Complex and Context Dependent Regulation of Hematopoiesis by TGF‐β Superfamily Signaling

Abstract

The transforming growth factor (TGF)-β superfamily of growth factors, including the TGF-βs, activins, and bone morphogenetic proteins (BMPs), provide cells with a broad spectrum of regulatory signals through the intracellular Smad pathway. Since lossof-function studies of a majority of the TGF-β superfamily members result in embryonic lethality, much of our current knowledge of the TGF-β superfamily's role in hematopoiesis is generated from studies performed in vitro, or in very early stages of embryonic development. TGF-β is well documented as a potent inhibitor of hematopoietic stem cell (HSC) proliferation in vitro, while its role in vivo is largely unknown. BMP signaling is crucial for the initiation of hematopoiesis in the developing embryo, although its role in adult hematopoiesis remains elusive. More recently we and others have used conditional knockout models to unravel the role of several components of TGF-β family signaling in adult hematopoiesis. Here we review the currently known functions for the major factors of this signaling family in embryonic and adult hematopoietic regulation and discuss the context dependency and complexity that permeate this regulation.

Tumor Microenvironment and Myeloid-Derived Suppressor Cells

“…Interestingly, VEGF and TGF-β have been also demonstrated to regulate the hematopoiesis [61,62], and being produced at high levels in various tumors could exert a strong impact on the MDSC generation and accumulation [24,25]. Thus, tumor-derived VEGF has been shown to interfere with the proliferation, differentiation and maturation of immature granulocyte-macrophage progenitors, blocking DC maturation and activation as well as inducing the development of immunosuppressive M2 TAMs and their recruitment to the tumor site [63,64].…”

Human hematopoietic stem/progenitor cells overexpressing Smad4 exhibit impaired reconstitution potential in vivo

“…9,10,[15][16][17][18][19][20]22 Having established that CB-derived HSPCs become hypersensitive to TGF-␤ in vitro on overexpression of Smad4, we sought to use this approach to evaluate how TGF-␤ functions in a transplantation setting in vivo. Therefore, we transplanted unsorted transduced CD34 ϩ CB cells into 3 or 4 sublethally irradiated NSG-mice in each of 4 independent experiments.…”

Bone morphogenetic protein 7 suppresses the progression of hepatic fibrosis and regulates the expression of gremlin and transforming growth factor β1

“…BMPs have been studied extensively for their involvement in embryonic development and cell differentiation, whereas, recently, a role for the BMP-7 signaling pathway in the regulation of fibrosis was recognized based on the counteractive effect of BMP-7 against the TGF-β/ Smad signaling pathways (15). TGF-β activates the smad2/3 proteins, while BMP-7 carries out its function by forming a receptor complex that subsequently promotes the phosphorylation of Smad1/5/8, leading to the suppression of the effects of TGF-β (16,17).…”