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

Rörby, Emma; Hägerström, Matilda Nifelt; Blank, Ulrika; Karlsson, Göran; Karlsson, Stefán

doi:10.1182/blood-2012-02-408658

Cited by 17 publications

(17 citation statements)

References 33 publications

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“…Additionally, overexpression of SMAD4 sensitizes human cord blood-derived candidate HSCs to TGF-b, resulting in reduced regenerative capacity in vivo. 73 Together, these findings suggest that transient inhibition of TGF-b …”

Section: 61-63mentioning

confidence: 69%

TGF-β signaling in the control of hematopoietic stem cells

Blank

Karlsson

2015

Blood

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228

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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.

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Section: 61-63mentioning

confidence: 69%

TGF-β signaling in the control of hematopoietic stem cells

Blank

Karlsson

2015

Blood

Self Cite

228

212

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“…TGFb ensures stem cell homeostasis by keeping HSCs in quiescence (Pietras et al 2011) while inducing growth arrest and apoptosis in early HSPCs (Rorby et al 2012). Thus, insensitivity to this inhibitory growth factor would render cells resistant to normal homeostatic mechanisms.…”

Section: Discussionmentioning

confidence: 99%

miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling

et al. 2014

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Although regulation of stem cell homeostasis by microRNAs (miRNAs) is well studied, it is unclear how individual miRNAs genomically encoded within an organized polycistron can interact to induce an integrated phenotype. miR-99a/100, let-7, and miR-125b paralogs are encoded in two tricistrons on human chromosomes 11 and 21. They are highly expressed in hematopoietic stem cells (HSCs) and acute megakaryoblastic leukemia (AMKL), an aggressive form of leukemia with poor prognosis. Here, we show that miR-99a/100~125b tricistrons are transcribed as a polycistronic message transactivated by the homeobox transcription factor HOXA10. Integrative analysis of global gene expression profiling, miRNA target prediction, and pathway architecture revealed that miR-99a/100, let-7, and miR-125b functionally converge at the combinatorial block of the transforming growth factor b (TGFb) pathway by targeting four receptor subunits and two SMAD signaling transducers. In addition, down-regulation of tumor suppressor genes adenomatous polyposis coli (APC)/APC2 stabilizes active b-catenin and enhances Wnt signaling. By switching the balance between Wnt and TGFb signaling, the concerted action of these tricistronic miRNAs promoted sustained expansion of murine and human HSCs in vitro or in vivo while favoring megakaryocytic differentiation. Hence, our study explains the high phylogenetic conservation of the miR-99a/100~125b tricistrons controlling stem cell homeostasis, the deregulation of which contributes to the development of AMKL.

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“…In fact, recent work published by Rörby et al 67 demonstrated the impact on CB HSC of a protein involved in the signaling cascade of TGF-b called SMAD4. They used a lentiviral overexpression technique and observed that CB HSC overexpressing SMAD4 were more susceptible to TGF-b and therefore presented higher levels of growth arrest and apoptosis in vitro.…”

Section: Interaction Between Nk Cells and Treg Cells In Hematopoieticmentioning

confidence: 99%

Interaction between natural killer cells and regulatory T cells: perspectives for immunotherapy

2013

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Regulatory T (Treg) cells and natural killer (NK) cells are key players in the immune system. The interaction between these two cell types has been reported to be beneficial in healthy conditions such as pregnancy. However, in the case of certain pathologies such as autoimmune diseases and cancer this interaction can become detrimental, as Treg cells have been described to suppress NK cells and in particular to impair NK cell effector functions. This review aims to discuss the recent information on the interaction between Treg cells and NK cells under healthy and pathologic conditions, to describe the specific conditions in which this interaction takes place, the effect of Treg cells on hematopoietic stem cell differentiation and the consequences of this interaction on the optimization of immunotherapeutic protocols.

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

Cited by 17 publications

References 33 publications

TGF-β signaling in the control of hematopoietic stem cells

TGF-β signaling in the control of hematopoietic stem cells

miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling

Interaction between natural killer cells and regulatory T cells: perspectives for immunotherapy

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