Transforming growth factor‐β: A bidirectional regulator of hematopoietic cell growth

Abstract

It is now apparent that the transforming growth factor-beta (TGF-beta) family of proteins has potent hematopoietic regulatory properties ranging from effects on the growth and differentiation of primitive stem cells to the differentiated functions of mature cells. Although most reports have described the inhibitory activities of TGF-beta on hematopoiesis, recent evidence supports the concept that TGF-beta can have both inhibitory and stimulatory actions on these systems. These differences depend on the differentiation state of the target cell and the other cytokines interacting with the cell. Furthermore, TGF-beta has direct bidirectional effects on cell surface expression of many cytokine receptors suggesting that it is part of the mechanism of action of TGF-beta. The major biological effect of TGF-beta on hematopoietic cell growth is the reversible inhibition of entry into the cell cycle. Importantly, the effect of in vivo administration of TGF-beta has mimicked the in vitro effects. Ultimately, well designed clinical trials will determine whether the exciting potential of TGF-beta can be used to treat or prevent myelotoxicity and other bone marrow dysfunctions.

Stimulation of Adult Human Bone Marrow by Factors Secreted by Fetal Liver Hematopoietic Cells: In Vitro Evaluation Using Semisolid Clonal Assay System

“…The observation that TGF-β1 was consistently associated with hematopoietically active tissues had clear implications of its involvement in hematopoiesis. It has even been observed that TGF-β1 could be an activator [36][37][38] or inhibitor [32,33,[39][40][41][42][43][44][45] of hematopoiesis, depending on the target population. The activatory role of TGF-β1 in these experiments was confined only to GM progenitors and required that higher concentrations of TGF-β1 (ng/ml) be applied.…”

Prominent role of TGF-β1 in thrombopoietin-induced myelofibrosis in mice

“…To ensure efficient transduction in primitive hematopoietic stem cells, the Lin Ϫ fraction from WT donors was prestimulated in vitro during 24 hours before being exposed during 48 hours to the virus at a multiplicity of infection of 20. Because TGF-␤1 negatively controls the cell cycle of primitive hematopoietic stem cells (HSCs), 27,28 we omitted the prestimulation step in the TGF-␤1 Ϫ/Ϫ group. At the end of the infection protocol, the cellular amplification was 1.5-to 2-fold in the 2 groups, and the mean CFC numbers per 5000 cells plated was comparable (153 Ϯ 73 in WT vs 122 Ϯ 19 in TGF-␤1 Ϫ/Ϫ ; n ϭ 5, respectively).…”

Disruption of Smad5 gene leads to enhanced proliferation of high-proliferative potential precursors during embryonic hematopoiesis

“…[3][4][5][6][7] Previous studies have strongly shown that TGF-␤ can either in vivo or in vitro preferentially inhibit proliferation of the most primitive types of hematopoietic cells, long-term culture-initiating cells (LTC-ICs) and their presumed immediate progeny, highproliferative potential colony-forming cells (HPP-CFCs), but spare more mature low-proliferative potential colony-forming cells (LPPCFCs). [8][9][10][11] Although conventionally thought to respond to BMP signals, a recent finding demonstrates that SMAD5 is also capable of transducing the inhibitory signal of TGF-␤1 and TGF-␤2 on proliferation of hematopoietic progenitor cells from human adult bone marrow. 12 Whether SMAD5 can also play a role in negative regulation of primitive multipotential progenitors by TGF-␤ during embryonic hematopoiesis is particularly investigated in this study.…”