Biological principles for ex vivo adult stem cell expansion

Adult stem cells (ASCs) are the engines that drive the renewal of adult mammalian tissues. They divide continuously, throughout life, to produce new progeny cells that undergo a robust development program of differentiation and maturation to replace older expired tissue cells. The same cell turnover program may function to provide limited repair and regeneration of adult tissues in some cases. The regenerative potential of ASCs drives the current intense interest in adapting them for applications in cell replacement therapy. However, research to explore this potential has been blunted by an unyielding biological problem. ASCs have proven highly refractory to expansion of their numbers and long-term propagation in culture. A review of reported strategies to overcome this problem reveals that many studies focus on traditional cell culture factors that may not apply to ASCs and overlook a special property of ASCs that may be universally critical for successful expansion, asymmetric cell kinetics (ACK). This property is reflected by the different kinetics fate of the two sister cells resulting from an ASC division: one cell remains an ASC and keeps the potential to divide for the entire life span of the tissue, while the other cell's progeny eventually differentiates and undergoes terminal division arrest. This unique property of ASCs may prove to be the obligatory factor that must be breached by any method that will succeed in accomplishing routine expansion of ASCs of diverse tissue origin.