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. 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