A ROLE FOR LEPTIN AND ITS COGNATE RECEPTOR IN HEMATOPOIESIS

Background: Hematopoiesis entails the production of multiple blood cel l lineages throughout the lifespan of the organism. This is accomplish ed by the regulated expansion and differentiation of hematopoietic pre cursors that originate from self-renewing hematopoietic stem cells. St udies of lineage commitment and proliferation have shown that the cyto kine family of growth factors plays an important role in hematopoietic differentiation. However, in hematopoiesis, as in most self-renewing biological systems, the molecules that regulate the stem cells directl y remain largely unknown. In this study, we have undertaken a search f or novel cytokines that may influence the fate of hematopoietic stem c ells. Results: We have cloned three splice variants of a novel cytokin e receptor from human hematopoietic stem cells expressing the CD34 ant igen, one of which is identical to the leptin receptor. Expression ana lysis revealed that the leptin receptor is expressed in both human and murine hematopoietic stem cell populations, and that leptin is expres sed by hematopoietic stroma. We show that leptin provides a proliferat ive signal in hematopoietic cells, Importantly, we demonstrate that le ptin provides a proliferative signal in BAF-3 cells and increases the proliferation of hematopoietic stem cell populations. The proliferativ e effects of leptin seem to be at the level of a multilineage progenit or, as shown by increased myelopoiesis, erythropoiesis and lymphopoies is. Analysis of db/db mice, in which the leptin receptor is truncated, revealed that the steady-state levels of peripheral blood B cells and CD4-expressing T cells were dramatically reduced, demonstrating that the leptin pathway plays an essential role in lymphopoiesis. Colony as says performed using marrow from db/db and wild-type mice indicated th at db/db marrow has a deficit in lymphopoietic progenitors; furthermor e, db/db mice are unable to fully recover the lymphopoietic population following irradiation insult, and although the levels of peripheral b lood erythrocytes are normal in db/db mice, spleen erythrocyte product ion is severely compromized. Conclusions: We have discovered that lept in and its cognate receptor constitute a novel hematopoietic pathway t hat is required for normal lymphopoiesis. This pathway seems to act at the level of the hematopoietic stem/progenitor cell, and may well als o impact upon erythropoiesis, particularly in anemic states that may r equire output from the spleen. These findings offer a new perspective on the role of the fat cell in hematopoiesis.