts should be done to elucidate the mechanisms on improving circRNAs to expose their binding sites to the corresponding miRNAs.

3.2. Sponging Protein

There is still a large class of circRNAs with many protein binding sites, which are essential for strong and direct interaction between protein and circRNAs. Target protein can impact circularization rates of circRNA, and circRNA could then sponge out the excess protein by binding to it [51, 52]. circRNAs function as protein sponge and are less found in regulating MSC differentiation. This function is more directly related to protein-protein interaction, which means they are significant for MSC differentiation [53].

3.3. Protein-Coding Function

circRNAs are generally considered “noncoding” RNAs; in fact, they also serve as templates for protein translation. A few publications provide initial evidence that circRNAs contain an open reading frame and can encode polypeptides and even a protein isoform in a splicing-dependent/cap-independent manner [10, 49, 54]. A protein-coding function of circRNAs is recently discovered; it not only corrects the wrong perception but also provides a new research area.

3.4. Other Functions

circRNAs can be linked to exon skipping and affect the splicing of their linear mRNA counterparts [55]. Nuclear retained circular RNAs regulate transcription of their parental genes and splicing of their linear cognates [56]. A mount of circRNA-derived pseudogenes has been identified by retrieving noncolinear backsplicing junction sequences, which demonstrates that circRNAs are resources for the derivation of pseudogenes [57]. circRNA can also act as a protein subunit associated with the holoenzyme in metabolic adaptation, assembles and stabilizes the holoenzyme complex, and maintains basal activity [58].

Based on the above studies, it enlightens us that it is necessary for exploring how circRNAs regulate MSC differentiation. Additionally, epigenetic modifications can also occur in RNA, called the epitranscriptome, which refers to stable and heritable changes in gene expression that do not alter the RNA sequence. N6-Methyladenosine (m6A) is always found to occur in the consensus sequence identified as RRACH (R = G or A; H = A, C, or U) and promote the translation of the circRNAs [59]. It is the most abundant epigenetic modification in eukaryotes and plays a significant role in autophagy and adipogenesis regulation [60]. If we combine with epigenetic modification, researches about regulating functions of circRNA in MSCs may come to a new stage.

4. circRNA and Regulation of MSC Differentiation

circRNAs are the key regulators of gene expression and protein functions in epigenetic regulation. As previously mentioned, the differentiation of MSC is a highly controlled process, which is regulated by both proteins and noncoding RNAs. Due to their functions in regulating epigenetic and molecular biological processes, recent research suggests that circRNAs play a considerable role in cell fate decisions of MSC differentiation [10]. Current studies demonstrate that the majority of circRNAs participate in the process of adipogenesis, myogenesis, and osteogenesis of MSCs [61, 62].

4.1. Adipogenesis and Osteogenesis of MSCs

Osteogenesis is thought to be most closely related to adipogenesis in the differentiation of MSCs. There is a balance between adipogenic and osteogenic differentiation processes. circRNAs regulate adipogenesis and osteogenesis by, respectively, affecting a variety of signaling pathways, but in the end, they will converge at several major transcription factors that are shared in differentiation including PPARγ and WNT [63, 64].

Cerebellar degeneration-related protein 1 transcript (CDR1as), also known as circular RNA sponge for miR-7 (ciRS-7), was reported to be involved in the osteogenesis [61, 65]. CDR1as can inhibit osteogenesis and promotes adipogenesis by inhibition of miR-7 via targeting GDF5 through the MAPK signaling pathway in bone mesenchymal stem cells (BMSCs) [66]. Beyond that, many circRNAs can regulate the proliferation and osteogenesis of MSCs through sponging some specific miRNAs which are similar to their effect on adipogenesis and other differentiation [6769].

4.2. Myogenesis and Neuronal Differentiation

circRNAs are also abundant in skeletal muscle tissue, and their expression levels can regulate muscle development, ageing, and differentiation. As described above, CDR1as is involved in various directions of differentiation in MSC. In skeletal muscle satellite cells (SMSCs), it subsequently activates myogenesis through sponging miR-7 [70, 71]. Several circRNAs also work in the same way by sponging miRNAs to promote or repress the myogenic differentiation of MSCs, such as circHIPK3 and circ-FoxO3 [7274]. Other than that, circRNAs have been identified to be differentially expressed in different differentiation stages of neural stem cells (NSCs). It is likely that some specific circRNAs resulted in the corresponding expression of mRNA and involved in neuronal differentiation [75].

These shreds of evidence suggest that circRNAs play a significant role in regulating MSC differentiation. The current review is aimed at highlighting the regulation of adipogenic differentiation of MSCs by circRNAs.

5. circRNAs Regulate Adipogenesis

The pathways of circRNAs regulating osteogenesis and myogenesis are closely related to adipogenic differentiation. Even certain circRNAs play a multiplicative role that antagonizes among these directions of differentiation. Therefore, circRNA regulating cell differentiation of MSC is an exchange network that each differentiation direction is closely related. It suggests that the perspective of adipogenesis will contribute to understanding the landscape of the cell differentiation network of mesenchymal stem cells. The research methods of circRNAs regulating osteogenesis and myogenesis can also be used in the study on circRNA regulating network of adipogenesis. It is efficient for gene chip technology and bioinformation analysis to be used to preliminary screen. Combined with molecular biology experiment, the pathway of circRNA regulating adipogenesis could be basically verified. According to the regulatory network of circRNAs in adipogenesis, researchers can explore more directions of MSCs in clinical transformation.

Recent studies have demonstrated a few circRNAs acting as a miRNA sponge to regulate adipogenic differentiation, while other circRNAs can also compete with proteins that participate in the regulation of adipogenesis. Therefore, we emphasized the regulatory network of circRNAs in regulating adipogenesis (Table 1).


circRNAmiRNA or proteinTarget gene(s)CellRelated processReference

Hsa_circ_0001946 (CDR1as)miR-7-5pWnt5bBMSCs↑Adipogenesis
↓Osteogenesis
[61]
Hsa_circ_0095570 (circH19)PTBP1SREBP1hADSCs↓Adipogenesis[53]
CircFOXP1miR-17-3p and miR-127-5pWnt5b and Wnt3aBMSCs↑Adipogenesis[76]
circRNA 2: 27713879|27755789 and circRNA 2: 240822115|240867796miR-328C/EBPαMC3T3-E1↓Adipogenesis
↑Osteogenesis
[77, 78]
miR-23a-5p and miR-326TGF-β
circRNA-11897miR-27a and miR-27bPPARγAdipocytes↑Adipogenesis[79]
circRNA-26852miR-874PPARαAdipocytes↑Adipogenesis[79]
miR-486FOXO1
CiRS-133miR-133PRDM16Preadipocytes↑WAT browning[80]
circRNA-0046366miR-34aPDGFRαAdipocytes↑Hepatocellular steatosis[81, 82]
CircSAMD4AmiR-138-5pEZH2Preadipocytes↑Adipogenesis[83]

5.1. CDR1as–miR-7-5p–WNT5B

Confronting research discovers that circRNA, hsa_circ_0001946 (CDR1as), may play a crucial role in adipogenic/osteogenic differentiation process via CDR1as–miR-7-5p–WNT5B axis in BMSCs [61]. CDR1as has been reported to affect the expression of target genes and plays an important role in the pathogenesis via adsorbing miR-7-5p [8486]. miR-7-5p can be sponged by CDR1as [66] and target WNT5B-3UTR [61]. Experiments show that the upregulation of CDR1as will promote the expression of WNT5B via competitively harboring miR-7-5p. WNT5B, a member of the WNT family, can inhibit β-catenin in the WNT/β-catenin signaling pathway [87, 88]. Downregulation of β-catenin can promote the expression of PPARγ, which promotes adipogenic differentiation and inhibits osteogenic differentiation in BMSCs [61]. In 3T3-L1 preadipocytes, low expression of β-catenin can also promote adipogenic differentiation and inhibit osteoclast differentiation by inducing the expression of PPARγ [89, 90]. However, further studies will be needed to demonstrate the effects of circRNAs on BMSC adipogenic differentiation in vivo.

