Cell Transplantation and Aging
Hornsby, Peter J., Generations
Consistent with the overall theme of this issue, my intent here is to give an overview of how genes with importance in aging can be studied by cell transplantation and also how cell transplantation can be used to deliver therapeutic gene products to patients.
In the process called cell transplantation, isolated human or animal cells are transplanted into a human patient or an experimental animal. In their new host, they become a functional part of the body, either by integrating into an existing tissue or alternatively by forming a new tissue or organ, in cooperation with host-derived connective tissue cells, blood vessels, and nerves. In my laboratory, we have applied cell transplantation techniques to the cells of the adrenal cortex (Thomas, Northrop, and Hornsby, r997; Hornsby et al.,1998), but this general overview addresses the uses and potential of cell transplantation generally, without an emphasis on any specific cell type.
It is only recently that cell transplantation has been recognized as a distinct discipline. It has emerged as a synthesis of several related areas of basic science and clinical therapy First, cell transplantation extends organ and tissue transplantation and shares with those procedures the same clinical objectives-the replacement of diseased or damaged organs and tissues and the correction of metabolic or hormonal defects. For example, much effort has gone into attempts to successfully transplant pancreatic islet beta cells for the treatment of insulin-dependent diabetes (Ricordi and Starzl, 1991). A second contributing area has been ex vivo gene therapy. In this technique, genetically modified cells (derived from the patient or from another source) are transplanted as a vehicle for therapeutic gene and protein delivery, as an alternative to in vivo gene delivery by viruses or other means. Transplanted cells could be used to deliver a therapeutic protein to a site in the body where it is needed or to deliver it systemically into the circulation (Gage,1998). Third, the science and medicine of tissue engineering are closely related to cell transplantation, with the emphasis on combining cells using synthetic polymer matrices before transplantation (Larger and Vacanti, 1993). These biodegradable and biocompatible polymers serve to support the growth and function of the cells and act as a guide or scaffold for the newly formed tissue after transplantation. The first tissue engineering products are now commercially available. One example is the Apligraf human skin equivalent.
Most emphasis has been on the practical aspects of cell transplantation, and the potential of the technique to answer basic science questions, has not received as much attention. Cell transplantation can be used to address questions in human physiology and biochemistry, and in the physiology of species other than the common laboratory organisms, that cannot be answered by techniques that are currently in common use. In using cell transplantation in this way, we take advantage of the same features of the technique that make it attractive for therapeutic procedures. That is, we combine the power of in vitro techniques, the growth of specialized cells in culture and genetic manipulation of cultured cells, for example, with growth of the cells in an appropriate host in vivo to form a functional tissue. The ability to construct tissues and organs from component cells enables us to address questions of cell origin, cell interactions, cell turnover, and cellular senescence within tissues. When these techniques are applied to human cells, in a suitable host animal, we can perform experiments that would be unethical and impractical in human subjects.
In the experiments from my lab on transplantation of adrenocortical cells (Hornsby et al., r998), there are two critical features of importance for cell transplantation as a method to study human biology. One is the use of a clonal cell population, and the second is the replacement of the animal's own organ by the transplanted cells. …