GATA-3 controls self-renewal in stressed HSCs

Yoshida, Toshimi; Georgopoulos, Katia

doi:10.1038/ni.2715

Cited by 5 publications

(4 citation statements)

References 8 publications

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“…donovani infection early hematopoietic progenitors accumulate in BM due to an increase in active proliferation, but at the expense of the reservoir of quiescent LT-HSCs. We found that alteration in the proliferative status of LT-HSCs was associated with the upregulation of the expression of GATA-3, a transcription factor previously associated with loss of reconstitution potential of HSCs [37], and confirmed loss of self -renewal capacity through serial transfer. As residual HSC function was reflected by multilineage differentiation, within the constraints of our analysis, the impact of infection with L .…”

Section: Discussionsupporting

confidence: 69%

TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis

et al. 2017

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Visceral leishmaniasis is associated with significant changes in hematological function but the mechanisms underlying these changes are largely unknown. In contrast to naïve mice, where most long-term hematopoietic stem cells (LT-HSCs; LSK CD150+ CD34- CD48- cells) in bone marrow (BM) are quiescent, we found that during Leishmania donovani infection most LT-HSCs had entered cell cycle. Loss of quiescence correlated with a reduced self-renewal capacity and functional exhaustion, as measured by serial transfer. Quiescent LT-HSCs were maintained in infected RAG2 KO mice, but lost following adoptive transfer of IFNγ-sufficient but not IFNγ-deficient CD4+ T cells. Using mixed BM chimeras, we established that IFNγ and TNF signalling pathways converge at the level of CD4+ T cells. Critically, intrinsic TNF signalling is required for the expansion and/or differentiation of pathogenic IFNγ+CD4+ T cells that promote the irreversible loss of BM function. These findings provide new insights into the pathogenic potential of CD4+ T cells that target hematopoietic function in leishmaniasis and perhaps other infectious diseases where TNF expression and BM dysfunction also occur simultaneously.

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Section: Discussionsupporting

confidence: 69%

TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis

et al. 2017

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“…This role for Srp is strikingly similar to the one for GATA-3 in Long Term HSCs (LT-HSCs), which sustain life-long production of all mammalian blood lineages [100]. Recent studies in mice suggest that stress signaling activates GATA-3 in LT-HSCs, which interferes with self-renewal and promotes differentiation [101], [102]. Thus, in both flies and mice, stress increases GATA activity to promote hematopoietic progenitor differentiation.…”

Section: Discussionmentioning

confidence: 84%

Antioxidants Maintain E-Cadherin Levels to Limit Drosophila Prohemocyte Differentiation

Gao

Simon

et al. 2014

PLoS ONE

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Mitochondrial reactive oxygen species (ROS) regulate a variety of biological processes by networking with signal transduction pathways to maintain homeostasis and support adaptation to stress. In this capacity, ROS have been shown to promote the differentiation of progenitor cells, including mammalian embryonic and hematopoietic stem cells and Drosophila hematopoietic progenitors (prohemocytes). However, many questions remain about how ROS alter the regulatory machinery to promote progenitor differentiation. Here, we provide evidence for the hypothesis that ROS reduce E-cadherin levels to promote Drosophila prohemocyte differentiation. Specifically, we show that knockdown of the antioxidants, Superoxide dismutatase 2 and Catalase reduce E-cadherin protein levels prior to the loss of Odd-skipped-expressing prohemocytes. Additionally, over-expression of E-cadherin limits prohemocyte differentiation resulting from paraquat-induced oxidative stress. Furthermore, two established targets of ROS, Enhancer of Polycomb and FOS, control the level of E-cadherin protein expression. Finally, we show that knockdown of either Superoxide dismutatase 2 or Catalase leads to an increase in the E-cadherin repressor, Serpent. As a result, antioxidants and targets of ROS can control E-cadherin protein levels, and over-expression of E-cadherin can ameliorate the prohemocyte response to oxidative stress. Collectively, these data strongly suggest that ROS promote differentiation by reducing E-cadherin levels. In mammalian systems, ROS promote embryonic stem cell differentiation, whereas E-cadherin blocks differentiation. However, it is not known if elevated ROS reduce E-cadherin to promote embryonic stem cell differentiation. Thus, our findings may have identified an important mechanism by which ROS promote stem/progenitor cell differentiation.

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“…GATA-2 loss of function mutation leads to dysfunctional adult human cord blood progenitors with self-renewal potential ( Menendez-Gonzalez et al, 2019 ). Conversely, LT-HSCs are enriched with GATA-3, whose activation has correlated signaling through the MAPK-p38a pathway ( Yoshida and Georgopoulos, 2013 ). The loss of GATA-3 in steady-state quiescent HSCs does not affect its self-renewal or proliferation ( Yoshida and Georgopoulos, 2013 ).…”

Section: Factors For Hematopoietic Stem Cells Stemness and Self-renewalmentioning

confidence: 99%

“…Conversely, LT-HSCs are enriched with GATA-3, whose activation has correlated signaling through the MAPK-p38a pathway ( Yoshida and Georgopoulos, 2013 ). The loss of GATA-3 in steady-state quiescent HSCs does not affect its self-renewal or proliferation ( Yoshida and Georgopoulos, 2013 ). However, under stress-activated p38a conditions, GATA-3 deletion restrains the self-renewal of LT-HSCs by balancing proliferation and differentiation without affecting the cell cycle ( Frelin et al, 2013 ; Yoshida and Georgopoulos, 2013 ).…”

Section: Factors For Hematopoietic Stem Cells Stemness and Self-renewalmentioning

confidence: 99%

Hematopoietic Stem Cell Factors: Their Functional Role in Self-Renewal and Clinical Aspects

Mann¹,

Sengar

Verma

et al. 2022

Front. Cell Dev. Biol.

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Hematopoietic stem cells (HSCs) possess two important properties such as self-renewal and differentiation. These properties of HSCs are maintained through hematopoiesis. This process gives rise to two subpopulations, long-term and short-term HSCs, which have become a popular convention for treating various hematological disorders. The clinical application of HSCs is bone marrow transplant in patients with aplastic anemia, congenital neutropenia, sickle cell anemia, thalassemia, or replacement of damaged bone marrow in case of chemotherapy. The self-renewal attribute of HSCs ensures long-term hematopoiesis post-transplantation. However, HSCs need to be infused in large numbers to reach their target site and meet the demands since they lose their self-renewal capacity after a few passages. Therefore, a more in-depth understanding of ex vivo HSCs expansion needs to be developed to delineate ways to enhance the self-renewability of isolated HSCs. The multifaceted self-renewal process is regulated by factors, including transcription factors, miRNAs, and the bone marrow niche. A developed classical hierarchical model that outlines the hematopoiesis in a lineage-specific manner through in vivo fate mapping, barcoding, and determination of self-renewal regulatory factors are still to be explored in more detail. Thus, an in-depth study of the self-renewal property of HSCs is essentially required to be utilized for ex vivo expansion. This review primarily focuses on the Hematopoietic stem cell self-renewal pathway and evaluates the regulatory molecular factors involved in considering a targeted clinical approach in numerous malignancies and outlining gaps in the current knowledge.

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GATA-3 controls self-renewal in stressed HSCs

Cited by 5 publications

References 8 publications

TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis

TNF signalling drives expansion of bone marrow CD4+ T cells responsible for HSC exhaustion in experimental visceral leishmaniasis

Antioxidants Maintain E-Cadherin Levels to Limit Drosophila Prohemocyte Differentiation

Hematopoietic Stem Cell Factors: Their Functional Role in Self-Renewal and Clinical Aspects

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