Regulation of Hematopoiesis and Hematological Disease by TGF-β Family Signaling Molecules

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Abstract

<p class="first" id="d4432899e108">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. </p><p class="first" id="d4432899e111">TGF-β signaling is essential for self-renewal in hematopoietic stem cells. Its dysregulation can lead to hematological diseases or malignancies. </p>

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Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease.

M Shull, I Ormsby, A Kier … (1992)

Transforming growth factor-beta 1 (TGF-beta 1) is a multifunctional growth factor that has profound regulatory effects on many developmental and physiological processes. Disruption of the TGF-beta 1 gene by homologous recombination in murine embryonic stem cells enables mice to be generated that carry the disrupted allele. Animals homozygous for the mutated TGF-beta 1 allele show no gross developmental abnormalities, but about 20 days after birth they succumb to a wasting syndrome accompanied by a multifocal, mixed inflammatory cell response and tissue necrosis, leading to organ failure and death. TGF-beta 1-deficient mice may be valuable models for human immune and inflammatory disorders, including autoimmune diseases, transplant rejection and graft versus host reactions.

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J Massagué (2000)

Cell proliferation, differentiation and death are controlled by a multitude of cell-cell signals, and loss of this control has devastating consequences. Prominent among these regulatory signals is the transforming growth factor-beta (TGF-beta) family of cytokines, which can trigger a bewildering diversity of responses, depending on the genetic makeup and environment of the target cell. What are the networks of cell-specific molecules that mould the TGF-beta response to each cell's needs?

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Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age.

Derrick Rossi, David Bryder, Jun Seita … (2007)

A diminished capacity to maintain tissue homeostasis is a central physiological characteristic of ageing. As stem cells regulate tissue homeostasis, depletion of stem cell reserves and/or diminished stem cell function have been postulated to contribute to ageing. It has further been suggested that accumulated DNA damage could be a principal mechanism underlying age-dependent stem cell decline. We have tested these hypotheses by examining haematopoietic stem cell reserves and function with age in mice deficient in several genomic maintenance pathways including nucleotide excision repair, telomere maintenance and non-homologous end-joining. Here we show that although deficiencies in these pathways did not deplete stem cell reserves with age, stem cell functional capacity was severely affected under conditions of stress, leading to loss of reconstitution and proliferative potential, diminished self-renewal, increased apoptosis and, ultimately, functional exhaustion. Moreover, we provide evidence that endogenous DNA damage accumulates with age in wild-type stem cells. These data are consistent with DNA damage accrual being a physiological mechanism of stem cell ageing that may contribute to the diminished capacity of aged tissues to return to homeostasis after exposure to acute stress or injury.