Autocrine transforming growth factor-β regulation of hematopoiesis: many outcomes that depend on the context

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Abstract
Transforming growth factor-β (TGF-β) is a pleiotropic regulator of all stages of hematopoieis. The three mammalian isoforms (TGF-β1, 2 and 3) have distinct but overlapping effects on hematopoiesis. Depending on the differentiation stage of the target cell, the local environment and the concentration and isoform of TGF-β, in vivo or in vitro, TGF-β can be pro- or antiproliferative, pro- or antiapoptotic, pro- or antidifferentiative and can inhibit or increase terminally differentiated cell function. TGF-β is a major regulator of stem cell quiescence, at least in vitro. TGF-β can act directly or indirectly through effects on the bone marrow microenvironment. In addition, paracrine and autocrine actions of TGF-β have overlapping but distinct regulatory effects on hematopoietic stem/progenitor cells. Since TGF-β can act in numerous steps in the hematopoietic cascade, loss of function mutations in hematopoeitic stem cells (HSC) have different effects on hematopoiesis than transient blockade of autocrine TGF-β1. Transient neutralization of autocrine TGF-β in HSC has therapeutic potential. In myeloid and erythroid leukemic cells, autocrine TGF-β1 and/or its Smad signals controls the ability of these cells to respond to various differentiation inducers, suggesting that this pathway plays a role in determining the cell fate of leukemic cells.