Stem Cells International

Review Article

Epigenetic Regulation in Mesenchymal Stem Cell Aging and Differentiation and Osteoporosis

Table 4

ncRNAs in MSC aging and related diseases.


Regulatory factors	Mechanism	In vivo or in vitro	Consequence	Material	Ref.

Senescence and aging
miR-10a↓	Insufficient to target Klf4 and repress its function	Both	Senescence, decreased differentiation	hBMSCs	[74, 75]
miR-20b-5p and miR-106a-5p↓	Insufficient to inhibit Smads/p21/CDK/E2F pathway, which alleviates suspension of DNA synthesis during oxidative stress-induced premature senescence	In vitro	Premature senescence	hBMSCs	[77]
miR-22 and miR-485-5p↑	Targets CKS1 to downregulate CDK1 and cyclin B	In vitro	Senescence	SHED	[69]
miR-31a-5p↑	Targets E2F2 and promotes SAHF formation	Both	Senescence	Rat BMSCs	[71]
miR-27b↑	Upregulates p16 expression and MAPK pathway activation	In vitro	Senescence	Pig ADSCs	[98]
miR-29c-3p↑	Targets CNOT6 thus inducing senescence via p53/p21 and p16/pRB pathways	In vitro	Senescence	hBMSCs	[72, 73]
miR-34a↑	Reduces CDK2, CDK4, CDK6, and cyclin D and E expression to hinder the SOX2-related self-renewal ability	In vitro	Senescence	hADSCs	[70]
miR-34a↑	Targets Sirt1 to induce senescence via Sirt1/FoxO3a pathway, induces mitochondrial dysfunction	In vitro	Senescence and intrinsic apoptosis	Mouse BMSCs, rat BMSCs	[89, 90]
miR-141-3p↑	Targets Zmpste24 transcripts, causing prelamin A accumulation in nuclear envelope and intracellular DNA damage	In vitro	Senescence	hUCSCs	[92]
miR-141-3p↑	Targets YAP to inhibit proliferation and accelerate senescence	In vitro	Senescence	Human papilla apical stem cells	[93]
miR-142↑	Targets Epas1 to downregulate pexophagic activity and induce ROS accumulation	In vitro	Aging	Mouse BMSCs	[81]
miR-155-5p↑	Targets Cab39 and then reduces mitochondrial fission and increases mitochondrial fusion via the Cab39/AMPK signaling pathway	Both	Aging	Mouse model, hBMSCs	[86]
miR-155-5p↑	Targets Bag5 that encodes partner protein of PINK1, to inhibit mitophagy and dysfunctional mitochondria elimination	In vitro	Aging	hBMSCs	[87]
miR-155-5p↑	Targets the common transcription factor C/EBP-β thus repressing antioxidant genes and inducing ROS production	Both	Aging	hBMSCs/mouse BMSCs	[82]
miR-182↑	Targets FoxO1, which is critical to protecting cells from ROS	In vitro	Aging, decreased proliferation, and osteogenesis	hBMSCs	[83]
miR-183-5p↑	Targets Hmox-1 to impair response to oxidative stress	In vitro	Senescence	Mouse BMSCs	[84]
miR-188↑	Targets HDAC9 and RICTOR	Both	Aging, decreased proliferation	Mouse BMSCs, mouse model	[94, 95]
miR-195↑	Targets Tert and prevents TERT to repair the shortened telomeres with replication	In vitro	Aging	Mouse BMSCs	[91]
miR-199b-5p↓	Insufficient to repress LAMC1	In vitro	Senescence	hBMSCs	[80]
miR-206↑	Targets Alpl, which is essential for the intracellular ATP level and AMPK pathway	Both	Premature senescence	Rat BMSCs, rat model	[96]
miR-363-3p↑	Targets TRAF3, which inhibits adipogenic differentiation and senescence	In vitro	Senescence, upregulated adipogenesis	Rat BMSCs	[99]
miR-486-5p↑	Targets Sirt1	In vitro	Senescence	hADSCs	[85]
