Signaling from Fibroblast Growth Factor Receptor 2 in Immature Hematopoietic Cells Facilitates Donor Hematopoiesis After Intra-Bone Marrow–Bone Marrow Transplantation

Shigematsu, Akio; Shi, Ming; Okigaki, Mitsuhiko; Adachi, Yasushi; Koike, Naoko; Che, Jishan; Iwasaki, Masanori; Matsubara, Hiroaki; Imamura, Masahiro; Ikehara, Susumu

doi:10.1089/scd.2009.0370

Cited by 6 publications

(7 citation statements)

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“…We also observed a strong increase in the expression of FGFR2 in CD71 + cells, which subsequently declined in Ter119 + cells. This correlates well with previous observations that indicate that FGFR2 plays a role in hematopoiesis [12] , [23] . In vitro differentiation of mouse ES cells using the hanging drop method without LIF showed induction of Spry1 expression is biphasic, with the first peak of expression occurring on day 4 of differentiation, before the rise in Flk1 expression ( Figure 1C ).…”

Section: Resultssupporting

confidence: 93%

“…Contradictory roles for FGFR signaling in the regulation of hematopoiesis have been reported, with FGFR1 having a positive effect, whereas FGFR2 negatively regulates hematopoiesis in mouse and chick embryogenesis, respectively [11] , [12] , [23] . We have shown a stage-dependent expression pattern of FGFR1 and FGFR2 during hemangioblast differentiation into primitive hematopoietic cells.…”

Section: Discussionmentioning

confidence: 99%

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Spry1 Is Expressed in Hemangioblasts and Negatively Regulates Primitive Hematopoiesis and Endothelial Cell Function

2011

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BackgroundDevelopment of the hematopoietic and endothelial lineages derives from a common mesodermal precursor, the Flk1+ hemangioblast. However, the signaling pathways that regulate the development of hematopoietic and endothelial cells from this common progenitor cell remains incompletely understood. Using mouse models with a conditional Spry1 transgene, and a Spry1 knockout mouse, we investigated the role of Spry1 in the development of the endothelial and hematopoietic lineages during development.Methodology/Principal FindingsQuantitative RT-PCR analysis demonstrates that Spry1, Spry2, and Spry4 are expressed in Flk1+ hemangioblasts in vivo, and decline significantly in c-Kit+ and CD41+ hematopoietic progenitors, while expression is maintained in developing endothelial cells. Tie2-Cre-mediated over-expression of Spry1 results in embryonic lethality. At E9.5 Spry1;Tie2-Cre embryos show near normal endothelial cell development and vessel patterning but have reduced hematopoiesis. FACS analysis shows a reduction of primitive hematopoietic progenitors and erythroblastic cells in Spry1;Tie2-Cre embryos compared to controls. Colony forming assays confirm the hematopoietic defects in Spry1;Tie2-Cre transgenic embryos. Immunostaining shows a significant reduction of CD41 or CD71 and dpERK co-stained cells in Spry1;Tie2-Cre embryos compared to controls, whereas the number of VEC+ and dpERK co-stained cells is comparable. Compared to controls, Spry1;Tie2-Cre embryos also show a decrease in proliferation and an increase in apoptosis. Furthermore, loss of Spry1 results in an increase of CD41+ and CD71+ cells at E9.5 compared with controls.Conclusions/SignificanceThese data indicate that primitive hematopoietic cells derive from Tie2-expressing hemangioblasts and that Spry1 over expression inhibits primitive hematopoietic progenitor and erythroblastic cell development and expansion while having no obvious effect on endothelial cell development.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Spry1 Is Expressed in Hemangioblasts and Negatively Regulates Primitive Hematopoiesis and Endothelial Cell Function

2011

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“… 10 However, FGFR2 is also highly expressed in healthy tissues, including the brain, 38 skin 39 and bone marrow. 40 Therefore, the identification of more specific surface markers of WNT2-secreting CAFs will be required to develop novel CAF-depletion strategies that can be used to improve the efficiency of anti-PD-1 therapy in OC (oesophageal cancer) and CRC.…”

