25 TGF-β as a Regulator of Myeloid and Lymphoid Development and Function

As in most systems, the three mammalian transforming growth factor-β (TGF-β) isoforms, TGF-β1, -β2, and -β3, have distinct but overlapping effects on hematopoiesis. The activity of each isoform is concentration dependent and invariably influenced by both the differentiation stage of the target cell and the local microenvironment (Ruscetti and Bartelmez 2001; Henckaerts et al. 2004). For example, TGF-β promotes or suppresses the proliferative, apoptotic, and differentiation responses in myeloid and lymphoid progenitors and can either inhibit or increase terminally differentiated cell function (Fig. 1). The molecular basis of these disparate responses is, in part, the result of cross-talk between the TGF-β signaling pathways and those of multiple other hematopoietic regulatory cytokines and may be related to the often indirect regulation of the function and differentiation of these cells, for example, through effects on the bone marrow microenvironment. In addition, the paracrine and autocrine actions of TGF-β have overlapping but distinct regulatory effects on hematopoietic stem/progenitor cells. Loss-of-function mutations affecting TGF-β signaling in hematopoietic stem cells (HSCs) have significant effects on hematopoiesis that frequently differ from those induced by a transient blockade of autocrine TGF-β1. Such differences, which are most apparent in assays of regulation of HSC quiescence by TGF-β, may be attributed to the activities of TGF-β at numerous steps in the hematopoietic cascade and suggest a therapeutic potential of transient neutralization of autocrine TGF-β in HSCs (Fortunel et al. 2000). During myeloid and lymphoid cell development, TGF-β1 and/or its Smad signals regulate the response of the progenitor cells to...