miR-543 and miR-590-3p↓	Insufficient to target AIMP3/p18 to inhibit expression, inducing an increase in CDK inhibitors p16^INK4A and p21^CIP1/WAF1	In vitro	Senescence	hUCSCs	[78]
miR-1292↑	Targets Wnt receptor FZD4, thus hindering the Wnt/β-catenin/TCF/LEF1 pathway	In vitro	Senescence, downregulated osteogenesis	hADSCs	[100]
lncRNA-Bmncr↓	Insufficient to serve as a scaffold to facilitate the interaction of ABL and transcriptional coactivator with TAZ, hindering the assembly of the TAZ and RUNX2/PPARγ transcriptional complex	Both	Aging, transition from osteogenesis to adipogenesis	hBMSCs, mouse BMSCs	[103]
lncRNA-HOTAIR↑	Modulates senescence-associated changes in gene expression and DNA methylation via triple helix DNA-DNA-RNA formation	In vitro	Senescence	hBMSCs	[102]
Skeletal diseases
miR-21↓	Insufficient to target Spry1, which negatively regulates osteogenesis via FGF and MAPK	Both	Osteoporosis	hBMSCs, mouse model	[112]
miR-21a↓	Insufficient to target Pten and PTEN downregulates AKT pathway to induce osteocyte apoptosis	Both	Glucocorticoid-induced osteonecrosis	hUCSCs, mouse model	[116]
miR-23b↑	Targets Runx2	Both	Osteoporosis	hBMSCs, mouse model	[106]
miR-27↓	Insufficient to target Mef2c, which facilitates the adipogenic differentiation	Both	Osteoporosis	hBMSCs, mouse model	[113]
miR-181a↓	Leads to the accumulation of FasL from BMSCs, followed by CD4+ T cell apoptosis	Both	Osteoporosis	Mouse BMSCs, mouse model	[115]
miR-212 and miR-384↑	Targets Runx2	Both	Osteoporosis	Mouse BMSCs, mouse model	[108]
miR-542-3p↓	Insufficient to inhibit sFRP1 expression, which is a negative regulator of Wnt pathway	Both	Osteoporosis	HEK293T cells, rat BMSCs, rat model	[111]
miR-596↑	Targets Smad3 to inhibit Runx2 expression and osteogenesis	In vitro	ONFH	hBMSCs	[109]
miR-705 and miR-3077-5p↑	Respectively, targets HOXA10 and Runx2 mRNA, leading to MSC lineage commitment transition to adipocytes	In vitro	Osteoporosis	hBMSCs	[107]
miR-708↑	Targets Smad3 to inhibit Runx2 expression	In vitro	ONFH	hBMSCs	[110]
miR-1263↓	Insufficient to suppress Mob-1/YAP/Hippo signaling pathway-induced apoptosis	Both	Disused osteoporosis	hUCSCs, rat model	[114]
lncRNA-MALAT1↓	Insufficient to inhibit miR-143, whose target is Osx	In vitro	Osteoporosis	hBMSCs	[117]
lncRNA-ORLNC1↑	Endogenously competes with miR-296 and eliminates miR-296’s suppression of Pten, which is a negative regulator of osteogenesis	Both	Osteoporosis	hBMSCs, mouse model	[119]
lncRNA-DEPTOR↑	Binds to ncRNA-MEG3’s promoter and reduces its function to activate BMP4 pathway	Both	Osteoporosis	Mouse BMSCs, mouse model	[120]
lncRNA-H19↓	Insufficient to inhibit MSC proliferation and osteogenic differentiation via suppressing miR-19b-3p	In vitro	Inhibits osteoporosis	hBMSCs	[121]
lncRNA-HOTAIR↑	Suppresses miR-17-5p to elevate Smad7 pathway	In vitro	Inhibits ONFH	hBMSCs	[122]

ABL1: oncogene homolog 1; AIMP3: aminoacyl-tRNA synthetase-interacting multifunctional protein-3; CKS1: cyclin-dependent kinase regulatory subunit 1; Mef2c: myocyte enhancer factor 2c; LAMC1: laminin gamma 1; PRC2: polycomb repressive complex 2; SAHF: senescence-associated heterochromatin foci; sFRP1: secreted Frizzled-related protein-1; Spry1: sprouty homolog 1.