Regulation of haematopoiesis by growth factors - emerging insights and therapies

Abstract

Haematopoiesis is regulated by a wide variety of glycoprotein hormones, including stem cell factor, granulocyte-macrophage colony-stimulating factor, thrombopoietin and IL-3. These haematopoietic growth factors (HGFs) share a number of properties, including redundancy, pleiotropy, autocrine and paracrine effects, receptor subunit oligomerisation and similar signal transduction mechanisms, yet each one has a unique spectrum of haematopoietic activity. Ongoing studies with knockout mice have discovered previously unrecognised physiological roles for HGFs, linking haematopoiesis to innate immunity, pulmonary physiology and bone metabolism. The regulation of stem cells by HGFs within niches of the bone marrow microenvironment is now well recognised and similar mechanisms appear to exist in the regulation of other stem cell compartments. Alternative signalling strategies, other than tyrosine kinase activation and phosphotyrosine cascades, may account for some of the more subtle differences between HGFs. Accumulating evidence suggests that some, but not all, HGF receptors can transduce a genuine lineage-determining signal at certain points in haematopoiesis. Further studies, primarily at the receptor level, are needed to determine the mechanisms of instructive signalling, which may include phosphoserine cascades. Novel haematopoietic regulators, as well as the development of biological therapies, including growth factor antagonists and peptide mimetics, are also discussed.