Long Noncoding RNA: Function and Mechanism on Differentiation of Mesenchymal Stem Cells and Embryonic Stem Cells

Author(s): Jian Zhu, Yitian Wang, Wei Yu, Kaishun Xia, Yuluan Huang, Junjie Wang, Bing Liu, Huimin Tao*, Chengzhen Liang*, Fangcai Li*.

Journal Name: Current Stem Cell Research & Therapy

Volume 14 , Issue 3 , 2019

Become EABM
Become Reviewer


Background: Long suspected as transcriptional noise, recently recognized, long non-coding RNAs (lncRNAs) are emerging as an indicator, biomarker and therapy target in the physiologic and pathologic process. Mesenchymal stem cells and embryonic stem cells are important source for normal and therapeutic tissue repair. However, the mechanism of stem cell differentiation is not completely understood. Research on lncRNAs may provide novel insights into the mechanism of differentiation process of the stem cell which is important for the application of stem cell therapy. The lncRNAs field is still very young, new insights into lncRNAs function are emerging to a greater understanding of biological processes.

Objective: In this review, we summarize the recent researches studying lncRNAs and illustrate how they act in the differentiation of the mesenchymal stem cells and embryonic stem cells, and discuss some future directions in this field.

Results: Numerous lncRNAs were differentially expressed during differentiation of mesenchymal stem cells and embryonic stem cells. LncRNAs were able to regulate the differentiation processes through epigenetic regulation, transcription regulation and post-transcription regulation.

Conclusion: LncRNAs are involved in the differentiation process of mesenchymal stem cells and embryonic stem cells, and they could become promising indicator, biomarker and therapeutic targets in the physiologic and pathologic process. However, the mechanisms of the role of lncRNAs still require further investigation.

Keywords: LncRNAs, mesenchymal stem cells, differentiation, embryonic stem cells, lncRNA, biomarker, therapeutic targets.

