New study changes understanding of stem cell development in bone marrow

Until now, it has been assumed that mesenchymal stem cells in the body were more susceptible to turning into fat cells than into bone-building cells. Now, however, a new study by former DDA postdoc Alexander Rauch, working at University of Southern Denmark professor Susanne Mandrup’s laboratory, shows that the opposite is the case. This will influence future research on osteoporosis and other metabolic diseases of the skeleton.

Bone is a highly dynamic structure that is damaged, removed and rebuilt every single day. The older we get, however, the poorer becomes our ability to rebuild our bones. In some people, the rebuilding capacity becomes so bad that they are diagnosed with osteoporosis, a disease characterized by the bones becoming porous, decalcified and brittle, so that fractures occur more easily.

Medication exists today that retards bone degradation to some extent in osteoporosis patients, but this treatment cannot regenerate lost bone mass. This is because researchers still lack answers to some crucial questions on which the development of a bone-building drug will depend.

Hard for stem cells to turn into fat cells

Now, though, it looks as though former DDA postdoc Alexander Rauch, together with a team building on research including work by three other DDA researchers (Naja Zenius Jespersen, Isabel Jepsen and Michaela Tencerova), has moved a small step closer to understanding exactly what takes place at a molecular level when a mesenchymal stem cell decides whether to develop into a bone-building osteoblast or a fat-storing adipocyte. In a new study published in Nature Genetics, they change the previous understanding of the processes taking place at cellular level.

‘What we have found in the new study is that there is a program running in stem cells from bone marrow that inhibits fat cell development, and that a stem cell actually has to do more work to turn into a fat cell than to become a bone-building cell. Until now, we believed that adipocyte differentiation was like an emergency program that activated when the cells had no other opportunity to develop, and that the increased accumulation of fat cells in the bone marrow in older people was due to an ‘accelerator’ that came in and sped up the process of fat cell development. It turns out that this is not the case. So, in our new study, we show that it is more a case of a ‘brake’ on the fat cell program that disappears with age’, explains Alexander Rauch.

Mesenchymal stem cells express many transcription factors that are  important to osteoblastogenesis, i.e. the development of osteoblast cells. On the other hand, these pro-osteoblast transcription factors have a negative effect on fat cell development. The researchers in Susanne Mandrup’s group interpret this as a mechanism ensuring that bone-building processes can be activated quickly, for example if damage occurs. Conversely, the more difficult route from mesenchymal stem cell to fat cell ensures that a single visit to the local burger bar will not lead to severe fat accumulation in the bone marrow.

Many different stem cells in the bone marrow

Researchers in the group found a network of approximately 200 transcription factors, all of which were important – the network quite simply collapses like a house of cards when just one transcription factor is removed. The researchers found that the expression of many transcription factors in the network changes when people are overweight or get older. Similarly, many of these transcription factors are associated with variations in the genome that affect body mass index and bone mineral density. All in all, this network of transcription factors is key to the greater likelihood of a mesenchymal stem cell turning into a bone-building cell than a fat cell and thus ensuring that the bones remain healthy.

It has long been believed that mesenchymal stem cells in the bone marrow are alike, but in reality this is a very heterogeneous population of cells. Some of the cells will be particularly good at bone cell development, for example. The goal now for Alexander Rauch, Research Assistant Professor at the Molecular Endocrinology & Stem Cell Research Unit, Odense University Hospital, and his colleagues, is therefore to identify those stem cells that make an especially big contribution to bone building. To date, very little is known about these cells.

‘We want to look at the cells individually – which cells promote bone building, and which don’t? And are the stem cells different when we get fat, or grow old, or get osteoporosis? We already have stem cells stored in a freezer, and we know that some will make good fat cells, some will make good bone cells, and some cannot be differentiated’, he says.

Possible stem cell transplantation

There are still numerous avenues to explore, however. For example, the clinical studies carried out to date show very varied results. This means that we are not immediately on the brink of a decisive breakthrough in terms of the development of an actual drug to rebuild lost bone mass. Nevertheless, Alexander Rauch is positive, and he also has hypotheses ready for further research in the field.

‘We are certain that the cells have great potential, but we lack understanding of what actually characterizes a mesenchymal stem cell with a particular property. One idea is to describe the genes characteristic of stem cells that are particularly good at bone building, for example. Then you can find molecules on the surface of the cells, and then isolate them with an antibody to these surface molecules. Then, you can transplant the isolated stem cells that are especially good at bone building into a patient who either has osteoporosis or has suffered a bone fracture’, says Alexander Rauch.