Secreted microvesicular miR-31 inhibits osteogenic differentiation of mesenchymal stem cells

Abstract

SummaryDamage to cells and tissues is one of the driving forces of aging and age‐related diseases. Various repair systems are in place to counteract this functional decline. In particular, the property of adult stem cells to self‐renew and differentiate is essential for tissue homeostasis and regeneration. However, their functionality declines with age (Rando, 2006). One organ that is notably affected by the reduced differentiation capacity of stem cells with age is the skeleton. Here, we found that circulating microvesicles impact on the osteogenic differentiation capacity of mesenchymal stem cells in a donor‐age‐dependent way. While searching for factors mediating the inhibitory effect of elderly derived microvesicles on osteogenesis, we identified miR‐31 as a crucial component. We demonstrated that miR‐31 is present at elevated levels in the plasma of elderly and of osteoporosis patients. As a potential source of its secretion, we identified senescent endothelial cells, which are known to increase during aging in vivo (Erusalimsky, 2009). Endothelial miR‐31 is secreted within senescent cell‐derived microvesicles and taken up by mesenchymal stem cells where it inhibits osteogenic differentiation by knocking down its target Frizzled‐3. Therefore, we suggest that microvesicular miR‐31 in the plasma of elderly might play a role in the pathogenesis of age‐related impaired bone formation and that miR‐31 might be a valuable plasma‐based biomarker for aging and for a systemic environment that does not favor cell‐based therapies whenever osteogenesis is a limiting factor.

MicroRNA‐31a‐5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment

“…It has been reported that miR‐31a‐5p negatively regulates skeletogenesis and osteogenesis (Deng, Wu et al., 2013; Jin et al., 2016; Stepicheva, & Song, 2015; Weilner et al., 2016). Previous studies also demonstrated that decreased stemness and increased senescence are the primary causes of declines in osteogenic differentiation of BMSCs (Fehrer, & Lepperdinger, 2005; Zhou et al., 2016).…”

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

“…Another limitation of this study is that miRNA expression levels of miR-188-3p, miR-382-3p, and miR-550a-5p in hASCs are endogenously very low, and that we could not observe any functional effects on osteogenic and adipogenic differentiation, following miR-knockdown of these three miRNAs, although we used a robust and well-working miRNA knockdown protocol including positive controls. (54) In summary, identifying and evaluating patients at increased risk for diabetes-related or osteoporosis-related fragility fractures is critical to disease prevention and management. Our results suggest that circulating miRNAs are indicative of fragility fractures in T2D and in osteoporotic women and that generating comprehensive sets of highly discriminatory miRNA-signatures can help identifying novel and biologically promising miRNAs which can be then subjected to further in vitro testing.…”

“…For osteogenic differentiation, alkaline phosphatase enzyme activity (ALP) and extent of mineralization via Alizarin red staining were measured as early and late markers of osteogenesis using standard methodology. (53,54) Because both assays were not normalized by cell number, we measured RUNX2 and ALP mRNA levels normalized by GAPDH in miR-transfected hASCs 6 days after osteogenic induction as additional, cell-number corrected markers of osteogenic differentiation (see Supporting Fig. 6).…”

Is microRNA-31 a key regulator of breast tumorigenesis?

“…Moreover, under physiological conditions miRNA-31 was identified as a significant regulator of adult muscle and mesenchymal mammary progenitor stem cells and also is involved in diverse biological processes including fertility, embryonic development and bone formation (3)(4)(5). Interestingly, in neoplastic diseases miRNA-31 is either considered as a tumor-suppressor miRNA or oncogenic miRNA.…”