Russell J, Lodge E, Andoniadou C. Basic research advances on pituitary stem cell function and regulation. Neuroendocrinology 2018; 107(2): 196-203.
Kim CS, Choi H, Park KC, et al. The ability of human nasal inferior turbinate-derived mesenchymal stem cells to repair vocal fold injuries. Otolaryngol Head Neck Surg 2018; 159(2): 335-42.
Reich HJ, Czer LSC, Ramzy D, et al. Combining stem cell therapy for advanced heart failure and ventricular assist devices: A review. ASAIO J 2018; 64(5): e80-7.
Wezyk M, Szybinska A, Wojsiat J, et al. Overactive BRCA1 affects presenilin 1 in induced pluripotent stem cell-derived neurons in alzheimer’s disease. J Alzheimers Dis 2018; 62: 175-202.
Ulyanova O, Baigenzhin A, Doskaliyev Z, et al. Transforming growth factor beta1 in Patients with type 2 diabetes mellitus after fetal pancreatic stem cell transplant. Exp Clin Transplant 2018; 16: 168-70.
Ibrahim ME, Bana EE, El-Kerdasy HI. Role of bone marrow derived mesenchymal stem cells and the protective effect of silymarin in cisplatin-induced acute renal failure in Rats. Am J Med Sci 2018; 355: 76-83.
Niwa H. The principles that govern transcription factor network functions in stem cells. Development 2018; 145: dev157420.
Giorgetti L, Lajoie BR, Carter AC, et al. Structural organization of the inactive X chromosome in the mouse. Nature 2016; 535: 575-9.
Bernardes de Jesus B, Marinho SP, Barros S, et al. Silencing of the lncRNA Zeb2-NAT facilitates reprogramming of aged fibroblasts and safeguards stem cell pluripotency. Nat Commun 2018; 9: 94.
Diehl AG, Boyle AP. Deciphering ENCODE. Trends Genet 2016; 32: 238-49.
Li Y, Zhang J, Pan J, et al. Insights into the roles of lncRNAs in skeletal and dental diseases. Cell Biosci 2018; 8: 8.
Kopp F, Mendell JT. Functional classification and experimental dissection of long noncoding RNAs. Cell 2018; 172: 393-407.
Tani H, Onuma Y, Ito Y, et al. Long non-coding RNAs as surrogate indicators for chemical stress responses in human-induced pluripotent stem cells. PLoS One 2014; 9: e106282.
Pefanis E, Wang J, Rothschild G, et al. RNA exosome-regulated long non-coding RNA transcription controls super-enhancer activity. Cell 2015; 161: 774-89.
Wu J, Zhao J, Sun L, et al. Long non-coding RNA H19 mediates mechanical tension-induced osteogenesis of bone marrow mesenchymal stem cells via FAK by sponging miR-138. Bone 2018; 108: 62-70.
Sassoli C, Vallone L, Tani A, et al. Combined use of bone marrow-derived mesenchymal stromal cells (BM-MSCs) and platelet rich plasma (PRP) stimulates proliferation and differentiation of myoblasts in vitro: new therapeutic perspectives for skeletal muscle repair/regeneration. Cell Tissue Res 2018; 372(3): 549-70.
Hawkins KE, Corcelli M, Dowding K, et al. Embryonic stem cell-derived mesenchymal stem cells (mscs) have a superior neuroprotective capacity over fetal mscs in the hypoxic-ischemic mouse brain. Stem Cells Transl Med 2018; 7(5): 439-49.
Yang S, Zhao N, Yang Y, et al. Mitotically Stable Modification of DNA Methylation in IGF2/H19 Imprinting Control Region Is Associated with Activated Hepatic IGF2 Expression in Offspring Rats from Betaine-Supplemented Dams. J Agric Food Chem 2018; 66(11): 2704-13.
Steck E, Boeuf S, Gabler J, et al. Regulation of H19 and its encoded microRNA-675 in osteoarthritis and under anabolic and catabolic in vitro conditions. J Mol Med (Berl) 2012; 90: 1185-95.
Wang L, Li Z, Li Z, et al. Long noncoding RNAs expression signatures in chondrogenic differentiation of human bone marrow mesenchymal stem cells. Biochem Biophys Res Commun 2015; 456: 459-64.
Zhang L, Chen S, Bao N, et al. Sox4 enhances chondrogenic differentiation and proliferation of human synovium-derived stem cell via activation of long noncoding RNA DANCR. J Mol Histol 2015; 46: 467-73.
Kim D, Song J, Han J, et al. Two non-coding RNAs, MicroRNA-101 and HOTTIP contribute cartilage integrity by epigenetic and homeotic regulation of integrin-alpha1. Cell Signal 2013; 25: 2878-87.
Jonnakuti VS, Raynor WY, Taratuta E, et al. A novel method to assess subchondral bone formation using [18F]NaF-PET in the evaluation of knee degeneration. Nucl Med Commun 2018; 39(5): 451-6.
Fitri AR, Pavasant P, Chamni S, et al. Asiaticoside induces osteogenic differentiation of human periodontal ligament cells through the wnt pathway. J Periodontol 2018; 89(5): 596-605.
