Restoration of tissue homeostasis by controlling stem cell aging is a promising therapeutic approach for geriatric disorders. The molecular mechanisms underlying age-related dysfunctions of specific types of adult tissue stem cells (TSCs) have been studied, and various microRNAs were recently reported to be involved. However, the central roles of microRNAs in stem cell aging remain unclear. Interest in this area was sparked by murine heterochronic parabiosis experiments, which demonstrated that systemic factors can restore the functions of TSCs. Age-related changes in secretion profiles, termed the senescence-associated secretory phenotype, have attracted attention, and several pro- and anti-aging factors have been identified. On the other hand, many microRNAs are linked with the age-dependent dysregulations of various physiological processes, including “stem cell aging.” This review summarizes microRNAs that appear to play common roles in stem cell aging. Keywords: Stem cell aging, microRNA, miR-17, miR-125b, miR-181a, SASP Background fashion [19, 20]. Several lines of evidence indicated Overcoming age-related diseases and elongating the that age-related TSC dysfunctions and tissue-level healthy lifespan are emerging issues for aging soci- pathologies can be improved by manipulating (reversing) eties. Dysfunctions of aged tissue stem cells (TSCs) cell-extrinsic/systemic conditions, at least in part. contribute to loss of tissue homeostasis, including re- We previously identified growth differentiation factor ductions in lymphopoiesis and the long-term repopu- 6 (Gdf6; also known as Bmp13 and CDMP-2) as a regen- lating abilities of hematopoietic stem/progenitor cells erative factor secreted by young MSCs [21, 22]. Upregu- (HSCs) [1, 2], the muscle repair capacity of skeletal lation of human GDF6 restores the differentiation muscle satellite cells , and the multipotency of potential of old MSCs in vitro and reverses multiple age- mesenchymal stem/stromal cells (MSCs) . The res- related pathologies in vivo. miR-17 and its paralogues toration of TSC functions in murine heterochronic miR-106a and 106b (miR-17/106) regulate not only dif- parabiosis experiments triggered interest in the reju- ferentiation potential but also expression of some venation of aged TSCs . Thereafter, several pro- secretory factors, including Gdf6, and are implicated in aging [6–12] and anti-aging [13–16] systemic factors the decline of these functions with age. Many micro- were identified, although some of the findings are RNAs are associated with age-related dysfunctions of conflicting . Senescent cells secrete a myriad of several types of TSCs. Here, we review microRNAs, inflammatory factors, referred to as the senescence- which are commonly downregulated with age and in- associated secretory phenotype (SASP) . Clearance duced dysregulation of cytogenesis, proliferation, and in- of senescent cells delays the induction of various geri- flammation in multiple TSCs, and discuss functional atric pathologies, supporting the concept that the similarities of microRNAs across different types of TSCs SASP promotes aging in a non-cell-autonomous in aging. * Correspondence: firstname.lastname@example.org Department of Anatomy, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Watanabe et al. Inflammation and Regeneration (2018) 38:9 Page 2 of 5 miR-17 family (miR-17-92a, 106b-25, and 106a-363 activates and is activated by the NF-κB pathway [38, 39] clusters) is sometimes regarded as an “inflamma-miR,” which is miR-17 family members play essential and pleiotropic implicated in the regulation of immune and