MiR-146a induces the aging of mesenchymal stem cell via CASK

Abstract

Mesenchymal stem cell (MSC) has elicited great hopes for regenerative medicine, however, its regenerative potential decreases with age, which raises questions about the efficiency of autologous transplantations in elderly patients. To elucidate the cellular consequences and epigenetic mechanisms of aging, the functional and epigenetic changes in bone marrow derived MSC (BMSC) from normal and aging rats were studied concurrently. The results demonstrate that the proliferation and differentiation abilities of BMSCs from aging rats declined compared with those from young rats. In order to identify which miRNA involve in the senescence of BMSC, miRNA expression profiles of both BMSCs from young and aging rats were examined. The results showed that miR-146a expression increased significantly in BMSCs from aging rats compared with that from young rats, following with a decrease in Calcium/calmodulin-dependent Serine protein kinase (CASK) expression. Inhibition of miR-146a can reduces the numbers of senescent cells and stimulates the differentiation of BMSC. Luciferase assay demonstrated that CASK was a direct target of miR-146a, inhibition of miR-146a significantly elevated the expression of CASK. Overexpression of CASK in aged BMSC can rescue its proliferation and differentiation abilities. All these results indicate that miR-146a may cause aging and senescence of BMSC through the inhibition of CASK expression, which may be potential target for BMSC aging and some age-related disease.

Keywords

Mesenchymal stem cell / Aging / miR-146a / CASK

References

[] Bartel DP. MicroRNAs: Target recognition and regulatory functions. Cell, 2009, 136(2): 215-233, pmcid: 3794896

[] Bi Y, Qiao X, Liu Q, Song S, Zhu K, Qiu X, Zhang X, Jia C, Wang H, Yang Z, Zhang Y, Ji G. Systemic proteomics and miRNA profile analysis of exosomes derived from human pluripotent stem cells. Stem Cell Research & Therapy, 2022, 13(1): 449,

[] Boehm M, Slack F. A developmental timing microRNA and its target regulate life span in C. elegans. Science, 2005, 310(5756): 1954-1957,

[] Bonifacio LN, Jarstfer MB. MiRNA profile associated with replicative senescence, extended cell culture, and ectopic telomerase expression in human foreskin fibroblasts. PLoS ONE, 2010, 5(9): 12489-12489,

[] Bou Kheir T, Futoma-Kazmierczak E, Jacobsen A, Krogh A, Bardram L, Hother C, Grønbæk K, Federspiel B, Lund AH, Friis-Hansen L. miR-449 inhibits cell proliferation and is down-regulated in gastric cancer. Molecular Cancer, 2011, 10: 29, pmcid: 3070685

[] Bustos ML, Luai H, Kapetanaki MG, Lino-Cardenas CL, Lyle M. Aging mesenchymal stem cells fail to protect because of impaired migration and anti-inflammatory response. American Journal of Respiratory and Critical Care Medicine, 2014, 189(7): 787-798, pmcid: 4061541

[] Cai Y, Song W, Li J, Jing Y, Liang C, Zhang L, Zhang X, Zhang W, Liu B, An Y, Li J, Tang B, Pei S, Wu X, Liu Y, Zhuang CL, Ying Y, Dou X, Chen Y, Xiao FH, Li D, Yang R, Zhao Y, Wang Y, Wang L, Li Y, Ma S, Wang S, Song X, Ren J, Zhang L, Wang J, Zhang W, Xie Z, Qu J, Wang J, Xiao Y, Tian Y, Wang G, Hu P, Ye J, Sun Y, Mao Z, Kong QP, Liu Q, Zou W, Tian XL, Xiao ZX, Liu Y, Liu JP, Song M, Han JJ, Liu GH. The landscape of aging. Science China Life Sciences, 2022, 65(12): 2354-2454, pmcid: 9446657

[] Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease. Nature, 2019, 571(7766): 489-499,

[] De D, Karmakar P, Bhattacharya D. Stem cell aging and regenerative medicine. Advances in Experimental Medicine and Biology, 2021, 1326: 11-37,

[] Demirel-Yalciner T, Sozen E, Ozer NK. Endoplasmic reticulum stress and miRNA impairment in aging and age-related diseases. Front Aging, 2022, 2: 790702, pmcid: 9261320

[] Duan R, Fu Q, Sun Y, Li Q. Epigenetic clock: A promising biomarker and practical tool in aging. Ageing Research Reviews, 2022, 81: 101743,

[] Fabiola O, Raffaella L, Rina R, Fiorella M, Maria RR. MiR-146a as marker of senescence-associated pro-inflammatory status in cells involved in vascular remodeling. Age, 2013, 35(4): 1157-1172,

[] Ghafouri-Fard S, Abak A, Talebi SF, Shoorei H, Branicki W, Taheri M, Akbari DN. Role of miRNA and lncRNAs in organ fibrosis and aging. Biomedicine & Pharmacotherapy, 2021, 143: 112132,

[] Guo Y, Jia X, Cui Y, Song Y, Wang S, Geng Y, Li R, Gao W, Fu D. Sirt3-mediated mitophagy regulates AGEs-induced BMSCs senescence and senile osteoporosis. Redox Biology, 2021, 41: 101915, pmcid: 7930642

