Kotton and his colleagues use dye-exclusion to isolate a population of very rare stem cells within the adult mouse liver, which have nearly equal potency to true bone marrow stem cells to restore hematopoiesis following intravenous infusion into irradiated hosts (i.e. stem cell transplantation). These adult liver stem cells themselves derive from bone marrow stem cells, but do not express the stem cell factor receptor, c-kit. The presence, physiology, and capacity of stem cells in non-hematopoietic tissues are key issues of interest among scientists, physicians, and the lay public. One central mystery in this growing field is the relation between hematopoietic stem cells (HSC) in the bone marrow and those in other organs. Are the rare HSCs found in other tissues simply contaminants from blood, or are they a distinct local population? If a distinct HSC population can be identified, does it originate in that non-hematopoietic tissue, or does it arise by migration and differentiation from the bone marrow? Can the same stem cell generate organ-specific cells in its organ of residence and hematopoietic cells when it migrates to bone marrow?
In this report, Kotton et al. capitalized on the capacity of stem cell populations to actively export a class of small molecules that include the fluorescent dye Hoescht as a first step to purifying adult fetal liver stem cells. They further segregated these cells, which they term liver side population (LISP) tip cells, into CD45+ and CD45- subsets, and found that the CD45+LISP cells were essentially as effective as purified bone marrow SP cells in bone marrow transplantation rescue assays, whereas all other liver and blood cell populations were ineffective. Although they function similarly to bone marrow stem cells after transplantation, freshly isolated LISP tip cells did not express c-kit, the receptor for the stem cell factor. This strongly suggests that LISP tip cells are not simply bone marrow stem cells that have been mobilized, circulate, and are passively trapped in the liver. On the other hand, isolating murine LISP tip cells after allogeneic bone marrow transplantation shows that at least some of them derive from the bone marrow donor, suggesting the fascinating conclusion that bone marrow stem cells can give rise to LISP tip cells, and vice versa.
One direct implication of these results is that liver transplants always have the potential to create bone marrow chimeras in their recipients. If such stable mixed chimeras can be routinely created in organ recipients, the patient's immune system might learn to become tolerant of the transplanted organ, without need for immunosuppression. Understanding the fate of LISP tip cells after organ transplantation and learning how to regulate LISP tip cell migration to encourage graft tolerance will therefore be an important and exciting next avenue of investigation. For, in immune tolerance as in stem cell biology, the secret to the behavior of these cells will likely be location, location, location.