inflamma- roles in development, metabolism, diseases, tumorigen- tory responses . miR-125b directly suppresses p53 esis, and aging [23, 24]. We first identified miR-17/106 expression in developing NSCs. miR-125b is expressed family members as key regulators of the neurogenic-to- throughout zebrafish embryos and is enriched in the gliogenic switch in developing neural stem/progenitor brain, while loss of miR-125b elevates p53 expression cells (NSCs) by controlling the “competence” necessary and triggers p53-dependent apoptosis in these embryos for NSCs to respond to gliogenic cell-extrinsic signals . miR-125b is also expressed in MSCs , epider- [25, 26]. Next, we found that downregulation of miR-17/ mal stem cells , and some types of tumor cells [44– 106 induces a decline in differentiation potential and 48]. Interestingly, lin-4,a Caenorhabditis elegans homo- dysregulated expression of secretory factors in old MSCs log of miR-125b, is a heterochronic gene and generates . Another group also reported a relationship between the temporal pattern of many cell lineages during devel- miR-17/106 and an age-dependent decrease in the osteo- opment , and is related to lifespan and tissue aging genic potential of MSCs . miR-17/106 also regulate via its control of the insulin/insulin-like growth factor–1 the proliferation and development of HSCs [28–30]. pathway . Overexpression of lin-4 elongates lifespan, Other reports studied the impact of miR-17 overexpres- whereas loss-of mutation accelerates tissue aging and sion in vivo. Transgenic mice expressing miR-17 exhibit shortens it. delayed tissue growth and have an elongated lifespan [31, 32]. Epidemiologic studies reported that miR-17 miR-181 family (miR-181a/b/c/d) family members are upregulated in centenarians, which Chronic inflammation accelerates systemic aging . supports the hypothesis that these microRNAs are im- miR-181 family members have anti-inflammatory func- portant for the young healthy conditions and involved in tions and are categorized as inflamma-miRs, together human aging [33, 34]. with miR-125b . miR-181 regulates the differenti- ation of multiple types of TSCs, such as HSCs , miR-125b myoblasts (activated progenitor cells) , MSCs , A myeloid skewing phenotype and a decline in engraft- and some types of cancer stem cells [54–56]. We con- ment capability have long been recognized as age-related firmed that miR-181 family members are downregulated dysfunctions of old HSCs . miR-125b is expressed in with age in multiple TSCs (HSCs, MSCs, and intestinal HSCs, and overexpression of miR-125b predominantly stem cells). However, they continue to be expressed in expands lymphoid-biased HSCs . In addition, miR- differentiated cells and function pleiotropically. The age- 125b can increase the level of myeloid progenitors . dependent decline in miR-181a expression induces func- Both reports showed that miR-125b overexpression in- tional defects in CD4+ T cells . miR-181a is down- creases the engraftment capabilities of HSCs and pro- regulated in old pancreatic beta cells and necessary for genitors in transplantation assays into irradiated mice. their proliferation . Extracellular vesicles derived Moreover, reduction of miR-125b increases expression from brain metastatic cancer cells contain miR-181c and levels of the chemokine CCL4 with age . miR-125b can destroy and pass through the blood-brain barrier Table 1 Functional similarities of microRNAs in different types of TSCs microRNA Differentiation (specification) Proliferation, survival, Secretion and Tumorigenesis Others family and apoptosis inflammation miR-17/106 MSCs (↑Ad, ↑Os) [22, 27] ↑HSCs [28–30] MSCs (↑Gdf6 and etc.)  