The Source of Your Mesenchymal Stem Cells Matters

Mesenchymal stem cells (MSCs) are found throughout the body. The most well-known source of MSCs is the bone marrow, and bone marrow MSCs are sometimes called “stromal cells,” because they compose a major part of the bone marrow stroma. In bone marrow, the stroma does not directly participate in making blood cells, but it greatly influences blood cell making by providing the proper microenvironment for blood cell making. Bone marrow MSCs produce a host of molecules called “cytokines” that have a significant effect on blood cell production.

However, bone marrow is not the only source of MSCs. MSCs are also found in fat tissue, liver and connective tissue, blood vessels, and umbilical cord. Are all these MSCs the same? This is not a trivial question because regenerative medicine often requires cells with various capacities. Bone treatments require cells that are the best at making bone tissue, heart treatments require cells that are the best at making heart muscle, and vascular disorders require cells that are the best at making blood vessels. Physicians must know the precise abilities of the cells available to them so that they can select the most effective treatment. Therefore, it is incumbent on scientists to properly characterize MSCs from different sources in order to determine what they can and cannot do. It is also important to establish it MSCs from multiple sources are all the same or have genuinely distinct properties.

A paper in the journal Stem Cells and Development examines MSCs from bone marrow and umbilical cord connective tissue (known as Warton’s Jelly) and extensively characterizes them (Hsieh, et al., Stem Cells and Development 2010, 19(12): 1895-910). The differences between these two cell populations are somewhat surprising.

Jui-Yu Hsieh,and his colleagues at National Yang-Ming University, Taipei, Taiwan subjected MSCs from bone marrow and umbilical cord to differentiation tests and examined the gene expression profile from both cell populations. They discovered that both bone marrow MSCs and umbilical cord MSCs had the same cell surface proteins.  However, the similarities ended there.  Bone marrow MSCs were superior to umbilical cord MSCs when it came to forming fat cells. The bone marrow MSCs showed a higher proportion of the cells forming functional fat cells and bone marrow MSCs also expressed fat cell-specific genes much more robustly than umbilical cord MSCs.

Next, this research group dissected the genes made by both cell populations. In this case, the results showed marked differences between the two cell types. Umbilical cord MSCs expressed more neural genes than their bone marrow counterparts, and also expressed several genes involved in making blood vessels. Umbilical cord MSCs also made more of the genes typically expressed in embryonic stem cells. This suggests that umbilical cord MSCs should grow better in culture than bone marrow MSCs, and in growth comparisons in culture, umbilical cord MSCs substantially outgrew bone marrow MSCs. Bone marrow MSCs, on the other hand, made lots of genes involved with making bone tissue, and also expressed genes involved in the immune system.

In order to determine if the gene expression differences between these MSCs translated into behavioral differences in culture, the two populations of MSCs were grown in culture and subjected to protocols to differentiate them into bone. As expected, the bone marrow MSCs greatly outperformed the umbilical cord MSCs when it came to bone differentiation. Likewise, when the two different cell populations were tested for activating the immune system of a host animal, the bone marrow MSCs were much more easily recognized by the immune system of the host animal than their umbilical cord counterparts.

There are several controversies that have emerged with the publication of this paper.  First of all, an earlier paper (Clavarella, et al., Stem Cells and Development 2009, 18: 1211-20) showed that umbilical cord MSCs formed bone as well as bone marrow MSCs.  However, in this paper, a side-by-side comparison was not done, which suggests that the results reported in this earlier paper are not as trustworthy as in this later work.  Secondly, the cell culture results in the later paper exactly parallel the gene expression data.  Also, another publication (Ishige, et al., International Journal of Hematology 2009, 90: 261-9) showed that umbilical cord stem cells taken from Warton’s Jelly possess the lowest capacity to form bone tissue in comparison to MSCs taken from umbilical veins or arteries.  This further corroborates the data in this later paper.

These data from this paper confirms something that clinicians have observed time and time again; namely that bone marrow MSCs are the best material for repairing joints and other musculoskeletal conditions. Also, this paper definitively demonstrates the vast gene expression differences between these two populations of MSCs. While several papers have shown distinct differentiation differences between various populations of MSCs from different sources, this paper shows that the profound differences in gene expression underlay these biological differences.  Furthermore, this work establishes that where you get your MSCs matters when it comes to using them for regenerative medicine.