scholarly journals Megakaryocyte TGFβ1 partitions erythropoiesis into immature progenitor/stem cells and maturing precursors

Blood ◽  
2020 ◽  
Vol 136 (9) ◽  
pp. 1044-1054 ◽  
Author(s):  
Silvana Di Giandomenico ◽  
Pouneh Kermani ◽  
Nicole Mollé ◽  
Maria Mia Yabut ◽  
Ghaith Abu-Zeinah ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Low Dose ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Subsequent Treatment ◽  
Modular Organization ◽  
Tgfβ Signaling ◽  
Survival Signal ◽  
New Strategy ◽  
First Time

Abstract Erythropoietin (EPO) provides the major survival signal to maturing erythroid precursors (EPs) and is essential for terminal erythropoiesis. Nonetheless, progenitor cells can irreversibly commit to an erythroid fate well before EPO acts, risking inefficiency if these progenitors are unneeded to maintain red blood cell (RBC) counts. We identified a new modular organization of erythropoiesis and, for the first time, demonstrate that the pre-EPO module is coupled to late EPO-dependent erythropoiesis by megakaryocyte (Mk) signals. Disrupting megakaryocytic transforming growth factor β1 (Tgfb1) disorganized hematopoiesis by expanding the pre-EPO pool of progenitor cells and consequently triggering significant apoptosis of EPO-dependent EPs. Similarly, pharmacologic blockade of TGFβ signaling in normal mice boosted the pre-EPO module, leading to apoptosis of EPO-sensitive EPs. Subsequent treatment with low-dose EPO triggered robust RBC production in both models. This work reveals modular regulation of erythropoiesis and offers a new strategy for overcoming chronic anemias.

Biphasic effect of pioglitazone on isolated human endothelial progenitor cells: Involvement of peroxisome proliferator-activated receptor-γ and transforming growth factor-β1

2007 ◽  
Vol 97 (06) ◽  
pp. 988-997 ◽  
Author(s):  
Mihail Hristov ◽  
Denis Gümbel ◽  
Teresa Tejerina ◽  
Santiago Redondo ◽  
Christian Weber
Keyword(s):  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Peroxisome Proliferator ◽  
Endothelial Progenitor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Patients With Diabetes ◽  
Tgf Β1

SummaryEndothelial progenitor cells (EPCs) have been implicated in vascular repair and found to be functionally impaired in patients with diabetes. We evaluated the effects of the anti-diabetic drug pioglitazone on human EPC function and the involvement of PPAR-γ and TGF-β1. EPCs in culture were characterized at day 7 by the development of colony-forming units (CFUs) and flow cytometry assessment of differentiation marker (DiI-ac-LDL/lectin, KDR and CD31). Adhesion on fibronectin and fibrinogen in flow was analyzed as functional parameter. Treatment with pioglitazone for 72 hours increased the number of EPC-CFUs, DiI-ac-LDL+/lectin+, CD31+ and KDR+ EPCs at 1 μM but not at 10 μM. Since pioglitazone did not significantly alter proliferation and apoptosis in cultured EPCs, the increase in EPC number was most likely attributable to augmented adhesion and differentiation. Indeed, pioglitazone increased EPC adhesion in flow at 1 μM, an effect prevented by PPAR-γ and β2-integrin blockade. In contrast, pioglitazone did not promote EPC adhesion at 10 μM; however, increased adhesion became evident by co-incubation with a blocking TGF-β1 antibody. As determined by ELISA, pioglitazone induced a persistent increase in TGF-β1 secretion only at 10 μM when a significantly elevated expression of endoglin, the accessory receptor forTGF-β1, was also observed. Taken together, pioglitazone exerts biphasic effects on the function of isolated EPCs, causing a PPAR-γ-dependent stimulation at 1 μM and a TGF-β1-mediated suppression at 10 μM. These results may help to define optimal therapeutic doses of pioglitazone for improving endothelial dysfunction.

Transforming growth factor-β1 primes proliferating adult neural progenitor cells to electrophysiological functionality

Glia ◽  
2013 ◽  
Vol 61 (11) ◽  
pp. 1767-1783 ◽  
Author(s):  
Sabrina Kraus ◽  
Bernadette Lehner ◽  
Nadine Reichhart ◽  
Sebastien Couillard-Despres ◽  
Katrin Wagner ◽  
...  
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Neural Progenitor Cells ◽  
Transforming Growth Factor ◽  
Neural Progenitor ◽  
Transforming Growth Factor Β1

scholarly journals Transforming growth factor-β1 modulates responses of CD34+ cord blood cells to stromal cell-derived factor-1/CXCL12

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 485-493 ◽  
Author(s):  
Sunanda Basu ◽  
Hal E. Broxmeyer
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Cord Blood ◽  
Progenitor Cells ◽  
Stromal Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Cd34 Cells ◽  
Stromal Cell Derived Factor ◽  
Tgf Β1