Lymphoma [28–30] NSCs (↑N, ↓G)  HSCs (↑B, ↑Ly, ↑My) [28–30] miR-125b HSCs (↑Ly, ↑My) [35, 36]MSCs ↑HSCs [35, 36]↑NSCs HSCs (↓CCL4, ↑NF-κB, Breast cancer  ↑HSC engraftment [35, (↑Ad, ↑Os)   ↓TNFAIP3) [37, 39, 40] Hepatocellular 36] Skin stem cells (↓Epi, ↓Oil, ↓HF) ↑Skin stem cells  carcinoma   Leukemia  Skin tumor  Stomach adenocarcinoma  miR-181 HSCs (↑Ly)  ↑Beta cells  HSCs (↓IL-1α, ↓c-fos, ↓NF-κB) Hepatic cancer stem ↑T cell receptor Myoblasts (↑Muscle)   cells  sensitivity  MSCs (↑IL-6)  Breast cancer  ↑Blood-brain barrier Leukemia  destruction  ↑: promotion/positive regulation, ↓: inhibition/negative regulation, Ad: adipocytes, Os: Osteoblasts, N: neurons, G: glial cells, B: B cells, Ly: lymphocytes, My: myeloid cells, Epi: epidermal cells, Oil: oil-gland cells, HF: hair follicle cells Watanabe et al. Inflammation and Regeneration (2018) 38:9 Page 3 of 5 Fig. 1 Schematic diagram of the disruption of microRNA-mediated stem cell competence. Decline in microRNAs for regulation of stem cell functions induces disruption of proper stem cell competence and dysfunctions . The critical roles of miR-181 in age-related cell- signal transduction and reflect abnormal phenotypes to sig- intrinsic dysfunctions of TSCs are unclear. The old TSCs nals (Fig. 1). All miR-17, miR-125b, miR-181 family mem- with downregulated miR-181 family members would bers are downregulated various old TSCs and generate abnormal somatic cells, which have something downregulation of them suppresses cytogenesis, prolifera- dysfunctions, and these cells may contribute to the dis- tion, and secretion of homeostatic factors and promotes turbance of tissue homeostasis. inflammation and tumorigenesis (Table 1). Commonality of microRNA functions among various types Conclusions of TSCs Some microRNAs have similar functions in different Recent studies have revealed that a part of microRNAs ap- types of TSCs. Downregulation of these specific- pear to play common roles in stem cell aging (Table 1). In microRNAs induces similar age-related dysfunctions of fact, many microRNAs, including miR-17 family, miR- TSCs. These microRNAs may define the “young compe- 125b, and miR-181 family members, show similar expres- tence” by specifying the signal pathways with suppres- sion pattern, namely they are expressed at higher levels dur- sion of their regulon, including signal mediators and ing proliferating phase and downregulated with age. This is transcription factors. Further investigation of the roles of supported by a report concerning the classification of the other microRNAs in stem cell aging will help to tumor cells derived from various tissues based on their elucidate the central molecular machinery of the aging microRNA, not their mRNA, expression profiles, suggest- and develop the next-generation therapeutic methods ing that the existence of functionally common microRNAs, for geriatric diseases. at least, for proliferation and undifferentiated states . Abbreviations We have focused on microRNA-mediated “competence Gdf6: Growth differentiation factor 6; HSCs: Hematopoietic stem/progenitor regulation,” which is responsible for the responsiveness to cells; miR-17/106: miR-17, miR-106a, and 106b; MSCs: Mesenchymal stem/ the various cell-extrinsic signals, as the fundamental ma- stromal cells; NSCs: Neural stem/progenitor cells; SASP: Senescence- associated secretory phenotype; TSCs: Tissue stem cells chinery controlling the properties of TSCs, and miR-17 family membersare keyregulatorsinthiscontext [22, 25, Funding 61]. In our previous study, we revealed that miR-17/106 