Gao X, Ge J, Li W, et al. LncRNA KCNQ1OT1 promotes osteogenic differentiation to relieve osteolysis via Wnt/beta-catenin activation. Cell Biosci 2018; 8: 19.
Liang M, Li W, Tian H, et al. Sequential expression of long noncoding RNA as mRNA gene expression in specific stages of mouse spermatogenesis. Sci Rep 2014; 4: 5966.
Yu C, Li L, Xie F, et al. LncRNA TUG1 sponges miR-204-5p to promote osteoblast differentiation through upregulating Runx2 in aortic valve calcification. Cardiovasc Res 2018; 114: 168-79.
Zhang J, Tao Z, Wang Y. Long noncoding RNA DANCR regulates the proliferation and osteogenic differentiation of human bone-derived marrow mesenchymal stem cells via the p38 MAPK pathway. Int J Mol Med 2018; 41: 213-9.
Shang G, Wang Y, Xu Y, et al. Long non-coding RNA TCONS_00041960 enhances osteogenesis and inhibits adipogenesis of rat bone marrow mesenchymal stem cell by targeting miR-204-5p and miR-125a-3p. J Cell Physiol 2018; 233(8): 6041-51.
Wang L, Wang Y, Li Z, et al. Differential expression of long noncoding ribonucleic acids during osteogenic differentiation of human bone marrow mesenchymal stem cells. Int Orthop 2015; 39: 1013-9.
Li H, Zhang Z, Chen Z, et al. Osteogenic growth peptide promotes osteogenic differentiation of mesenchymal stem cells mediated by LncRNA AK141205-induced upregulation of CXCL13. Biochem Biophys Res Commun 2015; 466: 82-8.
Reyes R, Rodriguez JA, Orbe J, et al. Combined sustained release of BMP2 and MMP10 accelerates bone formation and mineralization of calvaria critical size defect in mice. Drug Deliv 2018; 25: 750-6.
Zhuang W, Ge X, Yang S, et al. Upregulation of lncRNA MEG3 promotes osteogenic differentiation of mesenchymal stem cells from multiple myeloma patients by targeting BMP4 Transcription. Stem Cells 2015; 33: 1985-97.
Jia Q, Jiang W, Ni L. Down-regulated non-coding RNA (lncRNA-ANCR) promotes osteogenic differentiation of periodontal ligament stem cells. Arch Oral Biol 2015; 60: 234-41.
Backesjo CM, Li Y, Lindgren U, et al. Activation of Sirt1 decreases adipocyte formation during osteoblast differentiation of mesenchymal stem cells. Cells Tissues Organs 2009; 189: 93-7.
Xu Y, Wang S, Tang C, et al. Upregulation of long non-coding RNA HIF 1alpha-anti-sense 1 induced by transforming growth factor-beta-mediated targeting of sirtuin 1 promotes osteoblastic differentiation of human bone marrow stromal cells. Mol Med Rep 2015; 12: 7233-8.
Kasselman LJ, Vernice NA, DeLeon J, et al. The gut microbiome and elevated cardiovascular risk in obesity and autoimmunity. Atherosclerosis 2018; 271: 203-13.
Brouns F. Overweight and diabetes prevention: Is a low-carbohydrate-high-fat diet recommendable? Eur J Nutr 2018; 57(4): 1301-12.
Zhou H, Wang K, Zhou X, et al. Prevalence and gender-specific influencing factors of hypertension among Chinese Adults: A cross-sectional survey study in Nanchang, China. Int J Environ Res Public Health 2018; 15(2): E382.
Lo KA, Huang S, Esther Walet AC, et al. Adipocyte long noncoding rna transcriptome analysis of obese mice identified lnc-leptin which regulates leptin. Diabetes 2018; 67(6): 1045-56.
Xiao T, Liu L, Li H, et al. Long noncoding RNA ADINR regulates adipogenesis by transcriptionally activating C/EBPalpha. Stem Cell Reports 2015; 5: 856-65.
Gernapudi R, Wolfson B, Zhang Y, et al. MicroRNA 140 Promotes Expression of Long Noncoding RNA NEAT1 in Adipogenesis. Mol Cell Biol 2016; 36: 30-8.
Kallen AN, Zhou XB, Xu J, et al. The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol Cell 2013; 52: 101-12.
Dey BK, Pfeifer K, Dutta A. The H19 long noncoding RNA gives rise to microRNAs miR-675-3p and miR-675-5p to promote skeletal muscle differentiation and regeneration. Genes Dev 2014; 28: 491-501.
Wakao J, Kishida T, Fumino S, et al. Efficient direct conversion of human fibroblasts into myogenic lineage induced by co-transduction with MYCL and MYOD1. Biochem Biophys Res Commun 2017; 488: 368-73.
Gong C, Li Z, Ramanujan K, et al. A long non-coding RNA, LncMyoD, regulates skeletal muscle differentiation by blocking IMP2-mediated mRNA translation. Dev Cell 2015; 34: 181-91.
Hube F, Velasco G, Rollin J, et al. Steroid receptor RNA activator protein binds to and counteracts SRA RNA-mediated activation of MyoD and muscle differentiation. Nucleic Acids Res 2011; 39: 513-25.
