transforming-growth-factor-beta and Hematologic-Diseases

Throughout the lifetime of an individual, hematopoietic stem cells (HSCs) maintain the homeostasis of normal hematopoiesis through the precise generation of mature blood cells. Numerous genetic studies in mice have shown that stem-cell quiescence is critical for sustaining primitive long-term HSCs in vivo. In this review, we first examine the crucial roles of transforming growth factor β (TGF-β) and related signaling molecules in not only regulating the well-known cytostatic effects of these molecules but also governing the self-renewal capacity of HSCs in their in vivo microenvironmental niche. Second, we discuss the current evidence indicating that TGF-β signaling has a dual function in disorders of the hematopoietic system. In particular, we examine the paradox that, although intrinsic TGF-β signaling is essential for regulating the survival and resistance to therapy of chronic myelogenous leukemia (CML) stem cells, genetic changes that abrogate TGF-β signaling can lead to the development of several hematological malignancies.

Topics: Bone Morphogenetic Proteins; Cell Self Renewal; Hematologic Diseases; Hematopoiesis; Homeostasis; Humans; Models, Molecular; Signal Transduction; Stem Cell Niche; Transforming Growth Factor beta

Blood is a tissue with high cellular turnover, and its production is a tightly orchestrated process that requires constant replenishment. All mature blood cells are generated from hematopoietic stem cells (HSCs), which are the self-renewing units that sustain lifelong hematopoiesis. HSC behavior, such as self-renewal and quiescence, is regulated by a wide array of factors, including external signaling cues present in the bone marrow. The transforming growth factor-β (TGF-β) family of cytokines constitutes a multifunctional signaling circuitry, which regulates pivotal functions related to cell fate and behavior in virtually all tissues of the body. In the hematopoietic system, TGF-β signaling controls a wide spectrum of biological processes, from homeostasis of the immune system to quiescence and self-renewal of HSCs. Here, we review key features and emerging concepts pertaining to TGF-β and downstream signaling pathways in normal HSC biology, featuring aspects of aging, hematologic disease, and how this circuitry may be exploited for clinical purposes in the future.

Topics: Aging; Animals; Hematologic Diseases; Hematopoietic Stem Cells; Humans; Signal Transduction; Transforming Growth Factor beta

Mast cells may participate in tumor angiogenesis through the release of angiogenic cytokines from their secretory granules. To gain additional insight into the role of mast cells in bone marrow angiogenesis, we performed a semiquantitative measurement of bone marrow microvessel density in 52 consecutive adult patients with systemic mast cell disease (SMCD). The results were examined for potential correlations with mast cell expression of angiogenic cytokines and with other histologic features of the bone marrow. Standard immunohistochemical methods were used to visualize bone marrow microvessels (CD34 staining) and mast cell expression of transforming growth factor-beta, basic fibroblast growth factor, and their respective receptors. An increase in microvessel density was demonstrated in 32 of the 52 patients (62%) with SMCD, and the degree of bone marrow angiogenesis did not correlate with either the mast cell expression pattern of the study cytokines or the presence (23 patients) or absence (29 patients) of an associated hematologic disorder. In the 29 patients without an associated hematologic disorder, microvessel density was correlated significantly with the presence of an abnormal pattern of hematopoiesis but not with the degree of bone marrow involvement by mast cells. Furthermore, areas occupied by mast cell lesions were often devoid of neovascularization. We conclude that bone marrow angiogenesis characterizes a percentage of patients with SMCD and that the pathogenesis may not necessarily be linked to the mast cells themselves.

Topics: Antigens, CD34; Bone Marrow; Cohort Studies; Fibroblast Growth Factor 2; Hematologic Diseases; Hematopoiesis; Humans; Immunohistochemistry; Mast Cells; Mastocytosis; Microcirculation; Neovascularization, Pathologic; Receptors, Fibroblast Growth Factor; Receptors, Transforming Growth Factor beta; Retrospective Studies; Transforming Growth Factor beta

A case of Down's syndrome associated with liver fibrosis is reported. The fibrosis was diffusely distributed along sinusoids, and an excess of megakaryocytes was also found in the liver. To determine the mechanism of liver fibrosis in Down's syndrome, we immunohistochemically stained the liver with markers of myofibroblast-like cells, antialpha smooth muscle actin antibodies and antidesmin antibodies. The myofibroblast-like cells were found along sinusoids, suggesting that liver fibrosis in Down's syndrome is caused by the myofibroblast-like cells derived from Ito cells/lipocytes. The expression of transforming growth factor (TGF)-betal, which is an important mediator of the activation of lipocytes, was immunohistochemically examined. The accumulation of TGF-betal was observed in cells in the sinusoidal spaces, which involve the intracellular expression of megakaryocytes. Together, these findings suggest that megakaryocyte-derived TGF-betal is one of the likely candidates in the lipocyte activation of liver fibrogenesis in Down's syndrome.

Topics: Actins; Desmin; Down Syndrome; Fatal Outcome; Female; Hematologic Diseases; Humans; Immunohistochemistry; Infant, Newborn; Leukocyte Count; Leukopoiesis; Liver Cirrhosis; Platelet Glycoprotein GPIIb-IIIa Complex; Transforming Growth Factor beta

Topics: Colony-Stimulating Factors; Epidermal Growth Factor; Erythropoietin; Fibroblast Growth Factors; Hematologic Diseases; Humans; Interleukins; Platelet-Derived Growth Factor; Transforming Growth Factor beta