5.2. CircH19–PTBP1

Hsa_circ_0095570 derived from H19 pre-RNA, also called circH19, has putative binding sites with RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) [53]. PTBP1, also known as hnRNP I, belongs to a subfamily of heterogeneous nuclear ribonucleoproteins (hnRNPs), which moves rapidly between the nucleus and cytoplasm as a shuttling protein [91]. On the asexual amplification stage, a basic helix-loop-helix transcription factor is expressed in adipocytes during adipogenesis and determination, called sterol-regulatory element-binding protein 1 (SREBP1, ADD1). One of its isoforms, SREBP-1c, contributes to the generation of PPARγ ligands and promotes energy mobilization with phosphorylation by MAPK [92, 93]. A previous study demonstrated that PTBP1 played an important role in the cleavage of SREBP1 precursor and translocation of nSREBP1 protein [94]. circH19 might interact with PTBP1 to block the function of PTBP1, resulting in the inhibition of SREBP1 precursor cleavage. To sum up, has_circH19 suppresses PTBP1 and decreases the cleavage of the SREBP1 precursor, thus inhibiting the translocation of nSREBP1 to the nucleus. The inhibition of circH19 can promote the transcription of lipid-related genes, leading to lipid accumulation in hADSCs [53]. In other words, circH19 can function as an inhibitor of PTBP1 and prevents hADSCs from transforming into adipocytes with enhanced ability to absorb lipids. This is the first time to demonstrate that circRNA regulates MSC adipogenesis by sponging protein. High levels of hsa_circH19 is an independent risk factor for metabolic syndrome. So, the expression of hsa_circH19 might be related with lipid metabolism in adipose tissue from patients of metabolic syndrome.

5.3. CircFOXP1–miR-17-3p/miR127-5p

CircFOXP1 originates from the forkhead box (FOX) P1 gene, which is related to the maintenance of BMSC identity and regulation of differentiation. CircFOXP1 acts as an essential gatekeeper of BMSC identity, which can promote proliferation and differentiation by target sponging miR-17-3p and miR-127-5p [76]. The combined action of miR-17-3p and miR-127-5p may regulate growth, survival, and balance between undifferentiated and differentiated MSCs through epidermal growth factor receptor (EGFR) and noncanonical Wnt signaling [76, 9597]. In BMSCs, elevated levels of circFOXP1 can preserve the BMSC multipotent state by sponging multiple miRNAs, sustain noncanonical via Wnt5b, and consequently inhibit the canonical Wnt pathway via Wnt3a [76]. This functional interaction is fundamental to inhibit miRNA activity and avoid interference of signaling cascades associated with stemness and differentiation. CircFOXP1 should be regarded as a regulator of sustaining mesenchymal stem cell identity and the capacity of MSCs to differentiate into the adipocytic lineage [76]. Knockdown circFOXP1 in MSCs will inhibit adipogenic differentiation and decrease accumulation of intracellular lipid droplets.

5.4. circRNA 2: 27713879|27755789 and circRNA 2: 240822115|240867796

Estrogen receptor (ER) β is structurally and functionally related to isoforms of ER. Its expression is increased during osteoblast differentiation [98]. It was shown that ERβ was capable of upregulating the expression levels of osteogenesis-related markers and inducing the osteogenic differentiation of MC3T3-E1 [77]. Recently, the experiment demonstrates that ERβ may regulate the expression levels of miR-328, miR-23a-5p, and miR-326 via circRNA 2: 27713879|27755789 and circRNA 2: 240822115|240867796 and consequently impact on the balance between osteogenic differentiation and adipogenic differentiation. In their experiment, circRNA 2: 27713879|27755789 and circRNA 2: 240822115|240867796 were identified to target miR-328 [78], while miR-328 can upregulate the expression of C/EBPα to inhibit cell proliferation and is involved in the dynamic balance between osteogenesis and adipogenesis [78]. circRNA 2: 27713879|27755789 and circRNA 2: 240822115|240867796 can also target miR-23a-5p and miR-326 as miRNA sponge by regulating the TGF-β signaling pathway and serve as an inhibitor of adipogenic differentiation [78, 99, 100]. The above study shows that circRNAs can work together and affect several kinds of miRNA to achieve its regulating potential. This discovery is very helpful for contributing the circRNA regulating network in MSC differentiation.

5.5. circRNA-11897–miR-27a/miR-27b–PPARγ

miR-27 is an antiadipogenic microRNA partly by targeting prohibitin (PHB) and impairing mitochondrial function. Ectopic expression of miR-27a or miR-27b impaired mitochondrial biogenesis, structural integrity, and complex I activity accompanied by excessive reactive oxygen species production [101]. miR-27a can accelerate the hydrolysis of triglyceride and suppress adipocyte differentiation by repressing the expression of PPARγ [102]. Via identification and characterization of circRNAs, researchers find that circRNA-11897 can bind miR-27a and miR-27b [79]. By sponging miR-27a and miR-27b, circRNA-11897 regulates adipogenic differentiation and lipid metabolism of adipocyte in the subcutaneous adipose tissue [79]. Besides, the target genes of circRNA-11897 are also enriched in biological processes, which are related to lipid metabolisms such as fatty acid biosynthetic process, MAPK cascade reaction, extracellular-regulated protein kinase (ERK)1 and ERK2 cascade reaction, and cell proliferation [79]. In the early stage of adipogenic differentiation, the activated ERK signaling pathway can induce the expression of C/EBP and PPARγ and induce adipogenic differentiation of 3T3-L1 preadipocytes [103]. In a later stage, ERK1/2 is phosphorylated, and PPARγ is inactivated. Thus, preadipocyte differentiation is inhibited [104].

5.6. circRNA-26852–miR874-PPARα and circRNA-26852–miR486–FOXO1

miR-874 and miR-486 are the target genes of circRNA-26852, which are enriched in biological processes of adipocyte in the subcutaneous adipose tissue. These miRNAs are related to fat deposition and lipid metabolism, such as regulation of triglyceride catabolic process, negative regulation of lipid storage, and phosphatidic acid biosynthetic process [79]. miR-874 can regulate lipid metabolism, glycerophospholipid metabolism, adipocyte differentiation, and glucose metabolism by inhibiting the expression of PPAR pathway-related genes, PPARα [105, 106]. miR-486 can inhibit the transcription factor FOXO1 and plays a role in insulin functioning and triglyceride metabolism. Therefore, circRNA-26852 working as competing for endogenous RNAs of miR-874 and miR-486 may participate in adipogenic differentiation and lipid metabolism. The pathway enrichment analysis shows that the target genes of circRNA-26852 are enriched in the PPAR signaling pathway and transforming growth factor-β (TGFβ) signaling pathway. Through these two signaling pathways, circRNA-26852 regulates the transformation of mesenchymal stem cells into adipocytes [79]. In this research, it shows us a possibility of circRNA working in two directions simultaneously. It is going to be a new perspective in our future research.

