Smad4 is critical for self-renewal of hematopoietic stem cells

Members of the transforming growth factor β (TGF-β) superfamily of growth factors have been shown to regulate the in vitro proliferation and maintenance of hematopoietic stem cells (HSCs). Working at a common level of convergence for all TGF-β superfamily signals, Smad4 is key in orchestrating these effects. The role of Smad4 in HSC function has remained elusive because of the early embryonic lethality of the conventional knockout. We clarify its role by using an inducible model of Smad4 deletion coupled with transplantation experiments. Remarkably, systemic induction of Smad4 deletion through activation of MxCre was incompatible with survival 4 wk after induction because of anemia and histopathological changes in the colonic mucosa. Isolation of Smad4 deletion to the hematopoietic system via several transplantation approaches demonstrated a role for Smad4 in the maintenance of HSC self-renewal and reconstituting capacity, leaving homing potential, viability, and differentiation intact. Furthermore, the observed down-regulation of notch1 and c-myc in Smad4−/− primitive cells places Smad4 within a network of genes involved in the regulation HSC renewal

'How to know what you need to do': a cross-country comparison of maternal health guidelines in Burkina Faso, Ghana and Tanzania

Initiatives to raise the quality of care provided to mothers need to be given priority in Sub Saharan Africa (SSA). The promotion of clinical practice guidelines (CPGs) is a common strategy, but their implementation is often challenging, limiting their potential impact. Through a cross-country perspective, this study explored CPGs for maternal health in Burkina Faso, Ghana, and Tanzania. The objectives were to compare factors related to CPG use including their content compared with World Health Organization (WHO) guidelines, their format, and their development processes. Perceptions of their availability and use in practice were also explored. The overall purpose was to further the understanding of how to increase CPGs' potential to improve quality of care for mothers in SSA. The study was a multiple case study design consisting of cross-country comparisons using document review and key informant interviews. A conceptual framework to aid analysis and discussion of results was developed, including selected domains related to guidelines' implementability and use by health workers in practice in terms of usability, applicability, and adaptability. The study revealed few significant differences in content between the national guidelines for maternal health and WHO recommendations. There were, however, marked variations in the format of CPGs between the three countries. Apart from the Ghanaian and one of the Tanzanian CPGs, the levels of both usability and applicability were assessed as low or medium. In all three countries, the use of CPGs by health workers in practice was perceived to be limited. Our cross-country study suggests that it is not poor quality of content or lack of evidence base that constitute the major barrier for CPGs to positively impact on quality improvement in maternal care in SSA. It rather emphasises the need to prioritise the format of guidelines to increase their usability and applicability and to consider these attributes together with implementation strategies as integral to their development processes

The role of Smad signaling in hematopoiesis and translational hematology.

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-β (TGF-β) 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-β-superfamily signaling in normal and leukemic hematopoiesis.Leukemia advance online publication, 13 May 2011; doi:10.1038/leu.2011.95

Regulation of hematopoiesis by the Smad signaling pathway

Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) of adult individuals and are ultimately responsible for the continuous production of blood cells throughout life. The regulation of HSCs in vivo is tightly regulated by both intrinsic and extrinsic factors. The Smad-signaling pathway is an evolutionary conserved signaling circuitry with critical functions during embryogenesis and throughout adult life, regulating diverse biological processes. The transforming growth factor-? (TGF-?) superfamily of ligands transduce their signals intracellularly through the Smad pathway. A large number of studies, the majority of which have been carried out in vitro, have cataloged TGF-? as a potent negative regulator of HSC proliferation. However, due to embryonic lethality of knockout mice, in vivo investigations of the role of TGF-? and the downstream Smad pathway in the context of adult hematopoiesis have been hampered. To address this, we made use of the Cre/loxP system for inducible gene deletion of two different components of the TGF-? signaling pathway, the type I TGF-? receptor and Smad4 respectively. In addition, retroviral mediated gene transfer to HSCs was used as a tool to block the entire Smad-signaling pathway, by overexpression of the inhibitory Smad7. Induced disruption of the type I TGF-? receptor in adult mice resulted in an inflammatory disorder with a lethal outcome 8-10 weeks post induction. However, all hematopoietic parameters were normal under steady state conditions as well as the regenerative- and self-renewal capacity of mutant HSCs as assessed by transplantation. Smad4 null HSCs exhibited impaired repopulative capacity in a competitive repopulation assay, a behavior that was exacerbated upon secondary transplantation. Overexpression of Smad7 in HSCs resulted in increased regenerative capacity upon secondary transplantation, with a normal lineage distribution. Taken together, our data suggests that the Smad pathway is a critical regulator of HSC self-renewal in vivo

TGF-β signaling in the control of hematopoietic stem cells.

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 life-long hematopoiesis. HSC behavior, such as self-renewal and quiescence, are 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, hematological disease, and how this circuitry may be exploited for clinical purposes in the future

Signaling pathways governing stem cell fate.

Hematopoietic stem cells (HSCs) are historically the most thoroughly characterized type of adult stem cell, and the hematopoietic system has served as a principal model structure of stem-cell biology for several decades. However, paradoxically, although HSCs can be defined by function and even purified to near-homogeneity, the intricate molecular machinery and the signaling mechanisms regulating fate events, such as self-renewal and differentiation, have remained elusive. Recently, several developmentally conserved signaling pathways have emerged as important control devices of HSC fate, including Notch, Wingless-type (Wnt), Sonic hedgehog (Shh), and Smad pathways. HSCs reside in a complex environment in the bone marrow, providing a niche that optimally balances signals that control self-renewal and differentiation. These signaling circuits provide a valuable structure for our understanding of how HSC regulation occurs, concomitantly with providing information of how the bone marrow microenvironment couples and integrates extrinsic with intrinsic HSC fate determinants. It is the focus of this review to highlight some of the most recent developments concerning signaling pathways governing HSC fate

Quiescence of hematopoietic stem cells and maintenance of the stem cell pool is not dependent on TGF-beta signaling in vivo.

Abstract is not available. This is the final, accepted and revised manuscript of the article