1768 Loss of Stem Cell Function Upon

The earliest precursor cell or stem cell that populates the immunohemopoiet ic system in mammals must have a high proliferative potential. Stem cells can be transplanted by intravenous injections of single cell suspensions and can repopulate stem cell-depleted recipients (1, 2). Therefore, stem cells have been used to test the hypothesis that mammal ian aging is genetically programmed to cause loss of cell proliferation in all somatic cells of adults (3, 4). Yet hemopoietic stem cells from old donors transplanted into young recipients proliferate as well as cells from young donors, implying that aging is not an intrinsically timed phenomena (2, 5-11). However, after four to six successive serial transplantations, stem cells lose their ability to repopulate and proliferate normally, even if given long periods of time to recover after each transplantation (1, 2, 8-15). This loss may result from acceleration of the normal aging process, or perhaps from unique stresses caused by transplantation. It is important to distinguish between these possibilities: proof that transplantation causes unique stresses would add credibility to the theory that stem cell lines do not age. An understanding of how transplantation affects stem cells is also important in understanding their functioning, and is of clinical significance as the use of marrow transplantation in medicine increases (16, 17). Using the technique of competitive repopulation, we have shown that there is a substantial loss of proliferative capacity after a single marrow transplantation (10). This loss is detected even when large numbers of marrow cells are used, and the interval between transplantations is long (10, 18). Other techniques, such as measuring macroscopic spleen colony-forming cell (CFU-S) 1 numbers, detect little or no change after a single transplantation under these conditions (1, 2, 5-10, 12). Micklem and his colleagues developed the earliest competitive repopulation techniques (1). They transplanted mixtures of genetically distinguishable (19) stem cells and compared their abilities to repopulate lethally irradiated recipients and maintain continuous function for long periods of time. They showed that fetal liver cells were better than adult marrow cells (20), cells from the marrow were better than circulating cells (21) and young and old marrow cells functioned identically (9). Recently, this