New era of cell-based orthopedic therapies

Abstract

There has long been a described relationship between mesenchymal stem cells (MSCs) and blood vessels in aspects of bone and other skeletal tissues with regard to their embryonic formation and their adult repair and regeneration dynamics. The use of exogenously added MSCs to supplement the naturally available progenitor cell stock has been a standard practice in several orthopedic surgeries by adding bone marrow to the repair constructs. This, coupled with the well-established need for vasculature to orient and drive bone formation, firmly established the functional relationship between MSCs, osteoprogenitors, and blood vessels. It is now apparent that MSCs are pericytes (cells that surround blood vessels) throughout the body. In addition, MSCs can function to secrete bioactive factors that are immunomodulatory, thus allowing allogeneic MSCs to be infused into patients requiring clinically relevant treatments. Such infused MSCs trophically establish microenvironments that support the regeneration of the injured tissue. These new functions usher in a new era of cell-based therapies.

FIG. 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. The figure was first drawn to mirror the sequence of events observed in hematopoietic 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 Refs.^–

FIG. 2.

Tissue engineering using MSCs. A bone marrow aspirate provides the source for MSCs that can be expanded in culture. These MSCs can be stored frozen and thawed without loss of potency. Using tissue-specific scaffolds, cartilage, bone, tendon, and fat can be tissue engineered to fill defects and contribute to the functional regeneration of these tissues.

FIG. 3.

Bioactive factor secretion by MSCs. Culture-expanded MSCs were put into osteogenic, growth, or stromagenic (i.e., hematopoietic support conditions comparable to Dexter) conditions, and the 24 h media were assayed by ELISA for specific bioactive molecules as listed. MSCs from six donors were separately analyzed. The relative (to growth conditions) quantities are represented by “+” or “−” signs (+, increases; −, decreases); the “O” means none detected. Although the absolute quantities varied greatly from donor to donor, the percent change in osteogenic or stromagenic conditions relatively tightly clustered for all donors.