Section: Discussionmentioning

confidence: 99%

Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity

Huang

Tan

Huang

et al. 2021

Gut

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ObjectiveSolid tumours respond poorly to immune checkpoint inhibitor (ICI) therapies. One major therapeutic obstacle is the immunosuppressive tumour microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a key component of the TME and negatively regulate antitumour T-cell response. Here, we aimed to uncover the mechanism underlying CAFs-mediated tumour immune evasion and to develop novel therapeutic strategies targeting CAFs for enhancing ICI efficacy in oesophageal squamous cell carcinoma (OSCC) and colorectal cancer (CRC).DesignAnti-WNT2 monoclonal antibody (mAb) was used to treat immunocompetent C57BL/6 mice bearing subcutaneously grafted mEC25 or CMT93 alone or combined with anti-programmed cell death protein 1 (PD-1), and the antitumour efficiency and immune response were assessed. CAFs-induced suppression of dendritic cell (DC)-differentiation and DC-mediated antitumour immunity were analysed by interfering with CAFs-derived WNT2, either by anti-WNT2 mAb or with short hairpin RNA-mediated knockdown. The molecular mechanism underlying CAFs-induced DC suppression was further explored by RNA-sequencing and western blot analyses.ResultsA negative correlation between WNT2+ CAFs and active CD8+ T cells was detected in primary OSCC tumours. Anti-WNT2 mAb significantly restored antitumour T-cell responses within tumours and enhanced the efficacy of anti-PD-1 by increasing active DC in both mouse OSCC and CRC syngeneic tumour models. Directly interfering with CAFs-derived WNT2 restored DC differentiation and DC-mediated antitumour T-cell responses. Mechanistic analyses further demonstrated that CAFs-secreted WNT2 suppresses the DC-mediated antitumour T-cell response via the SOCS3/p-JAK2/p-STAT3 signalling cascades.ConclusionsCAFs could suppress antitumour immunity through WNT2 secretion. Targeting WNT2 might enhance the ICI efficacy and represent a new anticancer immunotherapy.

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“…Using mice overexpressing constitutively active FGFR2 (under control of the Tie-2 promoter), Shigematsu et al demonstrate that FGFR2 signaling facilitates donor hematopoietic engraftment in a transplantation scenario and that this is due to its anti-apoptotic effects [113] . Finally, high FGF activity negatively regulates the formation of primitive blood in chick embryo and promotes endothelial cell differentiation.…”

Section: Extrinsic Regulators Of Hematopoietic Stem Cell Generationmentioning

confidence: 99%

The biochemistry of hematopoietic stem cell development

Kaimakis

Crisan

Dzierzak

2013

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background The cornerstone of the adult hematopoietic system and clinical treatments for blood-related disease is the cohort of hematopoietic stem cells (HSC) that is harbored in the adult bone marrow microenvironment. Interestingly, this cohort of HSCs is generated only during a short window of developmental time. In mammalian embryos, hematopoietic progenitor and HSC generation occurs within several extra- and intra-embryonic microenvironments, most notably from ‘hemogenic’ endothelial cells lining the major vasculature. HSCs are made through a remarkable transdifferentiation of endothelial cells to a hematopoietic fate that is long-lived and self-renewable. Recent studies are beginning to provide an understanding of the biochemical signaling pathways and transcription factors/complexes that promote their generation. Scope of the review The focus of this review is on the biochemistry behind the generation of these potent long-lived self-renewing stem cells of the blood system. Both the intrinsic (master transcription factors) and extrinsic regulators (morphogens and growth factors) that affect the generation, maintenance and expansion of HSCs in the embryo will be discussed. Major conclusions The generation of HSCs is a stepwise process involving many developmental signaling pathways, morphogens and cytokines. Pivotal hematopoietic transcription factors are required for their generation. Interestingly, whereas these factors are necessary for HSC generation, their expression in adult bone marrow HSCs is oftentimes not required. Thus, the biochemistry and molecular regulation of HSC development in the embryo is overlapping, but differs significantly from the regulation of HSCs in the adult. General significance HSC numbers for clinical use are limiting, and despite much research into the molecular basis of HSC regulation in the adult bone marrow, no panel of growth factors, interleukins and/or morphogens has been found to sufficiently increase the number of these important stem cells. An understanding of the biochemistry of HSC generation in the developing embryo provides important new knowledge on how these complex stem cells are made, sustained and expanded in the embryo to give rise to the complete adult hematopoietic system, thus stimulating novel strategies for producing increased numbers of clinically useful HSCs.

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Signaling from Fibroblast Growth Factor Receptor 2 in Immature Hematopoietic Cells Facilitates Donor Hematopoiesis After Intra-Bone Marrow–Bone Marrow Transplantation

Cited by 6 publications

References 33 publications

Spry1 Is Expressed in Hemangioblasts and Negatively Regulates Primitive Hematopoiesis and Endothelial Cell Function

Spry1 Is Expressed in Hemangioblasts and Negatively Regulates Primitive Hematopoiesis and Endothelial Cell Function

Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity

The biochemistry of hematopoietic stem cell development

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