MSC give rise to numerous cell types that are present within the bone marrow, including osteoblasts, adipocytes and chondrocytes, while also having an important role within the HSC niche. It is not yet clear if MSCs contribute to the endosteal HSC niche, the perivascular HSC niche or both. MSCs express high levels of cytokine-related genes, with evidence to suggest that the expression of CXCL12, SCF, IL-7 and VCAM-1 is greater from MSCs than from osteoblasts.15, 106
The importance of MSC within the bone marrow niche in supporting HSC maintenance is evident as depletion of a specific population of nestin positive MSC resulted in a significant reduction in HSC homing and a concurrent increase in mobilisation.15
It remains unclear, however, whether these effects were due to depletion of MSC or the function of the sympathetic nervous system, which includes nestin positive cells. The signals generated by MSC that are involved in the maintenance of HSC in the bone marrow niche are also integral for the establishment and progression of MM disease.
Numerous studies have attempted to investigate the gene expression profiles of BMSC in MM patients. A recent study investigated gene expression profiles from MSCs and osteoblasts enriched from MM patients with or without lytic bone disease and found that there were no significant changes in gene expression from osteoblasts; however, a number of changes were identified in the primitive MSCs.107
The pathways modulated by MSCs in the presence of MM cells may therefore represent important mechanisms through which the bone marrow microenvironment contributes to MM disease development.
Gene expression relating to pathways specific to angiogenesis, inhibition of osteogenesis and tumour growth, and cell proliferation are enhanced in MSCs derived from MM patients, while genes involved in osteogenic differentiation pathways exhibit decreased expression.69, 70, 108, 109
Functionally, MSC derived from MM patients exhibit a decreased capacity for osteogenic differentiation in vitro
compared with those from healthy donors.108, 110
In combination, these data suggest that myeloma cells alter the function of MSC through changes in gene expression profiles, while concurrently providing a mechanism whereby MSC may mediate MM disease progression.
In recent years, it has become increasingly evident that factors expressed by MSCs, particularly in the presence of MM disease, aid myeloma cell proliferation and survival, as well as providing pro-angiogenic stimulatory factors, which together create an environment conducive to the enhanced growth of malignant plasma cells. Therefore, it is plausible that an increase in the number of MSC would support the development of MM. Indeed the transplantation of murine MSCs following ex vivo
expansion into a mouse model of myeloma resulted in decreased survival of mice,70
providing experimental evidence that an increase in the number of MSC may be directly involved in stimulating myeloma cell growth and the subsequent progression of MM disease. These data suggest that MSC may be a potential target for novel myeloma treatments, as decreasing the number of MSC and/or the signals produced by MSC in the course of MM disease progression may slow or halt disease development.
However, the effect of MM on MSC number in the bone marrow microenvironment is a current area of controversy. Historically, MSC have been isolated from BMSC using a method of plastic adherence. Using this method to isolate MSCs from bone marrow aspirates of healthy donors or patients with MM or MGUS, two independent studies have determined that there is no change108
or a decrease111
in MSC number with progression of MM. However, in a study which used a flow-cytometric approach to isolate MSC, a twofold increase in MSC number was seen in patients with MM compared with MGUS, although this finding was not significant.112
This suggests that the methods used to isolate MSC from bone marrow may bias results. Evidence to support this comes from two recent studies that investigated the tumour-promoting effects and phenotypes of MSCs isolated by plastic adherence. Studies from our laboratory investigated the properties of MSC following two independent methods of isolation. It was found that MSCs isolated by specific immunoselection were shown to have greater proliferative capacity, multi-lineage differentiation potential and clonogenicty than cells isolated by plastic adherence.113
In addition, plastic-adherent BMSC, which would typically contain the MSC population, were found to be contaminated with a population of myeloid precursor cells that exhibited independent gene expression patterns, phenotype and functional capabilities.114
As such the majority of studies that have investigated properties and gene expression profiles of MSC in MM are unreliable, owing to the presence of contaminating cells.