5.7. CiRS-133-miR-133-RDM16

Exosomes play a key role in mediating signaling transduction between neighboring or distant cells by delivering microRNAs, proteins, lncRNAs, circRNAs, and DNAs [107]. A recent study has indicated that circRNA is enriched and stable in exosomes [108]. One exosome delivered circRNA, hsa_circ_0010522 (also named ciRS-133), can suppress specific adipose miR-133 levels in preadipocytes by adsorptive action [80]. PR domain containing 16 (PRDM16), a zinc finger transcription factor controlling a brown fat/skeletal muscle switch, has been proposed to be a bidirectional cell fate switch. It promotes brown adipose tissue (BAT) differentiation while inhibits myogenesis in myoblasts [109, 110]. Loss of PRDM16 function results in myogenic differentiation of preadipocytes isolated from BAT, while the gain of PRDM16 function leads to the genesis of BAT in myoblasts [111]. PRDM16 has also been found to be a determining factor of beige adipocytes in subcutaneous white adipose tissue (WAT) and promote browning of WAT in gastric tumors [111, 112]. Previous studies have confirmed that miR-133 is the upstream regulator of PRDM16, and the miR-133/PRDM16 axis controls the formation of BAT and is linked to energy balance [7, 113]. By activating PRDM16 and suppressing miR-133, ciRS-133 activates uncoupling protein 1 (UCP1) and promotes the differentiation of preadipocytes into brown-like cells. Therefore, by targeting the miR-133/PRDM16 pathway, circulating exosomal ciRS-133 may be a common regulator that promotes white adipose browning of preadipocyte in WAT [80].

5.8. circRNA-0046366–miR-34a–PDGFRα

Studies reveal that circRNA-0046366 inhibits hepatocellular steatosis by normalizing PPAR signaling. Besides, circRNA-0046366 can antagonize the activity of miR-34a via meiotic recombination- (MRE-) based complementation [81]. miR-34a will inhibit adipogenesis by targeting PDGFRα [82]. By sponging miR-34a, circRNA-0046366 is associated with triglyceride metabolism at both transcriptional and translational levels. Consequently, circRNA-0046366 promotes the adipogenic differentiation through activating the ERK signaling pathway [81, 82].

5.9. CircSAMD4A–miR-138-5p–EZH2

Experiments indicate that circSAMD4A also named hsa_circ_0004846 regulate preadipocyte differentiation by sponging miR-138-5p. Previously, miR-138-5p has been reported targeting various proteins associated with adipogenesis in MSCs [114]. Binding to miR-138-5p, CircSAMD4A can increase the expression of EZH2 which has two downstream targets Wnt10b and Wnt1. Thus, circSAMD4A can induce adipocyte differentiation via the canonical Wnt signaling pathway [83]. It suggests that circSAMD4A can serve as a potential prognostic marker or treatment target for the therapy of tumors or metabolic diseases.

6. Potential circRNA Regulatory Path

As described above, circRNAs can sponge miRNA or protein to play the regulation role in adipogenesis. In general, circRNAs participate in adipogenic differentiation by modulating PPAR or Wnt pathway. Besides those targeted factors as mentioned above, there are still potential targets that may be regulated by circRNAs.

6.1. CircPVT1–miR-125–PPARα and PPARγ

CircPVT1, also known as circ6, is generated from exon 2 of the PVT1 gene. It is located on chromosome 8q2. As a homologous gene of the long noncoding RNA PVT1 (human genome GRch38/hg38), this circRNA plays a critical role in regulating human physiological and pathological functions. CircPVT1 is a senescence-associated circRNA showing markedly reduced levels in senescent fibroblasts [115]. By sponging the miR-125 family, CircPVT1 exhibits elevated levels in dividing cells and promotes cell proliferation [116]. The physiological functions of circPVT1 in gastric cancer cells include cell proliferation, cell apoptosis, and stem cell self-renewal [117]. On the launch signal of adipogenesis, c-Fos can bind to circPVT1 at its promoter region and promote the direct interaction between circPVT1 and miR-125 [116]. Studies have suggested that miR-125 can enhance the proliferation and differentiation of ADSCs [99]. The expression of miR-125 is significantly changed at day 8 after adipogenic induction. It can dramatically reduce the mRNA expression of adipogenic markers C/EBPα, PPARγ, FABP4, fatty acid synthase (FASN), lipoprotein lipase (LPL), aP2, and estrogen-related receptor α (ERRα) [118]. Furthermore, miR-125 can inhibit the differentiation of preadipocytes by directly targeting KLF13 and affect the fatty acid composition in adipocytes by regulating elongase of very-long-chain fatty acids 6 (ELOVL6) [119]. In summary, circPVT1 may be a potential regulatory factor of adipogenesis, which simultaneously upregulates PPARα and PPARγ by affecting miR-125.

6.2. Circ-0004194

Circ-0004194 expressed in a variety of human tissues is also called Circβ-catenin. It can be translated into a novel 370-amino acid β-catenin isoform that was termed “β-catenin-370aa.” As the linear β-catenin mRNA transcript, circβ-catenin uses the same start codon but its translation is terminated at a new stop codon created by circularization. A recent study demonstrates that this novel isoform can stabilize full-length β-catenin by antagonizing GSK3β-induced β-catenin phosphorylation and degradation. Thus circβ-catenin potentiates the activation of the Wnt/β-catenin pathway in liver cancer [49]. Perhaps, circβ-catenin can play the same role in adipogenesis, even in cell differentiation of MSCs. Protein coding by circRNA plays a significant role in adipogenesis but rare of them has been discovered. There is still a blank area waiting for exploration, especially in the regulation of MSC differentiation.

6.3. CircCDK13–miR-135b-5p–PI3K/AKT and JAK/STAT

CircCDK13 (hsa_circ_0001699), a novel circRNA transcribed from the human CDK13 gene, is closely related to cell senescence and regulation of cell cycle [120]. CircCDK13 may upregulate the relevant gene expression of the signaling pathway through sponge miR-135b-5p. Therefore, circCDK13 can inhibit the PI3K/AKT pathway and JAK/STAT signaling pathway which is a very critical regulatory machinery for cellular development and proliferation in liver cancer [121].

Beyond that, by repressing miR-9, circSMAD2 impedes the activation of STAT3 and MEK/ERK pathways in migration and epithelial-mesenchymal transition [122]. CircRNA-0044073 promotes the proliferation of cells by sponging miR-107 and activating the JAK/STAT signaling pathway [123]. There are still many factors that regulate adipogenesis which may be the targets of circRNAs, such as miR-143 [124], miR-130 [125], miR-145 [126], miR-181a [127], and let-7 [128].

7. Conclusion

Recent studies demonstrate that a large number of endogenous circRNAs have a major functional role in stem cell fate decision-making processes such as adipogenic differentiation. Therefore, we concluded the previous work into a primary molecular network on the regulation role of the circRNAs in adipogenesis of MSCs (Figure 1). The findings from circRNA investigations during adipogenesis suggest the potential application of circRNAs or target miRNAs to treat lipid metabolism, bone diseases, and metabolic disorders. The molecular mechanism of circFOXP1 in MSCs has been deeply discussed. It should be regarded as an essential gatekeeper of pivotal stem cell molecular networks and controlled MSC identification. With this being fundamental, circRNAs regulating cell differentiation can sum into a network which is helpful for clinical transformation. Exosomes are secreted by many different types of cells, which regulate cellular function by enabling cell-to-cell transfer of biologically active molecule, such as miRNA and circRNA. CiRS-133 in exosomes is closely linked with the browning of white adipose tissue by activating PRDM16 and suppressing miR-133. It not only provides a potential target for therapy but also lightens us with a possibility that exosomes serve as a messenger to deliver circRNAs into cells for clinical treatment.

While circRNAs are an epigenetic regulator, their potential role in modulating differentiation of MSCs is infinite. Current studies on circRNAs in MSCs’ adipogenesis concentrate on the regulation of triglyceride accumulation. However, the study on circRNA regulating the commitment step of adipogenesis is still a blank field. The modes of circRNA regulating adipogenesis in existing reports are also unitary. Previous experiments mainly focused on circRNAs’ function as sponge; the other functions should be explored in future study. To further elucidate the mechanisms of circRNAs on adipogenesis in stem cells, future work should be conducted to expose their binding sites to the corresponding miRNAs.