Abstract Disruption of stromal cell-derived factor-1 (SDF-1/CXCL12 [CXC chemokine ligand 12]) interaction leads to mobilization of stem/progenitor cells from bone marrow to circulation. However, prolonged exposure of CD34+ cells to SDF-1 desensitizes them to SDF-1. So how do cells remain responsive to SDF-1 in vivo when they are continuously exposed to SDF-1? We hypothesized that one or more mechanisms mediated by cytokines exist that could modulate SDF-1 responsiveness of CD34+ cells and the desensitization process. We considered transforming growth factor-β1 (TGF-β1) a possible candidate, since TGF-β1 has effects on CD34+ cells and is produced by stromal cells, which provide niches for maintenance and proliferation of stem/progenitor cells. TGF-β1 significantly restored SDF-1–induced chemotaxis and sustained adhesion responses in cord blood CD34+ cells preexposed to SDF-1. Effects of TGF-β1 were dependent on the dose and duration of TGF-β1 pretreatment. Phosphorylation of extracellular signal-regulated kinase 1 (Erk1)/Erk2 was implicated in TGF-β1 modulation of migratory and adhesion responses to SDF-1. Our results indicate that low levels of TGF-β1 can modulate SDF-1 responsiveness of CD34+ cells and thus may facilitate SDF-1–mediated retention and nurturing of stem/progenitor cells in bone marrow.

Unexpected Evidence That Dimethylsulphoxide (DMSO) Upregulates Expression of CXCR4 on Hematopoietic Stem/Progenitor Cells (HSPC), Increases Their Responsiveness to an SDF-1 Gradient and Enhances Homing to Bone Marrow.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1973-1973
Author(s):  
Marcin Majka ◽  
Danuta Jarocha ◽  
Marcin Wysoczynski ◽  
Duygu Sag ◽  
Ewa Zuba-Surma ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Mononuclear Cells ◽  
Short Exposure ◽  
Hematopoietic Stem ◽  
Akt Phosphorylation ◽  
Human Cd34 ◽  
New Strategy ◽  
First Time

Abstract Cryopreservation of bone marrow (BM), mobilized peripheral blood (mPB) and cord blood (CB) cells is a routine procedure to store hematopoietic stem/progenitor cells (HSPC) for transplantation. Dimethylsulphoxide (DMSO), the most commonly used cryoprotectant, is toxic to cells at higher concentrations (>10%); moreover, the freezing-thawing procedure itself is inevitably connected with the loss of HSPC. However, by chance we observed that short exposure of HSPC to DMSO enhances the responsiveness of these cells to an SDF-1 gradient and since SDF-1 is a major chemoattractant that navigates homing of HSPC to BM we became interested in elucidating this phenomenon. We found that short incubation (5–10 min) of human CB mononuclear cells (MNC) with DMSO at concentrations employed for cryopreservation (5–10%) significantly upregulates the expression of both CXCR4 (x 2–3) and CD34 (x 1.5) on CB MNC (as measured by FACS). Furthermore, DMSO significantly increased the chemotactic responsiveness (x 2–4) of CB MNC, BM MNC and selected CXCR4+ human hematopoietic cell lines (Jurkat, THP-1 cells) when the cells were exposed to 5–10% DMSO before chemotaxis assay. These responses to an SDF-1 gradient correlated with enhanced chemotaxis also of human CD34+, CD34+ CD38+, CD34+ CD38−, and CD34+ CXCR4+ clonogeneic progenitor cells, suggesting that DMSO directly enhances the responsiveness of human early progenitors (p<0.0001). At the molecular level, 5–10% DMSO strongly stimulated and prolonged SDF-1-dependent AKT phosphorylation. However, at the same time DMSO inhibited phosphorylation of MAPKp42/44. Similar observations were made for Sca-1+ BM-derived murine cells. In parallel experiments we found that murine Sca-1+ cells when preincubated with DMSO formed more 12 day-CFU-S colonies in spleens after transplantation into irradiated syngeneic recipients. Accordingly, x 2 more CFU-S were formed when Sca-1+ cells were exposed before transplantation to 5% DMSO and about x 4 more after exposure to 10% DMSO. Finally we employed a Ly5.1/Ly5.2 congeneic transplant model and showed that transplantation of Ly5.1 Sca-1+ cells exposed to 10% DMSO before transplantation resulted in higher chimerism in transplanted Ly5.2 mice as compared to untreated cells (control) (p<0.0001). In conclusion, we show for the first time an unexpected beneficial role of DMSO (5–10%) in regulation of homing of HSPC after transplantation and suggest that a short priming of HSPC with DMSO, even of non-cryopreserved cells, before transplantation may become a new strategy to enhance engraftment

Transforming Growth Factor-β1 Polarizes Murine Hematopoietic Progenitor Cells to Generate Langerhans Cell-Like Dendritic Cells Through a Monocyte/Macrophage Differentiation Pathway

Blood ◽  
1999 ◽  
Vol 93 (4) ◽  
pp. 1208-1220 ◽  
Author(s):  
Yi Zhang ◽  
Yan-yun Zhang ◽  
Masafumi Ogata ◽  
Pan Chen ◽  
Akihisa Harada ◽  
...  
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Macrophage Differentiation ◽  
Gm Csf ◽  
Tgf Β1 ◽  
E Cadherin