This work was supported by the Uehara Memorial Foundation and JSPS KAKENHI Grant Number JP16K08602. switches the usages of JAK-STAT and BMP pathways from neurogenic to gliogenic signals . In young states, micro- Authors’ contributions RNAs regulate signal transduction correctly. Downregula- HNK drafted and completed the manuscript. All authors read and approved tion of microRNAs with age should induce deregulation of the final manuscript. Watanabe et al. Inflammation and Regeneration (2018) 38:9 Page 4 of 5 Ethics approval and consent to participate 18. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Not applicable. Desprez PY, Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 2008;6(12):2853–68. Competing interests 19. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, The authors declare that they have no competing interests. Kirkland JL, van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479(7372):232–6. 20. Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Publisher’sNote Jeganathan KB, Verzosa GC, Pezeshki A, et al. Naturally occurring p16- Springer Nature remains neutral with regard to jurisdictional claims in positive cells shorten healthy lifespan. Nature. 2016; published maps and institutional affiliations. 21. Hisamatsu D, Naka-Kaneda H. Reversing multiple age-related pathologies by controlling the senescence-associated secretory phenotype of stem cells. Received: 1 February 2018 Accepted: 6 April 2018 Neural Regen Res. 2016;11(11):1746–7. 22. Hisamatsu D, Ohno-Oishi M, Nakamura S, Mabuchi Y, Naka-Kaneda H. Growth differentiation factor 6 derived from mesenchymal stem/stromal References cells reduces age-related functional deterioration in multiple tissues. Aging 1. Sudo K, Ema H, Morita Y, Nakauchi H. Age-associated characteristics of (Albany NY). 2016;8(6):1259–75. murine hematopoietic stem cells. J Exp Med. 2000;192(9):1273–80. 23. Mogilyansky E, Rigoutsos I. The miR-17/92 cluster: a comprehensive update 2. Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, Weissman IL. on its genomics, genetics, functions and increasingly important and Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl numerous roles in health and disease. Cell Death Differ. 2013;20(12): Acad Sci U S A. 2005;102(26):9194–9. 1603–14. 3. Renault V, Thornell LE, Eriksson PO, Butler-Browne G, Mouly V. Regenerative 24. Dellago H, Bobbili MR, Grillari J. MicroRNA-17-5p: at the crossroads of potential of human skeletal muscle during aging. Aging Cell. 2002; Cancer and aging - a mini-review. Gerontology. 2017;63(1):20–8. 1(2):132–9. 25. Naka-Kaneda H, Nakamura S, Igarashi M, Aoi H, Kanki H, Tsuyama J, 4. Zhou S, Greenberger JS, Epperly MW, Goff JP, Adler C, Leboff MS, Glowacki Tsutsumi S, Aburatani H, Shimazaki T, Okano H. The miR-17/106-p38 axis is a J. Age-related intrinsic changes in human bone-marrow-derived key regulator of the neurogenic-to-gliogenic transition in developing neural mesenchymal stem cells and their differentiation to osteoblasts. Aging Cell. stem/progenitor cells. Proc Natl Acad Sci U S A. 2014;111(4):1604–9. 2008;7(3):335–43. 26. Shimazaki T, Okano H. Heterochronic microRNAs in temporal specification 5. Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA. of neural stem cells: application toward rejuvenation. NPJ Aging Mech Dis. Rejuvenation of aged progenitor cells by exposure to a young systemic 2016;2:15014. environment. Nature. 2005;433(7027):760–4. 27. Liu W, Qi M, Konermann A, Zhang L, Jin F, Jin Y. The p53/miR-17/Smurf1 6. Acosta JC, O'Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli pathway mediates skeletal deformities in an age-related model via M, Da Costa M, Brown C, Popov N, et al. Chemokine signaling via the inhibiting the function of mesenchymal stem cells. Aging (Albany NY). 