Why are MSCs therapeutic? New data: new insight

Abstract

Adult marrow-derived mesenchymal stem cells (MSCs) are able to differentiate into bone, cartilage, muscle, marrow stroma, tendon-ligament, fat and other connective tissues. The questions can be asked, what do MSCs do naturally and where is the MSC niche? New insight and clinical experience suggest that MSCs are naturally found as perivascular cells, summarily referred to as pericytes, which are released at sites of injury, where they secrete large quantities of bioactive factors that are both immunomodulatory and trophic. The trophic activity inhibits ischaemia-caused apoptosis and scarring while stimulating angiogenesis and the mitosis of tissue intrinsic progenitor cells. The immunomodulation inhibits lymphocyte surveillance of the injured tissue, thus preventing autoimmunity, and allows allogeneic MSCs to be used in a variety of clinical situations. Thus, a new, enlightened era of experimentation and clinical trials has been initiated with xenogenic and allogeneic MSCs.

Figure 1.

The mesengenic process. Adult mesenchymal stem cells (MSCs) are able to differentiate into bone, cartilage, muscle, marrow stroma, tendon/ligament, fat and other connective tissues in a sequence of lineage transitions. This figure was first drawn to mirror the sequence of events observed in haematopoietic differentiation. The state of knowledge in the late 1980s and early 1990s provided the most information for the lineages on the left and the least information for the pathways on the right. (This information is reviewed in [–3])

Figure 2.

Marrow MSCs (CFU-F) and age. Bone marrow was obtained, dispersed, placed on a Percoll gradient and the light cell fraction seeded into culture [7]. After 7–10 days, colonies can be visualized as first described by Friedenstein and colleagues [8,9]. The CFU-F assay is an incomplete and crude estimate for the titre of MSCs in each marrow sample. Clearly, the number of MSCs in marrow decreases with age [8]

Figure 3.

Bioactive factor secretion by MSCs. Culture-expanded MSCs were put into osteogenic, growth or stromagenic conditions and the 24 h media were assayed by ELISA for specific bioactive molecules, as listed. MSCs from six donors were separately analysed. The quantities relative to growth conditions are represented by + or −signs. Although the absolute quantities varied greatly from donor to donor, the percentage change in osteogenic or stromagenic conditions clustered tightly for all donors [28]