We have recently demonstrated that CD11b−/dullCD11c+ and CD11b+hiCD11c+ dendritic cell (DC) precursor subsets represent two distinct DC differentiation pathways from murine bone marrow lineage-phenotype negative (Lin−)c-kit+ hematopoietic progenitor cells (HPCs) stimulated with granulocyte-macrophage colony-stimulating factor (GM-CSF) + stem cell factor (SCF) + tumor necrosis factor  (TNF). We show here that transforming growth factor-β1 (TGF-β1) significantly inhibits the generation of these CD11b−/dullCD11c+ and CD11b+hiCD11c+ DC precursors. Phenotypically, this inhibitory effect was accompanied by markedly suppressed expression of Ia and CD86 antigens as well as major histocompatibility complex (MHC) class II transactivator (CIITA) and CC-chemokine receptor 7 (CCR7) mRNAs in Lin−c-kit+ HPC cultures stimulated with GM-CSF + SCF + TNF at day 6. TGF-β1 could also suppress mature DC differentiation from CD11b+hiCD11c+ DC precursors, but not the differentiation from CD11b−/dullCD11c+ DC precursors. In the absence of TNF, TGF-β1 markedly suppressed the expression of CIITA and CCR7 mRNAs in GM-CSF + SCF-stimulated Lin−c-kit+ HPCs at either day 6 or day 12 and induced the differentiation solely into monocytes/macrophages as evident in morphology, active phagocytic, and endocytic activities. These cells expressed high levels of F4/80 and E-cadherin antigens, but low or undetectable levels of Ia, CD86, and CD40 molecules. However, upon the stimulation with TNF + GM-CSF, these cells could further differentiate into mature DCs expressing high levels of Ia and E-cadherin, characteristics for Langerhans cells (LCs), and gained the capacity of enhancing allogenic MLR. Taken together, all of these findings suggest that TGF-β1 polarizes murine HPCs to generate LC-like DCs through a monocyte/macrophage differentiation pathway.

The effect of a low dose of transforming growth factor β1 (TGF-β1) on the early bone-healing around oral implants inserted in trabecular bone

Biomaterials ◽  
2009 ◽  
Vol 30 (1) ◽  
pp. 94-99 ◽  
Author(s):  
Dimitris Nikolidakis ◽  
Gert J. Meijer ◽  
Daniel A.W. Oortgiesen ◽  
X. Frank Walboomers ◽  
John A. Jansen
Keyword(s):  
Growth Factor ◽  
Trabecular Bone ◽  
Bone Healing ◽  
Low Dose ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Oral Implants ◽  
Tgf Β1

Retroviral-Mediated Gene Transduction of c-kit Into Single Hematopoietic Progenitor Cells From Cord Blood Enhances Erythroid Colony Formation and Decreases Sensitivity to Inhibition by Tumor Necrosis Factor- and Transforming Growth Factor-β1

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2319-2332 ◽  
Author(s):  
Li Lu ◽  
Michael C. Heinrich ◽  
Li-Sheng Wang ◽  
Mu-Shui Dai ◽  
Amy J. Zigler ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Necrosis Factor ◽  
Progenitor Cells ◽  
Colony Formation ◽  
Tumor Necrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Gm Csf ◽  
Cd34 Cells ◽  
Necrosis Factor

The c-kit receptor and its ligand, steel factor (SLF), are critical for optimal hematopoiesis. We evaluated effects of transducing cord blood (CB) progenitor cells with a retrovirus encoding humanc-kit cDNA. CD34+ cells were sorted as a population or as 1 cell/well for cells expressing high levels of CD34+++ and different levels of c-kit (++, +, Lo/−), transduced and then cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), IL-6, erythropoietin (Epo) +/− SLF in the absence of serum. At a single-cell level, transduction with c-kit, but not with control (neo only), virus significantly increased colony formation, especially by erythroid and multipotential progenitors. The enhancing effect of c-kit transduction was inversely correlated with expression of c-kit protein before transduction. The greatest enhancing effects were noted in CD34+++kitLo/− cells transduced with c-kit. The stimulating effect was apparent even in the absence of exogenously added SLF, but in the presence of GM-CSF, IL-3, IL-6, and Epo. Enzyme-linked immunosorbent assay (ELISA) of SLF protein, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of SLF mRNA expression in CD34+ cells, and use of neutralizing antibodies to SLF and/or c-kit suggested the presence of endogenous, although probably very low level, expression of SLF by these progenitor cells. Transduction of c-kit significantly decreased sensitivity of progenitor cells to the inhibitory effects of transforming growth factor-β1 and tumor necrosis factor-.c-kit–transduced cells had increased expression ofc-kit protein and decreased spontaneous or cytokine-induced apoptosis. Our results suggest that transduced c-kit into selected progenitor cells can enhance proliferation and decrease apoptosis and that endogenous SLF may mediate this effect.

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