2015; CXCR2 receptor reinforces senescence. Cell. 2008;133(6):1006–18. 7(3):205–18. 7. Salminen A, Ojala J, Kaarniranta K, Haapasalo A, Hiltunen M, Soininen H. 28. Ventura A, Young AG, Winslow MM, Lintault L, Meissner A, Erkeland SJ, Astrocytes in the aging brain express characteristics of senescence- Newman J, Bronson RT, Crowley D, Stone JR, et al. Targeted deletion reveals associated secretory phenotype. Eur J Neurosci. 2011;34(1):3–11. essential and overlapping functions of the miR-17 through 92 family of 8. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, miRNA clusters. Cell. 2008;132(5):875–86. Ding Z, Eggel A, et al. The ageing systemic milieu negatively regulates 29. Meenhuis A, van Veelen PA, de Looper H, van Boxtel N, van den Berge IJ, neurogenesis and cognitive function. Nature. 2011;477(7362):90–4. Sun SM, Taskesen E, Stern P, de Ru AH, van Adrichem AJ, et al. MiR-17/20/ 9. Naito AT, Sumida T, Nomura S, Liu ML, Higo T, Nakagawa A, Okada K, Sakai 93/106 promote hematopoietic cell expansion by targeting sequestosome T, Hashimoto A, Hara Y, et al. Complement C1q activates canonical Wnt 1-regulated pathways in mice. Blood. 2011;118(4):916–25. signaling and promotes aging-related phenotypes. Cell. 2012;149(6): 30. Li Y, Vecchiarelli-Federico LM, Li YJ, Egan SE, Spaner D, Hough MR, Ben- 1298–313. David Y. The miR-17-92 cluster expands multipotent hematopoietic 10. Jurk D, Wilson C, Passos JF, Oakley F, Correia-Melo C, Greaves L, Saretzki G, progenitors whereas imbalanced expression of its individual oncogenic Fox C, Lawless C, Anderson R, et al. Chronic inflammation induces telomere miRNAs promotes leukemia in mice. Blood. 2012;119(19):4486–98. dysfunction and accelerates ageing in mice. Nat Commun. 2014;2:4172. 31. Shan SW, Lee DY, Deng Z, Shatseva T, Jeyapalan Z, Du WW, Zhang Y, Xuan 11. Smith LK, He Y, Park JS, Bieri G, Snethlage CE, Lin K, Gontier G, Wabl R, JW, Yee SP, Siragam V, et al. MicroRNA MiR-17 retards tissue growth and Plambeck KE. Udeochu J et al: beta2-microglobulin is a systemic pro-aging represses fibronectin expression. Nat Cell Biol. 2009;11(8):1031–8. factor that impairs cognitive function and neurogenesis. Nat Med. 2015; 32. Du WW, Yang W, Fang L, Xuan J, Li H, Khorshidi A, Gupta S, Li X, Yang BB. 12. Fry CS, Kirby TJ, Kosmac K, McCarthy JJ, Peterson CA. Myogenic progenitor miR-17 extends mouse lifespan by inhibiting senescence signaling cells control extracellular matrix production by fibroblasts during skeletal mediated by MKP7. Cell Death Dis. 2014;5:e1355. muscle hypertrophy. Cell Stem Cell. 2017;20(1):56–69. 33. Serna E, Gambini J, Borras C, Abdelaziz KM, Belenguer A, Sanchis P, Avellana 13. Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, JA, Rodriguez-Manas L, Vina J. Centenarians, but not octogenarians, up- Sinha M, Dall'Osso C, Khong D, Shadrach JL, et al. Growth differentiation regulate the expression of microRNAs. Sci Rep. 2012;2:961. factor 11 is a circulating factor that reverses age-related cardiac 34. Gombar S, Jung HJ, Dong F, Calder B, Atzmon G, Barzilai N, Tian XL, Pothof hypertrophy. Cell. 2013;153(4):828–39. J, Hoeijmakers JH, Campisi J, et al. Comprehensive microRNA profiling in B- 14. Elabd C, Cousin W, Upadhyayula P, Chen RY, Chooljian MS, Li J, Kung S, cells of human centenarians by massively parallel sequencing. BMC Jiang KP, Conboy IM. Oxytocin is an age-specific circulating hormone that is Genomics. 2012;13:353. necessary for muscle maintenance and regeneration. Nat Commun. 