The role of Smad signaling in hematopoiesis and translational hematology

Abstract

Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) of adult individuals and function to produce and regenerate the entire blood and immune system over the course of an individual's lifetime. Historically, HSCs are among the most thoroughly characterized tissue-specific stem cells. Despite this, the regulation of fate options, such as self-renewal and differentiation, has remained elusive, partly because of the expansive plethora of factors and signaling cues that govern HSC behavior in vivo. In the BM, HSCs are housed in specialized niches that dovetail the behavior of HSCs with the need of the organism. The Smad-signaling pathway, which operates downstream of the transforming growth factor-b (TGF-b) superfamily of ligands, regulates a diverse set of biological processes, including proliferation, differentiation and apoptosis, in many different organ systems. Much of the function of Smad signaling in hematopoiesis has remained nebulous due to early embryonic lethality of most knockout mouse models. However, recently new data have been uncovered, suggesting that the Smad-signaling circuitry is intimately linked to HSC regulation. In this review, we bring the Smad-signaling pathway into focus, chronicling key concepts and recent advances with respect to TGF-b-superfamily signaling in normal and leukemic hematopoiesis.

TGF-β–induced intracellular PAI-1 is responsible for retaining hematopoietic stem cells in the niche

“…In this paper, we elucidated a novel function of TGF-b, a well-known negative regulator of cell proliferation, 7,8,[12][13][14] in the retention of HSPCs within the BM niche. Although it is well established that the localization of HSPCs in the niche is essential for lifelong maintenance of hematopoiesis, [1][2][3] how and why HSPCs stay in the niche have been rarely discussed.…”

“…[9][10][11] HSPCs in close proximity to megakaryocytes exhibit Smad2/ 3 activation, and conditional deletion of TGF-b from megakaryocytes results in reduced phosphorylation of Smad2/3 as well as loss of quiescence and increased HSPC proliferation. Although TGF-b has been characterized as a negative regulator of HSPC proliferation, [12][13][14] its role in HSPC motility has not been studied. Meanwhile, it has been reported that plasminogen activator inhibitor (PAI)-1, a well-known downstream molecule of TGF-b signaling 15,16 and a major physiologic inhibitor of the fibrolytic system that inhibits the serine protease activity of urokinase and tissue plasminogen activator (tPA) during blood clotting, 16 regulates adhesion and migration of many cell types, including hematopoietic cells.…”

Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine β-thalassemia

“…Complexes containing activin receptor type IIA (ActRIIA), ActRIIB, or the TGFb type II receptor regulate gene expression primarily by activating the Smad2/3 subfamily of intracellular effectors, whereas BMP receptors and ligands signal primarily through Smad1/5/8. 12 Studies have documented effects of several superfamily ligands on erythroid precursors or cell lines, but the role of this superfamily in regulating erythropoiesis in vivo is not well understood. [12][13][14][15] Intriguingly, increased Smad2/3 activation is found in hematopoietic progenitors from patients with myelodysplastic syndromes (MDS), 16 a heterogeneous group of blood disorders in which IE occurs due to abortive erythroid precursor maturation.…”

The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease

“…13 SKI does not bind to DNA directly, 14 but when associated with active Smad-complexes it blocks their ability to initiate gene expression. [15][16][17][18][19][20][21] We have recently demonstrated that the Smad-signaling circuitry is intimately linked to HSC regulation, [22][23][24][25] suggesting that SKI may play a role in controlling hematopoiesis. To generate a model for investigation of the intrinsic role of SKI in hematopoiesis and its potential role in myeloid neoplasms, we have over-expressed human SKI in adult murine hematopoietic stem and progenitor cells.…”