The functions of circRNAs in regulating adipogenesis have a considerable reference value in the epigenetic regulation of cell differentiation. Future investigation on circRNAs has great potential usefulness and clinical transformation.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Authors’ Contributions

Fanglin Wang and Xiang Li contributed equally to this work, and should be considered co-first author.

Acknowledgments

This work was supported by LiaoNing Revitalization Talents Program (no. XLYC1907124) and the National Natural Science Foundation of China (no. 81571919).

References

  1. M. T. Hsu and M. Coca-Prados, “Electron microscopic evidence for the circular form of RNA in the cytoplasm of eukaryotic cells,” Nature, vol. 280, no. 5720, pp. 339-340, 1979. View at: Publisher Site | Google Scholar
  2. C. Cocquerelle, B. Mascrez, D. Hétuin, and B. Bailleul, “Mis-splicing yields circular RNA molecules,” The FASEB Journal, vol. 7, no. 1, pp. 155–160, 1993. View at: Publisher Site | Google Scholar
  3. Z. Pasman, M. D. Been, and M. A. Garcia-Blanco, “Exon circularization in mammalian nuclear extracts,” RNA, vol. 2, no. 6, pp. 603–610, 1996. View at: Google Scholar
  4. S. Braun, H. Domdey, and K. Wiebauer, “Inverse splicing of a discontinuous pre-mRNA intron generates a circular exon in a HeLa cell nuclear extract,” Nucleic Acids Research, vol. 24, no. 21, pp. 4152–4157, 1996. View at: Publisher Site | Google Scholar
  5. J. Salzman, R. E. Chen, M. N. Olsen, P. L. Wang, and P. O. Brown, “Correction: Cell-type specific features of circular RNA expression,” PLoS Genetics, vol. 9, no. 12, 2013. View at: Publisher Site | Google Scholar
  6. W. R. Jeck and N. E. Sharpless, “Detecting and characterizing circular RNAs,” Nature Biotechnology, vol. 32, no. 5, pp. 453–461, 2014. View at: Publisher Site | Google Scholar
  7. W. R. Jeck, J. A. Sorrentino, K. Wang et al., “Circular RNAs are abundant, conserved, and associated with ALU repeats,” RNA, vol. 19, no. 2, pp. 141–157, 2013. View at: Publisher Site | Google Scholar
  8. A. Rybak-Wolf, C. Stottmeister, P. Glažar et al., “Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed,” Molecular Cell, vol. 58, no. 5, pp. 870–885, 2015. View at: Publisher Site | Google Scholar
  9. I. F. Hall, M. Climent, M. Quintavalle et al., “Circ_Lrp6, a circular RNA enriched in vascular smooth muscle cells, acts as a sponge regulating miRNA-145 function,” Circulation Research, vol. 124, no. 4, pp. 498–510, 2019. View at: Publisher Site | Google Scholar
  10. I. Legnini, G. di Timoteo, F. Rossi et al., “Circ-ZNF609 is a circular RNA that can be translated and functions in myogenesis,” Molecular Cell, vol. 66, no. 1, pp. 22–37.e9, 2017, e9. View at: Publisher Site | Google Scholar
  11. L. da Silva Meirelles, “Mesenchymal stem cells reside in virtually all post-natal organs and tissues,” Journal of Cell Science, vol. 119, no. 11, pp. 2204–2213, 2006. View at: Publisher Site | Google Scholar
  12. M. Packer, “The alchemist's nightmare: might mesenchymal stem cells that are recruited to repair the injured heart be transformed into fibroblasts rather than cardiomyocytes?” Circulation, vol. 137, no. 19, pp. 2068–2073, 2018. View at: Publisher Site | Google Scholar
  13. J. Bartolucci, F. J. Verdugo, P. L. González et al., “Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure: a phase 1/2 randomized controlled trial (RIMECARD trial [Randomized Clinical Trial of Intravenous Infusion Umbilical Cord Mesenchymal Stem Cells on Cardiopathy]),” Circulation Research, vol. 121, no. 10, pp. 1192–1204, 2017. View at: Publisher Site | Google Scholar
  14. T. T. Tran and C. R. Kahn, “Transplantation of adipose tissue and stem cells: role in metabolism and disease,” Nature Reviews Endocrinology, vol. 6, no. 4, pp. 195–213, 2010. View at: Publisher Site | Google Scholar
  15. I. R. Suhito, Y. Han, J. Min, H. Son, and T. H. Kim, “In situ label-free monitoring of human adipose-derived mesenchymal stem cell differentiation into multiple lineages,” Biomaterials, vol. 154, pp. 223–233, 2018. View at: Publisher Site | Google Scholar
  16. P. Bianco, M. Riminucci, S. Gronthos, and P. G. Robey, “Bone marrow stromal stem cells: nature, biology, and potential applications,” Stem Cells, vol. 19, no. 3, pp. 180–192, 2001. View at: Publisher Site | Google Scholar
  17. P. M. de Sá, A. J. Richard, H. Hang, and J. M. Stephens, “Transcriptional regulation of adipogenesis,” Comprehensive Physiology, vol. 7, no. 2, pp. 635–674, 2017. View at: Publisher Site | Google Scholar
  18. A. L. Ghaben and P. E. Scherer, “Adipogenesis and metabolic health,” Nature Reviews. Molecular Cell Biology, vol. 20, no. 4, pp. 242–258, 2019. View at: Publisher Site | Google Scholar
  19. J. M. Stephens, M. Butts, R. Stone, P. H. Pekala, and D. A. Bernlohr, “Regulation of transcription factor mRNA accumulation during 3T3-L1 preadipocyte differentiation by antagonists of adipogenesis,” Molecular and Cellular Biochemistry, vol. 123, no. 1-2, pp. 63–71, 1993. View at: Publisher Site | Google Scholar
  20. R. J. Distel, H. S. Ro, B. S. Rosen, D. L. Groves, and B. M. Spiegelman, “Nucleoprotein complexes that regulate gene expression in adipocyte differentiation: direct participation of c- _fos_,” Cell, vol. 49, no. 6, pp. 835–844, 1987. View at: Publisher Site | Google Scholar
  21. J. B. Harp, D. Franklin, A. A. Vanderpuije, and J. M. Gimble, “Differential expression of signal transducers and activators of transcription during human adipogenesis,” Biochemical and Biophysical Research Communications, vol. 281, no. 4, pp. 907–912, 2001. View at: Publisher Site | Google Scholar
  22. M. Kawai, N. Namba, S. Mushiake et al., “Growth hormone stimulates adipogenesis of 3T3-L1 cells through activation of the Stat5A/5B-PPARγ pathway,” Journal of Molecular Endocrinology, vol. 38, no. 1, pp. 19–34, 2007. View at: Publisher Site | Google Scholar
  23. G. Donati, V. Proserpio, B. M. Lichtenberger et al., “Epidermal Wnt/beta-catenin signaling regulates adipocyte differentiation via secretion of adipogenic factors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 15, pp. E1501–E1509, 2014. View at: Publisher Site | Google Scholar
  24. M. Chen, P. Lu, Q. Ma et al., “CTNNB1/β-catenindysfunction contributes to adiposity by regulating the cross-talk of mature adipocytes and preadipocytes,” Science Advances, vol. 6, no. 2, p. eaax9605, 2020. View at: Publisher Site | Google Scholar