2014; 35. Ooi AG, Sahoo D, Adorno M, Wang Y, Weissman IL, Park CY. MicroRNA-125b 5:4082. expands hematopoietic stem cells and enriches for the lymphoid-balanced 15. Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz and lymphoid-biased subsets. Proc Natl Acad Sci U S A. 2010;107(50): GR, Chen JW, Lee RT, Wagers AJ, Rubin LL. Vascular and neurogenic 21505–10. rejuvenation of the aging mouse brain by young systemic factors. Science. 36. O'Connell RM, Chaudhuri AA, Rao DS, Gibson WS, Balazs AB, Baltimore D. 2014;344(6184):630–4. MicroRNAs enriched in hematopoietic stem cells differentially regulate long- 16. Sinha M, Jang YC, Oh J, Khong D, Wu EY, Manohar R, Miller C, Regalado SG, term hematopoietic output. Proc Natl Acad Sci U S A. 2010;107(32): Loffredo FS, Pancoast JR, et al. Restoring systemic GDF11 levels reverses 14235–40. age-related dysfunction in mouse skeletal muscle. Science. 2014;344(6184): 649–52. 37. Cheng NL, Chen X, Kim J, Shi AH, Nguyen C, Wersto R, Weng NP. 17. Egerman MA, Cadena SM, Gilbert JA, Meyer A, Nelson HN, Swalley SE, MicroRNA-125b modulates inflammatory chemokine CCL4 expression in Mallozzi C, Jacobi C, Jennings LL, Clay I, et al. GDF11 increases with age and immune cells and its reduction causes CCL4 increase with age. Aging Cell. inhibits skeletal muscle regeneration. Cell Metab. 2015;22(1):164–74. 2015;14(2):200–8. Watanabe et al. Inflammation and Regeneration (2018) 38:9 Page 5 of 5 38. Tan G, Niu J, Shi Y, Ouyang H, Wu ZH. NF-kappaB-dependent microRNA- containing extracellular vesicles capable of destructing blood-brain barrier. 125b up-regulation promotes cell survival by targeting p38alpha upon Nat Commun. 2015;6:6716. ultraviolet radiation. J Biol Chem. 2012;287(39):33036–47. 60. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero 39. Kim SW, Ramasamy K, Bouamar H, Lin AP, Jiang D, Aguiar RC. MicroRNAs A, Ebert BL, Mak RH, Ferrando AA, et al. MicroRNA expression profiles miR-125a and miR-125b constitutively activate the NF-kappaB pathway by classify human cancers. Nature. 2005;435(7043):834–8. targeting the tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20). 61. Naka H, Nakamura S, Shimazaki T, Okano H. Requirement for COUP-TFI and Proc Natl Acad Sci U S A. 2012;109(20):7865–70. II in the temporal specification of neural stem cells in CNS development. Nat Neurosci. 2008;11(9):1014–23. 40. Rippo MR, Olivieri F, Monsurro V, Prattichizzo F, Albertini MC, Procopio AD. MitomiRs in human inflamm-aging: a hypothesis involving miR-181a, miR- 34a and miR-146a. Exp Gerontol. 2014;56:154–63. 41. Le MT, Teh C, Shyh-Chang N, Xie H, Zhou B, Korzh V, Lodish HF, Lim B. MicroRNA- 125b is a novel negative regulator of p53. Genes Dev. 2009;23(7):862–76. 42. Yu JM, Wu X, Gimble JM, Guan X, Freitas MA, Bunnell BA. Age-related changes in mesenchymal stem cells derived from rhesus macaque bone marrow. Aging Cell. 2011;10(1):66–79. 43. Zhang L, Stokes N, Polak L, Fuchs E. Specific microRNAs are preferentially expressed by skin stem cells to balance self-renewal and early lineage commitment. Cell Stem Cell. 2011;8(3):294–308. 44. Saetrom P, Biesinger J, Li SM, Smith D, Thomas LF, Majzoub K, Rivas GE, Alluin J, Rossi JJ, Krontiris TG, et al. A risk variant in an miR-125b binding site in BMPR1B is associated with breast cancer pathogenesis. Cancer Res. 2009; 69(18):7459–65. 45. Kim JK, Noh JH, Jung KH, Eun JW, Bae HJ, Kim MG, Chang YG, Shen Q, Park WS, Lee JY, et al. Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b. Hepatology. 2013;57(3):1055–67. 