Control of hematopoietic differentiation: lack of specificity in signaling by cytokine receptors.

Abstract

Blood consists of eight principal cell types of diverse function. They have in common a limited life span and an inability to replicate; they therefore must be replaced continuously throughout life. A small pool of pluripotent hemopoietic stem cells that reside in the bone marrow gives rise to all blood cell types through a process of simultaneous lineage commitment, cell proliferation, and differentiation (Fig. 1). In the last two decades, numerous cytokines have been identified as essential extracellular factors in this process (1–4). Some, like stem cell factor, interleukin 3, or granulocyte–macrophage colony-stimulating factor (GM-CSF), contribute to the progeny of many blood cell types. Others, like Epo, G-CSF, or thrombopoietin, exert their principal action on progenitors of a single lineage. Mice in which the genes for lineage- specific cytokines or their receptors are disrupted show a severe deficiency in the blood cells that constitute the progeny of their physiological targets (5, 6). For example, disruption of the EpoR gene results in embryonic lethality caused by the absence of red blood cells; similarly, disruption of the interleukin 7 receptor leads to severe lymphocyte deficiency. Therefore, lineage-restricted cytokine receptors each play an essential and specific role in differentiation. What is it that makes their signaling essential? The report in this issue of Proceedings by Goldsmith et al. (7) builds on a series of reports in the last year (8–11) that is fundamentally altering our view on the role of cytokine receptors in hematopoietic differentiation. Figure 1 Structure of the hematopoietic compartment. Bone marrow pluripotent stem cells may either self-renew or give rise to eight different hematopoietic lineages through a gradual process of commitment and differentiation. Some of the cytokines involoved in supporting this process are illustrated. M-CSF, Macrophage colony stimulating factor; SCF, stem cell factor; Epo, erythropoietin; Tpo, thrombopoietin; …