Watts R, Johnsen VL, Shearer J, et al. Myostatin-induced inhibition of the long noncoding RNA Malat1 is associated with decreased myogenesis. Am J Physiol Cell Physiol 2013; 304: C995-C1001.
Han X, Yang F, Cao H, et al. Malat1 regulates serum response factor through miR-133 as a competing endogenous RNA in myogenesis. FASEB J 2015; 29: 3054-64.
Cesana M, Cacchiarelli D, Legnini I, et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 2011; 147: 358-69.
Lu L, Sun K, Chen X, et al. Genome-wide survey by ChIP-seq reveals YY1 regulation of lincRNAs in skeletal myogenesis. EMBO J 2013; 32: 2575-88.
Quan Z, Zheng D, Qing H. Regulatory roles of long non-coding rnas in the central nervous system and associated neurodegenerative diseases. Front Cell Neurosci 2017; 11: 175.
Ramos AD, Andersen RE, Liu SJ, et al. The long noncoding RNA Pnky regulates neuronal differentiation of embryonic and postnatal neural stem cells. Cell Stem Cell 2015; 16: 439-47.
Ng SY, Bogu GK, Soh BS, et al. The long noncoding RNA RMST interacts with SOX2 to regulate neurogenesis. Mol Cell 2013; 51: 349-59.
Klattenhoff CA, Scheuermann JC, Surface LE, et al. Braveheart, a long noncoding RNA required for cardiovascular lineage commitment. Cell 2013; 152: 570-83.
Kataoka M, Huang ZP, Wang DZ. Build a braveheart: The missing linc (RNA). Circ Res 2013; 112: 1532-4.
Kurian L, Aguirre A, Sancho-Martinez I, et al. Identification of novel long noncoding RNAs underlying vertebrate cardiovascular development. Circulation 2015; 131: 1278-90.
Xie P, Sun Y, Ouyang Q, et al. Physiological oxygen prevents frequent silencing of the DLK1-DIO3 cluster during human embryonic stem cells culture. Stem Cells 2014; 32: 391-401.
Winzi M, Casas Vila N, Paszkowski-Rogacz M, et al. The long noncoding RNA lncR492 inhibits neural differentiation of murine embryonic stem cells. PLoS One 2018; 13: e0191682.
Park JH, Park BW, Kang YH, et al. Lin28a enhances in vitro osteoblastic differentiation of human periosteum-derived cells. Cell Biochem Funct 2017; 35: 497-509.
Wianny F, Blachere T, Godet M, et al. Epigenetic status of H19/IGF2 and SNRPN imprinted genes in aborted and successfully derived embryonic stem cell lines in non-human primates. Stem Cell Res 2016; 16: 557-67.
Bergmann JH, Li J, Eckersley-Maslin MA, et al. Regulation of the ESC transcriptome by nuclear long noncoding RNAs. Genome Res 2015; 25: 1336-46.
Yin Y, Yan P, Lu J, et al. Opposing roles for the lncRNA haunt and its genomic locus in regulating hoxa gene activation during embryonic stem cell differentiation. Cell Stem Cell 2015; 16: 504-16.
Terashima M, Tange S, Ishimura A, et al. MEG3 long noncoding RNA contributes to the epigenetic regulation of epithelial-mesenchymal transition in lung cancer cell lines. J Biol Chem 2017; 292: 82-99.
Kaneko S, Bonasio R, Saldana-Meyer R, et al. Interactions between JARID2 and noncoding RNAs regulate PRC2 recruitment to chromatin. Mol Cell 2014; 53: 290-300.
Li J, Cao Y, Xu X, et al. Increased New lncRNA-mRNA gene pair levels in human cumulus cells correlate with oocyte maturation and embryo development. Reprod Sci 2015; 22: 1008-14.
Boo K, Bhin J, Jeon Y, et al. Pontin functions as an essential coactivator for Oct4-dependent lincRNA expression in mouse embryonic stem cells. Nat Commun 2015; 6: 6810.
Fujimori H, Mukai H, Murakami Y, et al. The H19 induction triggers trophoblast lineage commitment in mouse ES cells. Biochem Biophys Res Commun 2013; 436: 313-8.
Liu Z, Chi L, Fang Y, et al. Specific expression pattern of a novel Otx2 splicing variant during neural differentiation. Gene 2013; 523: 33-8.
Lu W, Han L, Su L, et al. A 3'UTR-associated RNA, FLJ11812 maintains stemness of human embryonic stem cells by targeting miR-4459. Stem Cells Dev 2015; 24: 1133-40.
Wu CS, Yu CY, Chuang CY, et al. Integrative transcriptome sequencing identifies trans-splicing events with important roles in human embryonic stem cell pluripotency. Genome Res 2014; 24: 25-36.
Scarola M, Comisso E, Pascolo R, et al. Epigenetic silencing of Oct4 by a complex containing SUV39H1 and Oct4 pseudogene lncRNA. Nat Commun 2015; 6: 7631.
Savic N, Bar D, Leone S, et al. lncRNA maturation to initiate heterochromatin formation in the nucleolus is required for exit from pluripotency in ESCs. Cell Stem Cell 2014; 15: 720-34.
Lin N, Chang KY, Li Z, et al. An evolutionarily conserved long noncoding RNA TUNA controls pluripotency and neural lineage commitment. Mol Cell 2014; 53: 1005-19.
