Stem Cells for Cartilage and Tendon Regeneration

Take-home message

Stem cells hold tremendous promise for the treatment of tendonitis and joint repair. There are several therapies currently being employed or marketed under the guise of stem cell therapy; therefore understanding the fundamentals of stem cell biology is important for choosing the appropriate treatment type and application protocol. The goal of this talk is to discuss the definitions of stem cells and review current studies and clinical outcomes of the various stem cells therapies being used in tendon and cartilage regenerative efforts.

What is a stem cell?

Stem cells are broadly defined as undifferentiated cells that possess the ability to divide for indefinite periods in culture and may give rise to highly specialized cells of each tissue type (mesoderm, ectoderm, endoderm). There are two broad categories of stem cells, embryonic and adult-derived. Embryonic stem cells (ES cells) used to be defined as those derived from embryos; more specifically from day 8, pre-implantation blastocyts. More recently advances have been made so that ES cells can be generated from adult fibroblasts using many of the same technologies that were used to clone Dolly the sheep. These cells are known as iPS (induced pluripotent stem) cells.

Adult-derived mesenchymal stem cells (MSC) can be obtained from bone marrow, fat, umbilical cord blood, muscle, and many other tissues including cartilage, trabecular bone and tendon. Hematopoetic stem cells (HSC) are those cells in the bone marrow which are the basis of bone marrow transplantation, and are capable of forming all types of blood cells. Arguments can be made regarding the optimal stem cell source for applications in regenerative therapies, and importantly, studies are needed to define the need for stem cells in such endeavors. There is more data available regarding cartilage tissue engineering, and those data support the need for the presence of cells (chondrocytes or stem cells) in a graft composite, but similar data is less abundant for tendon regenerative studies.

The definition/identification of stem cells is constantly evolving. Confounding the issue of stem cell definition is the concept of stem cell plasticity where a lineage committed stem cell might differentiate, or transdifferentiate into a cell of a completely different tissue lineage; this is commonly termed “plasticity of stem cells”. Therefore, the identification of stem/lineage committed cells can be ambiguous. There is no current consensus on a gold standard assay to isolate or identify stem cells. It is important to remember when evaluating cell surface marker expression that several markers are common to multiple cells types, particularly nucleated white blood cells. Since there is no single marker for MSCs, a panel of markers must be evaluated together. For example, a marker commonly used to assert isolation of stem cells is CD44 (cluster of differentiation 44). But many cells, including lymphocytes, granulocytes, and thymocytes (realistically, nearly everything but platelets) display surface antigens for CD44. Therefore, a mesenchymal or adipose-derived stem cell should be positive for CD44, but should also be negative for CD34 which is only present on HSCs and endothelial cells, or negative for CD45 which is displayed on granulocytes and lymphocytes. Our laboratory is working toward developing a panel of markers for identification of equine adult-tissue derived stem cells. The aim is to use this panel of antibodies to determine the absolute number of stem cells derived from bone marrow aspirate, adipose tissue, and muscle.

In pre-clinical studies, some of the most convincing experiments of stem cell differentiation use cell surface markers to demonstrate isolation and in vitro differentiation, and they show functionality of the stem cells in animal models of disease. However, all of the studies so far have been performed in rodents, the majority employing severe, chemical or irradiation-induced animal models of disease. [...]