In a study on the aging bone marrow microenvironment, it was found that, with age, expression of microRNA-141-3p goes way up, while stromal-cell derived factor, or SDF-1, a key signaling molecule that helps stem cells make healthy bone, goes down. This shift, observed in both mouse and human mesenchymal stem cells, was found to result in weaker bones.
These findings were reported last month in the Journal of Gerontology: Biological Sciences by researchers at the Medical College of Georgia at Augusta University. "If you are 20 years old and making great bone, you would still have microRNA-141-3p in your mesenchymal stem cells. But when you are 81 and making weaker bone, you have a lot more of it," explains Dr. Sadanand Fulzele, bone biologist in the department of orthopaedic surgery.
Mesenchymal stem cells can differentiate into the major components of our skeleton: bone-forming osteoblasts, osteocytes, chondrocytes, as well as adipocytes. In addition to regulating the differentiation of stem cells into these cells, SDF-1 has a myriad of other roles including helping mesenchymal stem cells get to the right spot during bone formation and bone repair and protecting cells from the ravages of oxidative stress.
It was SDF-1's clear significance in bone health—and the fact that it declines with age—that got the scientists interested in how it's regulated. They hypothesized that decreasing SDF-1 is at least one way that microRNA-141-3p impacts healthy differentiation of mesenchymal stem cells.
They suspected microRNA-141-3p as a culprit because Fulzele had already found it suppresses a transporter of vitamin C, which is also important for bone health. The scientists also had already found it could hinder that important differentiation of mesenchymal stem cells and knew levels of microRNA-141-3p increase with aging. Their animal studies had indicated that oxidative stress in mesenchymal stem cells decreases SDF-1, and that the signaling molecule could protect those cells from death by oxidative stress.
Putting the pieces together they found that higher oxidative stress elevates microRNA-141-3p expression, which in turn decreases SDF-1 levels. In both mice and human mesenchymal stem cells, they found levels of microRNA-141-3p were low in young cells but levels were tripled or more in older cells. They found essentially the opposite for SDF-1 levels.
When they injected a microRNA-141 mimic inside the stem cells, it essentially created a model of aging and SDF-1 levels again went down. Consequences of that included another shift that normally occurs with age as we make more bone-eating osteoclasts than bone-forming osteoblasts. The shift also resulted in mesenchymal stem cells making more fat, which they tend to do with age because it's easier.
"We have identified a number of microRNAs that change in the bone marrow stem cells with aging and we are going after each one of these to understand how they are working and are they working together or independently," Dr. William D. Hill, a stem cell researcher and author on the paper, adds. "We are starting to take more of a biological systems approach, not just changing one target molecule, but looking at how this network of molecules is changed with age or disease and how we can reach in and sort of reset these different pathways."