  25. M. Laudes, “Role of WNT signalling in the determination of human mesenchymal stem cells into preadipocytes,” Journal of Molecular Endocrinology, vol. 46, no. 2, pp. R65–R72, 2011. View at: Publisher Site | Google Scholar
  26. R. R. Bowers and M. D. Lane, “Wnt signaling and adipocyte lineage commitment,” Cell Cycle, vol. 7, no. 9, pp. 1191–1196, 2014. View at: Publisher Site | Google Scholar
  27. L. A. Davis and N. I. Zur Nieden, “Mesodermal fate decisions of a stem cell: the Wnt switch,” Cellular and Molecular Life Sciences, vol. 65, no. 17, pp. 2658–2674, 2008. View at: Publisher Site | Google Scholar
  28. Q. Q. Tang, M. Gronborg, H. Huang et al., “Sequential phosphorylation of CCAAT enhancer-binding protein β by MAPK and glycogen synthase kinase 3β is required for adipogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 28, pp. 9766–9771, 2005. View at: Publisher Site | Google Scholar
  29. S. L. Clarke, C. E. Robinson, and J. M. Gimble, “CAAT/Enhancer Binding Proteins Directly Modulate Transcription from the Peroxisome Proliferator- Activated Receptor γ2 Promoter,” Biochemical and Biophysical Research Communications, vol. 240, no. 1, pp. 99–103, 1997. View at: Publisher Site | Google Scholar
  30. U. A. White and J. M. Stephens, “Transcriptional factors that promote formation of white adipose tissue,” Molecular and Cellular Endocrinology, vol. 318, no. 1-2, pp. 10–14, 2010. View at: Publisher Site | Google Scholar
  31. Y. Liu, Y. D. Zhang, L. Guo et al., “Protein inhibitor of activated STAT 1 (PIAS1) is identified as the SUMO E3 ligase of CCAAT/enhancer-binding protein β (C/EBPβ) during adipogenesis,” Molecular and Cellular Biology, vol. 33, no. 22, pp. 4606–4617, 2013. View at: Publisher Site | Google Scholar
  32. Q. Q. Tang and M. D. Lane, “Adipogenesis: from stem cell to adipocyte,” Annual Review of Biochemistry, vol. 81, no. 1, pp. 715–736, 2012. View at: Publisher Site | Google Scholar
  33. C. Christodoulides, C. Lagathu, J. K. Sethi, and A. Vidal-Puig, “Adipogenesis and WNT signalling,” Trends in Endocrinology and Metabolism, vol. 20, no. 1, pp. 16–24, 2009. View at: Publisher Site | Google Scholar
  34. L. Michalik, B. Desvergne, and W. Wahli, “Peroxisome-proliferator-activated receptors and cancers: complex stories,” Nature Reviews. Cancer, vol. 4, no. 1, pp. 61–70, 2004. View at: Publisher Site | Google Scholar
  35. C. Song, Y. Huang, Z. Yang et al., “RNA-Seq analysis identifies differentially expressed genes insubcutaneous adipose tissuein Qaidamford cattle, cattle-yak, and Angus cattle,” Animals, vol. 9, no. 12, p. 1077, 2019. View at: Publisher Site | Google Scholar
  36. S. Starke, I. Jost, O. Rossbach et al., “Exon circularization requires canonical splice signals,” Cell Reports, vol. 10, no. 1, pp. 103–111, 2015. View at: Publisher Site | Google Scholar
  37. X. O. Zhang, H. B. Wang, Y. Zhang, X. Lu, L. L. Chen, and L. Yang, “Complementary sequence-mediated exon circularization,” Cell, vol. 159, no. 1, pp. 134–147, 2014. View at: Publisher Site | Google Scholar
  38. Y. Zhang, X. O. Zhang, T. Chen et al., “Circular intronic long noncoding RNAs,” Molecular Cell, vol. 51, no. 6, pp. 792–806, 2013. View at: Publisher Site | Google Scholar
  39. A. Ivanov, S. Memczak, E. Wyler et al., “Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals,” Cell Reports, vol. 10, no. 2, pp. 170–177, 2015. View at: Publisher Site | Google Scholar
  40. M. C. Kramer, D. Liang, D. C. Tatomer et al., “Combinatorial control of Drosophila circular RNA expression by intronic repeats, hnRNPs, and SR proteins,” Genes & Development, vol. 29, no. 20, pp. 2168–2182, 2015. View at: Publisher Site | Google Scholar
  41. X. O. Zhang, R. Dong, Y. Zhang et al., “Diverse alternative back-splicing and alternative splicing landscape of circular RNAs,” Genome Research, vol. 26, no. 9, pp. 1277–1287, 2016. View at: Publisher Site | Google Scholar
  42. S. J. Conn, K. A. Pillman, J. Toubia et al., “The RNA binding protein quaking regulates formation of circRNAs,” Cell, vol. 160, no. 6, pp. 1125–1134, 2015. View at: Publisher Site | Google Scholar
  43. D. Han, J. Li, H. Wang et al., “Circular RNA circMTO1 acts as the sponge of microRNA-9 to suppress hepatocellular carcinoma progression,” Hepatology, vol. 66, no. 4, pp. 1151–1164, 2017. View at: Publisher Site | Google Scholar
  44. Y. Zhang, L. Du, Y. Bai et al., “CircDYM ameliorates depressive-like behavior by targeting miR-9 to regulate microglial activation via HSP90 ubiquitination,” Molecular Psychiatry, vol. 25, no. 6, pp. 1175–1190, 2020. View at: Publisher Site | Google Scholar
  45. S. Shen, Y. Wu, J. Chen et al., “CircSERPINE2 protects against osteoarthritis by targeting miR-1271 and ETS-related gene,” Annals of the Rheumatic Diseases, vol. 78, no. 6, pp. 826–836, 2019. View at: Publisher Site | Google Scholar
  46. Q. Li, X. Pan, D. Zhu, Z. Deng, R. Jiang, and X. Wang, “Circular RNA MAT2B promotes glycolysis and malignancy of hepatocellular carcinoma through the miR-338-3p/PKM2 Axis under hypoxic stress,” Hepatology, vol. 70, no. 4, pp. 1298–1316, 2019. View at: Publisher Site | Google Scholar
  47. L. Salmena, L. Poliseno, Y. Tay, L. Kats, and P. P. Pandolfi, “A _ceRNA_ Hypothesis: The Rosetta Stone of a Hidden RNA Language?” Cell, vol. 146, no. 3, pp. 353–358, 2011. View at: Publisher Site | Google Scholar
  48. Z. Cheng, C. Yu, S. Cui et al., “c _ircTP63_ functions as a ceRNA to promote lung squamous cell carcinoma progression by upregulating FOXM1,” Nature Communications, vol. 10, no. 1, p. 3200, 2019. View at: Publisher Site | Google Scholar
  49. W. C. Liang, C. W. Wong, P. P. Liang et al., “Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway,” Genome Biology, vol. 20, no. 1, p. 84, 2019. View at: Publisher Site | Google Scholar
  50. A. Guria, K. Velayudha Vimala Kumar, N. Srikakulam et al., “Circular RNA profiling by Illumina sequencing via template-dependent multiple displacement amplification,” BioMed Research International, vol. 2019, Article ID 2756516, 12 pages, 2019. View at: Publisher Site | Google Scholar
  51. R. Ashwal-Fluss, M. Meyer, N. R. Pamudurti et al., “circRNA biogenesis competes with pre-mRNA splicing,” Molecular Cell, vol. 56, no. 1, pp. 55–66, 2014. View at: Publisher Site | Google Scholar
  52. W. W. Du, W. Yang, Y. Chen et al., “Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses,” European Heart Journal, vol. 38, no. 18, pp. ehw001–eh1412, 2016. View at: Publisher Site | Google Scholar
