miR‐10a restores human mesenchymal stem cell differentiation by repressing KLF4

Abstract

miRNAs have recently been shown to play a significant role in human aging. However, data demonstrating the effects of aging-related miRNAs in human mesenchymal stem cells (hMSCs) are limited. We observed that hMSC differentiation decreased with aging. We also identified that miR-10a expression was significantly decreased with age by comparing the miRNA expression of hMSCs derived from young and aged individuals. Therefore, we hypothesized that the downregulation of miR-10a may be associated with the decreased differentiation capability of hMSCs from aged individuals. Lentiviral constructs were used to up- or downregulate miR-10a in young and old hMSCs. Upregulation of miR-10a resulted in increased differentiation to adipogenic, osteogenic, and chondrogenic lineages and in reduced cell senescence. Conversely, downregulation of miR-10a resulted in decreased cell differentiation and increased cell senescence. A chimeric luciferase reporter system was generated, tagged with the full-length 3′-UTR region of KLF4 harboring the seed-matched sequence with or without four nucleotide mutations. These constructs were cotransfected with the miR-10a mimic into cells. The luciferase activity was significantly repressed by the miR-10a mimic, proving the direct binding of miR-10a to the 3′-UTR of KLF4. Direct suppression of KLF4 in aged hMSCs increased cell differentiation and decreased cell senescence. In conclusion, miR-10a restores the differentiation capability of aged hMSCs through repression of KLF4. Aging-related miRNAs may have broad applications in the restoration of cell dysfunction caused by aging. J. Cell. Physiol. 228: 2324–2336, 2013. © The Authors. Published by Wiley Periodicals, Inc.

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue–Derived Mesenchymal Stem Cells In Vitro

“…(72) In this study, we observed higher levels of miR-486-5p, miR-378a-5p, and miR-196b-5p in DMFx women compared to fracture-free DM subjects. Similar expression pattern and fold changes were reported by Li and colleagues, (73) who compared miRNA expression levels in bone marrow mesenchymal stem cells from 80-year-olds to those of young, 30-year-old human subjects. Our DFMx patients are not significantly, but are on average three years older than our DM subjects, which could explain the higher expression-rate of senescence-related miRNAs in their serum.…”

miR-135a modulates tendon stem/progenitor cell senescence via suppressing ROCK1

“…Induction of premature senescence in HDFs was accompanied by upregulation of p16 INK4a ; an important downstream target of BMI1 and a major regulator of senescence [23]. It has been reported that miR-141-3p, miR-10a and miR-199b-5p regulate senescence in human mesenchymal stem cells by targeting ZMPSTE24, KLF4 or LAMC networks, respectively [24][25][26]. Thus, we focused on miRNA as a candidate regulator of ROCK1 during TSPC aging.…”

Differential regulated microRNA by wild type and mutant p53 in induced pluripotent stem cells

“…This suggests that these miRNAs are regulated by p53 during reprogramming by complex mechanisms. An example is miR-10a that on the one hand is known to promote the differentiation of human mesenchymal stem cells 69 and on the other contributes to cancer development. 70, 71 This miR is downregulated during reprogramming of p53 wt cells, but upregulated in cells expressing mutant p53.…”