Potential benefits of co-transplanting autologous adult stem cells together with human embryonic stem cells or their differentiated derivatives.

In recent years, adult stem cells isolated from postnatal tissues have aroused tremendous interest as to their potential applications in human regenerative medicine [1]. The overwhelming majority of studies in animal models and phase I human clinical trials have focused on the transplantation of relatively uncommitted or undifferentiated adult stem cells. This has disadvantages that could reduce the efficacy of tissue/organ regeneration by the transplanted cells. Undifferentiated or uncommitted adult stem cells obviously lack expression of specific cell-surface markers that could facilitate their rapid engraftment and integration within the recipient tissue or organ, ie, gap-junction connexin proteins, surface ligands for interaction with extracellular matrix. Further complications may arise from the pathological state of damaged or diseased tissues/organs providing an abnormal milieu for the differentiation of the transplanted adult stem cells. The presence of necrotic/apoptotic cells, free radicals, and inflammatory cytokines within the pathological environment may exert an adverse effect on the differentiation pathway of the transplanted adult stem cells. This could reduce the proportion of transplanted cells giving rise to the required lineage of interest, as well as result in the formation of undesired tissue lineages at the transplantation site, which could impair tissue/organ regeneration. Thus, in a study by Wang et al [2], transplantation of undifferentiated mesenchymal stem cells into the pathological environment of damaged cardiac muscles resulted in differentiation of some of these cells into fibroblastic scar tissue, which could impair the subsequent recovery of cardiac function after myocardial infarction. A possible solution to these problems would be to direct adult stem cell commitment or differentiation into specific lineages prior to transplantation in situ. This may be achieved by exposing adult stem cells to exogenous cytokines, growth factors, chemicals, or extracellular matrix substratum during prolonged in vitro culture [3]. However, this has disadvantages if autologous cells are to be utilized for transplantation therapy. Obviously, this would delay treatment of the patient, who is likely to be in dire need of therapeutic intervention. There is also evidence that prolonged duration of ex vivo culture can somehow alter the immunogenicity of cultured autologous cells, which may lead to immuno-rejection following transplantation [4-6]. Adult stem cells in the pathway of terminal differentiation may have reduced proliferative potential, which could reduce their ability to contribute to tissue/organ regeneration. Hence, differentiated derivatives of autologous adult stem cells that arise from prolonged ex vivo culture may not be ideal for cell-transplantation therapy. Genetic modulation with recombinant DNA technology could potentially offer a rapid and efficient means of directing autologous adult stem