  53. Y. Zhu, W. Gui, X. Lin, and H. Li, “Knock-down of circular RNA H19 induces human adipose-derived stem cells adipogenic differentiation via a mechanism involving the polypyrimidine tract- binding protein 1,” Experimental Cell Research, vol. 387, no. 2, p. 111753, 2020. View at: Publisher Site | Google Scholar
  54. N. R. Pamudurti, O. Bartok, M. Jens et al., “Translation of CircRNAs,” Molecular Cell, vol. 66, no. 1, pp. 9–21.e7, 2017, e7. View at: Publisher Site | Google Scholar
  55. S. Kelly, C. Greenman, P. R. Cook, and A. Papantonis, “Exon skipping is correlated with exon circularization,” Journal of Molecular Biology, vol. 427, no. 15, pp. 2414–2417, 2015. View at: Publisher Site | Google Scholar
  56. Z. Li, C. Huang, C. Bao et al., “Exon-intron circular RNAs regulate transcription in the nucleus,” Nature Structural & Molecular Biology, vol. 22, no. 3, pp. 256–264, 2015. View at: Publisher Site | Google Scholar
  57. R. Dong, X. O. Zhang, Y. Zhang, X. K. Ma, L. L. Chen, and L. Yang, “CircRNA-derived pseudogenes,” Cell Research, vol. 26, no. 6, pp. 747–750, 2016. View at: Publisher Site | Google Scholar
  58. Q. Li, Y. Wang, S. Wu et al., “CircACC1 regulates assembly and activation of AMPK complex under metabolic stress,” Cell Metabolism, vol. 30, no. 1, pp. 157–173.e7, 2019. View at: Publisher Site | Google Scholar
  59. S. Meng, H. Zhou, Z. Feng, Z. Xu, Y. Tang, and M. Wu, “Epigenetics in neurodevelopment: emerging role of circular RNA,” Frontiers in Cellular Neuroscience, vol. 13, p. 327, 2019. View at: Publisher Site | Google Scholar
  60. X. Wang, R. Wu, Y. Liu et al., “m6A mRNA methylation controls autophagy and adipogenesis by targeting Atg5 and Atg7,” Autophagy, vol. 16, no. 7, pp. 1221–1235, 2020. View at: Publisher Site | Google Scholar
  61. G. Chen, Q. Wang, Z. Li et al., “Circular RNA CDR1as promotes adipogenic and suppresses osteogenic differentiation of BMSCs in steroid-induced osteonecrosis of the femoral head,” Bone, vol. 133, p. 115258, 2020. View at: Publisher Site | Google Scholar
  62. Y. Wang, M. L. Li, Y. H. Wang et al., “A Zfp609 circular RNA regulates myoblast differentiation by sponging miR-194-5p,” International Journal of Biological Macromolecules, vol. 121, pp. 1308–1313, 2019. View at: Publisher Site | Google Scholar
  63. Z. Yuan, Q. Li, S. Luo et al., “PPARγ and Wnt signaling in adipogenic and osteogenic differentiation of mesenchymal stem cells,” Current Stem Cell Research & Therapy, vol. 11, no. 3, pp. 216–225, 2016. View at: Publisher Site | Google Scholar
  64. I. Takada, A. P. Kouzmenko, and S. Kato, “Wnt and PPARγ signaling in osteoblastogenesis and adipogenesis,” Nature Reviews Rheumatology, vol. 5, no. 8, pp. 442–447, 2009. View at: Publisher Site | Google Scholar
  65. Y. Zheng, X. Li, Y. Huang, L. Jia, and W. Li, “The circular RNA landscape of periodontal ligament stem cells during osteogenesis,” Journal of Periodontology, vol. 88, no. 9, pp. 906–914, 2017. View at: Publisher Site | Google Scholar
  66. N. Chen, G. Zhao, X. Yan et al., “A novel FLI1 exonic circular RNA promotes metastasis in breast cancer by coordinately regulating TET1 and DNMT1,” Genome Biology, vol. 19, no. 1, p. 218, 2018. View at: Publisher Site | Google Scholar
  67. M. Zhang, L. Jia, and Y. Zheng, “circRNA expression profiles in human bone marrow stem cells undergoing osteoblast differentiation,” Stem Cell Reviews and Reports, vol. 15, no. 1, pp. 126–138, 2019. View at: Publisher Site | Google Scholar
  68. S. Xiang, Z. Li, and X. Weng, “Changed cellular functions and aberrantly expressed miRNAs and circRNAs in bone marrow stem cells in osteonecrosis of the femoral head,” International Journal of Molecular Medicine, vol. 45, no. 3, pp. 805–815, 2020. View at: Publisher Site | Google Scholar
  69. Z. Ouyang, T. Tan, X. Zhang et al., “CircRNA hsa_circ_0074834 promotes the osteogenesis-angiogenesis coupling process in bone mesenchymal stem cells (BMSCs) by acting as a ceRNA for miR-942-5p,” Cell Death & Disease, vol. 10, no. 12, p. 932, 2019. View at: Publisher Site | Google Scholar
  70. L. Li, Y. Chen, L. Nie et al., “MyoD-induced circular RNA CDR1as promotes myogenic differentiation of skeletal muscle satellite cells,” Biochim Biophys Acta Gene Regul Mech, vol. 1862, no. 8, pp. 807–821, 2019. View at: Publisher Site | Google Scholar
  71. B. Kyei, L. Li, L. Yang, S. Zhan, and H. Zhang, “CDR1as/miRNAs-related regulatory mechanisms in muscle development and diseases,” Gene, vol. 730, p. 144315, 2020. View at: Publisher Site | Google Scholar
  72. B. Chen, J. Yu, L. Guo et al., “Circular RNA circHIPK3 promotes the proliferation and differentiation of chicken myoblast cells by sponging miR-30a-3p,” Cells, vol. 8, no. 2, p. 177, 2019. View at: Publisher Site | Google Scholar
  73. X. Li, C. Li, Z. Liu et al., “Circular RNA circ-FoxO3 inhibits myoblast cells differentiation,” Cell, vol. 8, no. 6, p. 616, 2019. View at: Publisher Site | Google Scholar
  74. R. Chen, T. Jiang, S. Lei et al., “Expression of circular RNAs during C2C12 myoblast differentiation and prediction of coding potential based on the number of open reading frames and N6-methyladenosine motifs,” Cell Cycle, vol. 17, no. 14, pp. 1832–1845, 2018. View at: Publisher Site | Google Scholar
  75. Q. Yang, J. Wu, J. Zhao et al., “Circular RNA expression profiles during the differentiation of mouse neural stem cells,” BMC Systems Biology, vol. 12, Suppl 8, p. 128, 2018. View at: Publisher Site | Google Scholar
  76. A. Cherubini, M. Barilani, R. L. Rossi et al., “FOXP1 circular RNA sustains mesenchymal stem cell identity via microRNA inhibition,” Nucleic Acids Research, vol. 47, no. 10, pp. 5325–5340, 2019. View at: Publisher Site | Google Scholar
  77. X. Yin, X. Wang, X. Hu, Y. Chen, K. Zeng, and H. Zhang, “ERβ induces the differentiation of cultured osteoblasts by both Wnt/β-catenin signaling pathway and estrogen signaling pathways,” Experimental Cell Research, vol. 335, no. 1, pp. 107–114, 2015. View at: Publisher Site | Google Scholar
  78. X. Li, B. Peng, X. Zhu et al., “Changes in related circular RNAs following ERβ knockdown and the relationship to rBMSC osteogenesis,” Biochemical and Biophysical Research Communications, vol. 493, no. 1, pp. 100–107, 2017. View at: Publisher Site | Google Scholar