46. So AY, Sookram R, Chaudhuri AA, Minisandram A, Cheng D, Xie C, Lim EL, Flores YG, Jiang S, Kim JT, et al. Dual mechanisms by which miR-125b represses IRF4 to induce myeloid and B-cell leukemias. Blood. 2014;124(9): 1502–12. 47. Zhang L, Ge Y, Fuchs E. miR-125b can enhance skin tumor initiation and promote malignant progression by repressing differentiation and prolonging cell survival. Genes Dev. 2014;28(22):2532–46. 48. Kim BC, Jeong HO, Park D, Kim CH, Lee EK, Kim DH, Im E, Kim ND, Lee S, Yu BP, et al. Profiling age-related epigenetic markers of stomach adenocarcinoma in young and old subjects. Cancer Inform. 2015;14:47–54. 49. Lee RC, Feinbaum RL, Ambros V. The C. Elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993; 75(5):843–54. 50. Boehm M, Slack F. A developmental timing microRNA and its target regulate life span in C. Elegans. Science. 2005;310(5756):1954–7. 51. Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303(5654):83–6. 52. Naguibneva I, Ameyar-Zazoua M, Polesskaya A, Ait-Si-Ali S, Groisman R, Souidi M, Cuvellier S, Harel-Bellan A. The microRNA miR-181 targets the homeobox protein Hox-A11 during mammalian myoblast differentiation. Nat Cell Biol. 2006;8(3):278–84. 53. Liu L, Wang Y, Fan H, Zhao X, Liu D, Hu Y, Kidd AR 3rd, Bao J, Hou Y. MicroRNA-181a regulates local immune balance by inhibiting proliferation and immunosuppressive properties of mesenchymal stem cells. Stem Cells. 2012;30(8):1756–70. 54. Ji J, Yamashita T, Budhu A, Forgues M, Jia HL, Li C, Deng C, Wauthier E, Reid LM, Ye QH, et al. Identification of microRNA-181 by genome-wide screening as a critical player in EpCAM-positive hepatic cancer stem cells. Hepatology. 2009;50(2):472–80. 55. Wang Y, Yu Y, Tsuyada A, Ren X, Wu X, Stubblefield K, Rankin-Gee EK, Wang SE. Transforming growth factor-beta regulates the sphere-initiating stem cell-like feature in breast cancer through miRNA-181 and ATM. Oncogene. 2011;30(12):1470–80. 56. Su R, Lin HS, Zhang XH, Yin XL, Ning HM, Liu B, Zhai PF, Gong JN, Shen C, Song L, et al. MiR-181 family: regulators of myeloid differentiation and acute myeloid leukemia as well as potential therapeutic targets. Oncogene. 2015; 34(25):3226–39. 57. Li G, Yu M, Lee WW, Tsang M, Krishnan E, Weyand CM, Goronzy JJ. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat Med. 2012; 58. Tugay K, Guay C, Marques AC, Allagnat F, Locke JM, Harries LW, Rutter GA, Regazzi R. Role of microRNAs in the age-associated decline of pancreatic beta cell function in rat islets. Diabetologia. 2016;59(1):161–9. 59. Tominaga N, Kosaka N, Ono M, Katsuda T, Yoshioka Y, Tamura K, Lotvall J, Nakagama H, Ochiya T. Brain metastatic cancer cells release microRNA-181c-
Inflammation and Regeneration – Springer Journals
Published: Jun 6, 2018
It’s your single place to instantly
discover and read the research
that matters to you.
Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.
All for just $49/month
Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly
Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.
Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.
Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.
All the latest content is available, no embargo periods.
“Hi guys, I cannot tell you how much I love this resource. Incredible. I really believe you've hit the nail on the head with this site in regards to solving the research-purchase issue.”Daniel C.
“Whoa! It’s like Spotify but for academic articles.”@Phil_Robichaud
“I must say, @deepdyve is a fabulous solution to the independent researcher's problem of #access to #information.”@deepthiw
“My last article couldn't be possible without the platform @deepdyve that makes journal papers cheaper.”@JoseServera