Tomorrow's skeleton staff: mesenchymal stem cells and the repair of bone and cartilage

Abstract

Stem cells are regenerating medicine. Advances in stem cell biology, and bone marrow-derived mesenchymal stem cells in particular, are demonstrating that many clinical options once thought to be science fiction may be attainable as fact. The extra- and intra-cellular signalling used by stem cells as they differentiate into lineages appropriate to their destination are becoming understood. Thus, the growth stimuli afforded by LIF, FGF-2 and HGF, as well as the complementary roles of Wnt and Dickkopf-1 in stem cell proliferation are evident. The ability to direct multi-lineage mesenchymal stem sell (MSC) potential towards an osteogenic phenotype by stimulation with Menin and Shh are important, as are the modulatory roles of Notch-1 and PPARgamma. Control of chondrocytic differentiation is effected by interplay of Brachyury, BMP-4 and TGFbeta3. Smads 1, 4 and 5 also play a role in these phenotypic expressions. The ability to culture MSC has led to their use in tissue repair, both as precursor and differentiated cell substitutes, and with successful animal models of bone and cartilage repair using MSC, their clinical use is accelerating. However, MSC also suppress some T-cell functions in transplanted hosts, and could facilitate tumour growth, so a cautious approach is needed.

Figure 1

MSC progression to osteocytic and chondrocytic lineages and some influencing factors. Several lineages from Table 2 are omitted for simplicity. The timing of each lineage event is unclear, and is left undefined. How many steps exist between each level in a lineage is unknown, and there may well be bi‐ or tri‐potentialities in any population, which may even reverse. Maturation is presumed to be tissue or organ specific, dependent on local cues, whereas prior steps may be possible during the circulatory or homing phases. Factors may not act simultaneously or continuously, and may act in more than one lineage.

Figure 2

Murine MSC in culture. (a) Untreated mouse bone marrow‐derived MSC clone 2 cells after 3 weeks of culture. Phase‐contrast. (b) Adipocytic differentiation. Oil Red O stain for intra‐cellular lipid droplets. (c) Chondrogenic differentiation in micromass culture. 5‐µ section, PAS/diastase with haematoxylin counterstain. (d) Osteogenic differentiation. Alizarin Red stain for deposits of calcium salts. Original magnifications 200 ×. Scale bar 100 µ. (Rao, unpublished results).