  79. A. Li, W. Huang, X. Zhang, L. Xie, and X. Miao, “Identification and characterization of CircRNAs of two pig breeds as a new biomarker in metabolism-related diseases,” Cellular Physiology and Biochemistry, vol. 47, no. 6, pp. 2458–2470, 2018. View at: Publisher Site | Google Scholar
  80. H. Zhang, L. Zhu, M. Bai et al., “Exosomal circRNA derived from gastric tumor promotes white adipose browning by targeting the miR-133/PRDM16 pathway,” International Journal of Cancer, vol. 144, no. 10, pp. 2501–2515, 2019. View at: Publisher Site | Google Scholar
  81. X. Y. Guo, F. Sun, J. N. Chen, Y. Q. Wang, Q. Pan, and J. G. Fan, “circRNA_0046366 inhibits hepatocellular steatosis by normalization of PPAR signaling,” World Journal of Gastroenterology, vol. 24, no. 3, pp. 323–337, 2018. View at: Publisher Site | Google Scholar
  82. Y. M. Sun, J. Qin, S. G. Liu et al., “PDGFRα regulated by miR-34a and FoxO1 promotes adipogenesis in porcine intramuscular preadipocytes through Erk signaling pathway,” International Journal of Molecular Sciences, vol. 18, no. 11, p. 2424, 2017. View at: Publisher Site | Google Scholar
  83. Y. Liu, H. Liu, Y. Li et al., “Circular RNA SAMD4A controls adipogenesis in obesity through the miR-138-5p/EZH2 axis,” Theranostics, vol. 10, no. 10, pp. 4705–4719, 2020. View at: Publisher Site | Google Scholar
  84. B. Kleaveland, C. Y. Shi, J. Stefano, and D. P. Bartel, “A network of noncoding regulatory RNAs acts in the mammalian brain,” Cell, vol. 174, no. 2, pp. 350–362.e17, 2018, e17. View at: Publisher Site | Google Scholar
  85. R. C. Li, S. Ke, F. K. Meng et al., “CiRS-7 promotes growth and metastasis of esophageal squamous cell carcinoma via regulation of miR-7/HOXB13,” Cell Death & Disease, vol. 9, no. 8, p. 838, 2018. View at: Publisher Site | Google Scholar
  86. Z. Liu, Y. Ran, C. Tao, S. Li, J. Chen, and E. Yang, “Detection of circular RNA expression and related quantitative trait loci in the human dorsolateral prefrontal cortex,” Genome Biology, vol. 20, no. 1, p. 99, 2019. View at: Publisher Site | Google Scholar
  87. H. K. Choi, H. Yuan, F. Fang et al., “Tsc1 regulates the balance between osteoblast and adipocyte differentiation through autophagy/Notch1/β-catenin cascade,” Journal of Bone and Mineral Research, vol. 33, no. 11, pp. 2021–2034, 2018. View at: Publisher Site | Google Scholar
  88. M. M. Weivoda, M. Ruan, C. M. Hachfeld et al., “Wnt signaling inhibits osteoclast differentiation by activating canonical and noncanonical cAMP/PKA pathways,” Journal of Bone and Mineral Research, vol. 34, no. 8, pp. 1546–1548, 2019. View at: Publisher Site | Google Scholar
  89. A. Kanazawa, S. Tsukada, M. Kamiyama, T. Yanagimoto, M. Nakajima, and S. Maeda, “_Wnt5b_ partially inhibits canonical Wnt/ β-catenin signaling pathway and promotes adipogenesis in 3T3-L1 preadipocytes,” Biochemical and Biophysical Research Communications, vol. 330, no. 2, pp. 505–510, 2005. View at: Publisher Site | Google Scholar
  90. F. H. J. van Tienen, H. Laeremans, C. J. H. van der Kallen, and H. J. M. Smeets, “_Wnt5b_ stimulates adipogenesis by activating _PPAR γ_, and inhibiting the β-catenin dependent Wnt signaling pathway together with _Wnt5a_,” Biochemical and Biophysical Research Communications, vol. 387, no. 1, pp. 207–211, 2009. View at: Publisher Site | Google Scholar
  91. E. Monzón-Casanova, M. Screen, M. D. Díaz-Muñoz et al., “The RNA-binding protein PTBP1 is necessary for B cell selection in germinal centers,” Nature Immunology, vol. 19, no. 3, pp. 267–278, 2018. View at: Publisher Site | Google Scholar
  92. D. Eberlé, B. Hegarty, P. Bossard, P. Ferré, and F. Foufelle, “SREBP transcription factors: master regulators of lipid homeostasis,” Biochimie, vol. 86, no. 11, pp. 839–848, 2004. View at: Publisher Site | Google Scholar
  93. M. M. Aagaard, R. Siersbaek, and S. Mandrup, “Molecular basis for gene-specific transactivation by nuclear receptors,” Biochimica et Biophysica Acta, vol. 1812, no. 8, pp. 824–835, 2011. View at: Publisher Site | Google Scholar
  94. C. Liu, Z. Yang, J. Wu et al., “Long noncoding RNA H19 interacts with polypyrimidine tract-binding protein 1 to reprogram hepatic lipid homeostasis,” Hepatology, vol. 67, no. 5, pp. 1768–1783, 2018. View at: Publisher Site | Google Scholar
  95. S. Yu, Q. Geng, J. Ma et al., “Heparin-binding EGF-like growth factor and miR-1192 exert opposite effect on Runx2-induced osteogenic differentiation,” Cell Death & Disease, vol. 4, no. 10, p. e868, 2013. View at: Publisher Site | Google Scholar
  96. S. C. Dickinson, C. A. Sutton, K. Brady et al., “The Wnt5a receptor, receptor tyrosine kinase-like orphan receptor 2, is a predictive cell surface marker of human mesenchymal stem cells with an enhanced capacity for chondrogenic differentiation,” Stem Cells, vol. 35, no. 11, pp. 2280–2291, 2017. View at: Publisher Site | Google Scholar
  97. R. Bilkovski, D. M. Schulte, F. Oberhauser et al., “Role of WNT-5a in the determination of human mesenchymal stem cells into preadipocytes,” The Journal of Biological Chemistry, vol. 285, no. 9, pp. 6170–6178, 2010. View at: Publisher Site | Google Scholar
  98. A. B. Khalid and S. A. Krum, “Estrogen receptors alpha and beta in bone,” Bone, vol. 87, pp. 130–135, 2016. View at: Publisher Site | Google Scholar
  99. Y. F. Tang, Y. Zhang, X. Y. Li, C. Li, W. Tian, and L. Liu, “Expression of miR-31, miR-125b-5p, and miR-326 in the adipogenic differentiation process of adipose-derived stem cells,” OMICS, vol. 13, no. 4, pp. 331–336, 2009. View at: Publisher Site | Google Scholar
  100. L. Guan, X. Hu, L. Liu et al., “bta-miR-23a involves in adipogenesis of progenitor cells derived from fetal bovine skeletal muscle,” Scientific Reports, vol. 7, no. 1, 2017. View at: Publisher Site | Google Scholar
  101. T. Kang, W. Lu, W. Xu et al., “MicroRNA-27 (miR-27) targets prohibitin and impairs adipocyte differentiation and mitochondrial function in human adipose-derived stem cells,” The Journal of Biological Chemistry, vol. 288, no. 48, pp. 34394–34402, 2013. View at: Publisher Site | Google Scholar
  102. T. Wang, M. Li, J. Guan et al., “MicroRNAs miR-27a and miR-143 regulate porcine adipocyte lipid metabolism,” International Journal of Molecular Sciences, vol. 12, no. 11, pp. 7950–7959, 2011. View at: Publisher Site | Google Scholar