Sun Y, Wei G, Luo H, et al. The long noncoding RNA SNHG1 promotes tumor growth through regulating transcription of both local and distal genes. Oncogene 2017; 36: 6774-83.
Joung J, Engreitz JM, Konermann S, et al. Genome-scale activation screen identifies a lncRNA locus regulating a gene neighbourhood. Nature 2017; 548: 343-6.
Amin V, Harris RA, Onuchic V, et al. Epigenomic footprints across 111 reference epigenomes reveal tissue-specific epigenetic regulation of lincRNAs. Nat Commun 2015; 6: 6370.
de la Cruz CC, Fang J, Plath K, et al. Developmental regulation of Suz 12 localization. Chromosoma 2005; 114: 183-92.
Tsai MC, Manor O, Wan Y, et al. Long noncoding RNA as modular scaffold of histone modification complexes. Science 2010; 329: 689-93.
Del Rosario BC, Del Rosario AM, Anselmo A, et al. Genetic Intersection of Tsix and Hedgehog Signaling during the Initiation of XChromosome Inactivation. Dev Cell 2017.43: 359-371 e6.
Payer B, Lee JT. Coupling of X-chromosome reactivation with the pluripotent stem cell state. RNA Biol 2014; 11: 798-807.
Figueroa DM, Darrow EM, Chadwick BP. Two novel DXZ4-associated long noncoding RNAs show developmental changes in expression coincident with heterochromatin formation at the human (Homo sapiens) macrosatellite repeat. Chromosome Res 2015; 23: 733-52.
Eun B, Sampley ML, Van Winkle MT, et al. The Igf2/H19 muscle enhancer is an active transcriptional complex. Nucleic Acids Res 2013; 41: 8126-34.
Luo M, Jeong M, Sun D, et al. Long non-coding RNAs control hematopoietic stem cell function. Cell Stem Cell 2015; 16: 426-38.
Lepoivre C, Belhocine M, Bergon A, et al. Divergent transcription is associated with promoters of transcriptional regulators. BMC Genomics 2013; 14: 914.
Peng W, Zhu SX, Wang J, et al. Lnc-NTF3-5 promotes osteogenic differentiation of maxillary sinus membrane stem cells via sponging miR-93-3p. Clin Implant Dent Relat Res 2018; 20(2): 110-21.
Yoon JH, Abdelmohsen K, Srikantan S, et al. LincRNA-p21 suppresses target mRNA translation. Mol Cell 2012; 47: 648-55.
Tripathi V, Ellis JD, Shen Z, et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Mol Cell 2010; 39: 925-38.
Gong C, Maquat LE. lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3′ UTRs via Alu elements. Nature 2011; 470: 284-8.
Gu X, Li M, Jin Y, et al. Identification and integrated analysis of differentially expressed lncRNAs and circRNAs reveal the potential ceRNA networks during PDLSC osteogenic differentiation. BMC Genet 2017; 18: 100.
Wang Y, Xu Z, Jiang J, et al. Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Dev Cell 2013; 25: 69-80.
Li R, Fu D, Zhu B, et al. CRISPR/Cas9-mediated mutagenesis of lncRNA1459 alters tomato fruit ripening. Plant J 2018; 94(3): 513-24.
Covarrubias S, Robinson EK, Shapleigh B, et al. CRISPR/Cas-based screening of long non-coding RNAs (lncRNAs) in macrophages with an NF-kappaB reporter. J Biol Chem 2017; 292: 20911-20.
Lin N, Dang J, Rana TM. Haunting the HOXA locus: Two faces of lncRNA regulation. Cell Stem Cell 2015; 16: 449-50.
Huang JZ, Chen M. Chen, et al. A peptide encoded by a putative lncrna hoxb-as3 suppresses colon cancer growth. Mol Cell 2017. 68: 171-184 e6.
Li LJ, Leng RX, Fan YG, et al. Translation of noncoding RNAs: Focus on lncRNAs, pri-miRNAs, and circRNAs. Exp Cell Res 2017; 361: 1-8.
Tajbakhsh S. lncRNA-Encoded Polypeptide SPAR(s) with mTORC1 to regulate skeletal muscle regeneration. cell stem. Cell 2017; 20: 428-30.
Rion N, Ruegg MA. LncRNA-encoded peptides: More than translational noise? Cell Res 2017; 27: 604-5.
Matsumoto A, Pasut A, Matsumoto M, et al. mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. Nature 2017; 541: 228-32.
Kapusta A, Feschotte C. Volatile evolution of long noncoding RNA repertoires: mechanisms and biological implications. Trends Genet 2014; 30: 439-52.
Johnsson P, Lipovich L, Grander D, et al. Evolutionary conservation of long non-coding RNAs; sequence, structure, function. Biochim Biophys Acta 2014; 1840: 1063-71.
Di C, Yuan J, Wu Y, et al. Characterization of stress-responsive lncRNAs in Arabidopsis thaliana by integrating expression, epigenetic and structural features. Plant J 2014; 80: 848-61.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [259 - 267]
Pages: 9
DOI: 10.2174/1574888X14666181127145809
Price: $58

Article Metrics

PDF: 15