[] Kasper G, Mao L, Geissler S, Draycheva A, Trippens J, Kühnisch J, Tschirschmann M, Kaspar K, Perka C, Duda GN, Klose J. Insights into mesenchymal stem cell aging: Involvement of antioxidant defense and actin cytoskeleton. Stem Cells, 2009, 27(6): 1288-1297,

[] Li N, Muthusamy S, Liang R, Sarojini H, Wang E. Increased expression of miR-34a and miR-93 in rat liver during aging, and their impact on the expression of Mgst1 and Sirt1. Mechanisms of Ageing and Development, 2011, 132(3): 75-85,

[] Liu J, Gao J, Liang Z, Gao C, Niu Q, Wu F, Zhang L. Mesenchymal stem cells and their microenvironment. Stem Cell Research & Therapy, 2022, 13(1): 429,

[] Liu Y, Liu Y, Guo Y, Xu L, Wang H. Phlorizin exerts potent effects against aging induced by D-galactose in mice and PC12 cells. Food & Function, 2021, 12(5): 2148-2160,

[] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell, 2023, 186(2): 243-278,

[] Mortazavi-Jahromi SS, Aslani M, Mirshafiey A. A comprehensive review on miR-146a molecular mechanisms in a wide spectrum of immune and non-immune inflammatory diseases. Immunology Letters, 2020, 227: 8-27,

[] Papathanasiou I, Trachana V, Mourmoura E, Tsezou A. DNA methylation regulates miR-140-5p and miR-146a expression in osteoarthritis. Life Sciences, 2019, 228: 274-284,

[] Qi J, Su YY, Sun RJ, Zhang F, Luo XF, Yang ZC, Luo XD. CASK inhibits ECV304 cell growth and interacts with Id1. Biochemical and Biophysical Research Communications, 2005, 328(2): 517-521,

[] Rudolph KL. Stem cell aging. Mechanisms of Ageing and Development, 2021, 193: 111394,

[] So AY, Jung JW, Lee S, Kim HS, Kang KS. DNA methyltransferase controls stem cell aging by regulating BMI1 and EZH2 through microRNAs. PLoS ONE, 2011, 6(5): e19503, pmcid: 3091856

[] Sun R, Su Y, Zhao X, Qi J, Luo X, Yang Z, Yao Y, Luo X, Xia Z. Human calcium/calmodulin-dependent serine protein kinase regulates the expression of p21 via the E2A transcription factor. The Biochemical Journal, 2009, 419(2): 457-466,

[] Yamakawa H, Kusumoto D, Hashimoto H, Yuasa S. Stem cell aging in skeletal muscle regeneration and disease. International Journal of Molecular Sciences, 2020, 21(5): 1830, pmcid: 7084237

[] Yang K, Lin L, Yuan F, Li X, Liu Z, Lan X, Wang Y, Ren Y, Li J, Chen Y. Two heterozygous mutations in the calcium/calmodulin-dependent serine protein kinase gene (CASK) in cases with developmental disorders. Molecular Genetics & Genomic Medicine, 2022, 10(11): e2065,

[] Ye M, Liu J, Deng G, Cai X, Zhang X, Yao L, Wu J, He X, Peng D, Yu N. Protective effects of Dendrobium huoshanense polysaccharide on D-gal induced PC12 cells and aging mice, in vitro and in vivo studies. Journal of Food Biochemistry, 2022, 46(12): e14496,

[] Zhang H, Shang H, Wang Z, Li K. Associations of miRNA-146a and miRNA-223 with rheumatoid arthritis and their predictive values. Int J Gen Med, 2023, 16: 3211-3218, pmcid: 10402887

[] Zhang H, Zheng W, Li D, Zheng J. miR-146a-5p promotes chondrocyte apoptosis and inhibits autophagy of osteoarthritis by targeting NUMB. Cartilage, 2021, 13(2): 1467S-1477S, pmcid: 8804840

[] Zhang L, Lu Q, Chang C. Epigenetics in health and disease. Advances in Experimental Medicine and Biology, 2020, 1253: 3-55,

[] Zhang L, Zhou J, Xu M, Yuan G. Exploration of the Hsa-miR-1587-protein interaction and the inhibition to CASK. International Journal of Molecular Sciences, 2021, 22(19): 10716, pmcid: 8509502

[] Zhao T, Li J, Chen AF. MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1. American Journal of Physiology, Endocrinology and Metabolism, 2010, 299(1): 110-116,

[] Zhu J, Yang S, Qi Y, Gong Z, Zhang H, Liang K, Shen P, Huang YY, Zhang Z, Ye W, Yue L, Fan S, Shen S, Mikos AG, Wang X, Fang X. Stem cell-homing hydrogel-based miR-29b-5p delivery promotes cartilage regeneration by suppressing senescence in an osteoarthritis rat model. Science Advances, 2022, 8(13): eabk0011, pmcid: 8967232

[] Zhu Y, Liu T, Song K, Fan X, Ma X, Cui Z. Adipose-derived stem cell: A better stem cell than BMSC. Cell Biochemistry and Function, 2008, 26(6): 664-675,

Funding

Innovative Research Group Project of the National Natural Science Foundation of China(82272292)