  103. D. Prusty, B. H. Park, K. E. Davis, and S. R. Farmer, “Activation of MEK/ERK signaling promotes adipogenesis by enhancing peroxisome proliferator-activated receptor gamma (PPARgamma ) and C/EBPalpha gene expression during the differentiation of 3T3-L1 preadipocytes,” The Journal of Biological Chemistry, vol. 277, no. 48, pp. 46226–46232, 2002. View at: Publisher Site | Google Scholar
  104. Y. Xing, F. Yan, Y. Liu, Y. Liu, and Y. Zhao, “Matrine inhibits 3T3-L1 preadipocyte differentiation associated with suppression of ERK1/2 phosphorylation,” Biochemical and Biophysical Research Communications, vol. 396, no. 3, pp. 691–695, 2010. View at: Publisher Site | Google Scholar
  105. Y. Guo, X. Zhang, W. Huang, and X. Miao, “Identification and characterization of differentially expressed miRNAs in subcutaneous adipose between Wagyu and Holstein cattle,” Scientific Reports, vol. 7, no. 1, 2017. View at: Publisher Site | Google Scholar
  106. X. Zhang, J. Guo, Y. Zhou, and G. Wu, “The roles of bone morphogenetic proteins and their signaling in the osteogenesis of adipose-derived stem cells,” Tissue Engineering. Part B, Reviews, vol. 20, no. 1, pp. 84–92, 2014. View at: Publisher Site | Google Scholar
  107. C. Thery, L. Zitvogel, and S. Amigorena, “Exosomes: composition, biogenesis and function,” Nature Reviews. Immunology, vol. 2, no. 8, pp. 569–579, 2002. View at: Publisher Site | Google Scholar
  108. Y. Li, Q. Zheng, C. Bao et al., “Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis,” Cell Research, vol. 25, no. 8, pp. 981–984, 2015. View at: Publisher Site | Google Scholar
  109. P. Seale, B. Bjork, W. Yang et al., “PRDM16 controls a brown fat/skeletal muscle switch,” Nature, vol. 454, no. 7207, pp. 961–967, 2008. View at: Publisher Site | Google Scholar
  110. P. Seale, S. Kajimura, W. Yang et al., “Transcriptional control of brown fat determination by PRDM16,” Cell Metabolism, vol. 6, no. 1, pp. 38–54, 2007. View at: Publisher Site | Google Scholar
  111. P. Seale, H. M. Conroe, J. Estall et al., “Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice,” The Journal of Clinical Investigation, vol. 121, no. 1, pp. 96–105, 2011. View at: Publisher Site | Google Scholar
  112. H. Ding, S. Zheng, D. Garcia-Ruiz et al., “Fasting induces a subcutaneous-to-visceral fat switch mediated by microRNA-149-3p and suppression of PRDM16,” Nature Communications, vol. 7, no. 1, 2016. View at: Publisher Site | Google Scholar
  113. H. Yin, A. Pasut, V. D. Soleimani et al., “MicroRNA-133 controls brown adipose determination in skeletal muscle satellite cells by targeting Prdm16,” Cell Metabolism, vol. 17, no. 2, pp. 210–224, 2013. View at: Publisher Site | Google Scholar
  114. Z. Yang, C. Bian, H. Zhou et al., “MicroRNA hsa-miR-138 inhibits adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells through adenovirus EID-1,” Stem Cells and Development, vol. 20, no. 2, pp. 259–267, 2011. View at: Publisher Site | Google Scholar
  115. A. C. Panda, I. Grammatikakis, K. M. Kim et al., “Identification of senescence-associated circular RNAs (SAC-RNAs) reveals senescence suppressor CircPVT1,” Nucleic Acids Research, vol. 45, no. 7, pp. 4021–4035, 2017. View at: Publisher Site | Google Scholar
  116. X. Li, Z. Zhang, H. Jiang et al., “Circular RNA circPVT1 promotes proliferation and invasion through sponging miR-125b and activating E2F2 signaling in non-small cell lung cancer,” Cellular Physiology and Biochemistry, vol. 51, no. 5, pp. 2324–2340, 2018. View at: Publisher Site | Google Scholar
  117. J. Chen, Y. Li, Q. Zheng et al., “Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer,” Cancer Letters, vol. 388, pp. 208–219, 2017. View at: Publisher Site | Google Scholar
  118. H. L. Ji, C. C. Song, Y. F. Li et al., “miR-125a inhibits porcine preadipocytes differentiation by targeting ERRα,” Molecular and Cellular Biochemistry, vol. 395, no. 1-2, pp. 155–165, 2014. View at: Publisher Site | Google Scholar
  119. J. Du, Y. Xu, P. Zhang et al., “MicroRNA-125a-5p affects adipocytes proliferation, differentiation and fatty acid composition of porcine intramuscular fat,” International Journal of Molecular Sciences, vol. 19, no. 2, p. 501, 2018. View at: Publisher Site | Google Scholar
  120. A. K. Greifenberg, D. Hönig, K. Pilarova et al., “Structural and functional analysis of the Cdk13/Cyclin K complex,” Cell Reports, vol. 14, no. 2, pp. 320–331, 2016. View at: Publisher Site | Google Scholar
  121. Q. Lin, Y. B. Ling, J. W. Chen et al., “Circular RNA circCDK13 suppresses cell proliferation, migration and invasion by modulating the JAK/STAT and PI3K/AKT pathways in liver cancer,” International Journal of Oncology, vol. 53, no. 1, pp. 246–256, 2018. View at: Publisher Site | Google Scholar
  122. N. Han, L. Ding, X. Wei, L. Fan, and L. Yu, “circSMAD2 governs migration and epithelial-mesenchymal transition by inhibiting microRNA-9,” Journal of Cellular Biochemistry, 2019. View at: Publisher Site | Google Scholar
  123. L. Shen, Y. Hu, J. Lou et al., “CircRNA‑0044073 is upregulated in atherosclerosis and increases the proliferation and invasion of cells by targeting miR‑107,” Molecular Medicine Reports, vol. 19, no. 5, pp. 3923–3932, 2019. View at: Publisher Site | Google Scholar
  124. H. Li, Z. Zhang, X. Zhou, Z. Y. Wang, G. L. Wang, and Z. Y. Han, “Effects of microRNA-143 in the differentiation and proliferation of bovine intramuscular preadipocytes,” Molecular Biology Reports, vol. 38, no. 7, pp. 4273–4280, 2011. View at: Publisher Site | Google Scholar
  125. E. K. Lee, M. J. Lee, K. Abdelmohsen et al., “miR-130 suppresses adipogenesis by inhibiting peroxisome proliferator-activated receptor gamma expression,” Molecular and Cellular Biology, vol. 31, no. 4, pp. 626–638, 2011. View at: Publisher Site | Google Scholar
  126. S. Lorente-Cebrián, N. Mejhert, A. Kulyté et al., “MicroRNAs regulate human adipocyte lipolysis: effects of miR-145 are linked to TNF-α,” PLoS One, vol. 9, no. 1, article e86800, 2014. View at: Publisher Site | Google Scholar
  127. H. Li, X. Chen, L. Guan et al., “MiRNA-181a regulates adipogenesis by targeting tumor necrosis factor-α (TNF-α) in the porcine model,” PLoS One, vol. 8, no. 10, article e71568, 2013. View at: Publisher Site | Google Scholar
  128. T. Sun, M. Fu, A. L. Bookout, S. A. Kliewer, and D. J. Mangelsdorf, “MicroRNA let-7 regulates 3T3-L1 adipogenesis,” Molecular Endocrinology, vol. 23, no. 6, pp. 925–931, 2009. View at: Publisher Site | Google Scholar

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