Publications by authors named "Akihisa Oda"

7 Publications

  • Page 1 of 1

Transcription factor Tlx1 marks a subset of lymphoid tissue organizer-like mesenchymal progenitor cells in the neonatal spleen.

Sci Rep 2019 12 31;9(1):20408. Epub 2019 Dec 31.

Division of Development and Aging, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan.

The spleen is comprised of spatially distinct compartments whose functions, such as immune responses and removal of aged red blood cells, are tightly controlled by the non-hematopoietic stromal cells that provide regionally-restricted signals to properly activate hematopoietic cells residing in each area. However, information regarding the ontogeny and relationships of the different stromal cell types remains limited. Here we have used in vivo lineage tracing analysis and in vitro mesenchymal stromal cell assays and found that Tlx1, a transcription factor essential for embryonic spleen organogenesis, marks neonatal stromal cells that are selectively localized in the spleen and retain mesenchymal progenitor potential to differentiate into mature follicular dendritic cells, fibroblastic reticular cells and marginal reticular cells. Furthermore, by establishing a novel three-dimensional cell culture system that enables maintenance of Tlx1-expressing cells in vitro, we discovered that signals from the lymphotoxin β receptor and TNF receptor promote differentiation of these cells to express MAdCAM-1, CCL19 and CXCL13, representative functional molecules expressed by different subsets of mature stromal cells in the spleen. Taken together, these findings indicate that mesenchymal progenitor cells expressing Tlx1 are a subset of lymphoid tissue organizer-like cells selectively found in the neonatal spleen.
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http://dx.doi.org/10.1038/s41598-019-56984-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938487PMC
December 2019

Niche-induced extramedullary hematopoiesis in the spleen is regulated by the transcription factor Tlx1.

Sci Rep 2018 05 29;8(1):8308. Epub 2018 May 29.

Division of Development and Aging, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan.

Extramedullary hematopoiesis (EMH) in postnatal life is a pathological process in which the differentiation of hematopoietic stem/progenitor cells (HSPCs) occurs outside the bone marrow (BM) to respond to hematopoietic emergencies. The spleen is a major site for EMH; however, the cellular and molecular nature of the stromal cell components supporting HSPC maintenance, the niche for EMH in the spleen remain poorly understood compared to the growing understanding of the BM niche at the steady-state as well as in emergency hematopoiesis. In the present study, we demonstrate that mesenchymal progenitor-like cells expressing Tlx1, an essential transcription factor for spleen organogenesis, and selectively localized in the perifollicular region of the red pulp of the spleen, are a major source of HSPC niche factors. Consistently, overexpression of Tlx1 in situ induces EMH, which is associated with mobilization of HSPC into the circulation and their recruitment into the spleen where they proliferate and differentiate. The alterations in the splenic microenvironment induced by Tlx1 overexpression in situ phenocopy lipopolysaccharide (LPS)-induced EMH, and the conditional loss of Tlx1 abolished LPS-induced splenic EMH. These findings indicate that activation of Tlx1 expression in the postnatal splenic mesenchymal cells is critical for the development of splenic EMH.
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http://dx.doi.org/10.1038/s41598-018-26693-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974313PMC
May 2018

Germ cell-intrinsic requirement for the homeodomain transcription factor PKnox1/Prep1 in adult spermatogenesis.

PLoS One 2018 2;13(1):e0190702. Epub 2018 Jan 2.

Division of Development and Aging, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan.

PKnox1 (also known as Prep1) belongs to the TALE family of homeodomain transcription factors that are critical for regulating growth and differentiation during embryonic and postnatal development in vertebrates. We demonstrate here that PKnox1 is required for adult spermatogenesis in a germ cell-intrinsic manner. Tamoxifen-mediated PKnox1 loss in the adult testes, as well as its germ cell-specific ablation, causes testis hypotrophy with germ cell apoptosis and, as a consequence, compromised spermatogenesis. In PKnox1-deficient testes, spermatogenesis was arrested at the c-Kit+ spermatogonia stage, with a complete loss of the meiotic spermatocytes, and was accompanied by compromised differentiation of the c-Kit+ spermatogonia. Taken together, these results indicate that PKnox1 is a critical regulator of maintenance and subsequent differentiation of the c-Kit+ stage of spermatogonia in the adult testes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190702PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749842PMC
February 2018

Loss of the Homeodomain Transcription Factor Prep1 Perturbs Adult Hematopoiesis in the Bone Marrow.

PLoS One 2015 18;10(8):e0136107. Epub 2015 Aug 18.

Division of Development and Aging, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan.

Prep1, a TALE-family homeodomain transcription factor, has been demonstrated to play a critical role in embryonic hematopoiesis, as its insufficiency caused late embryonic lethality associated with defective hematopoiesis and angiogenesis. In the present study, we generated hematopoietic- and endothelial cell-specific Prep1-deficient mice and demonstrated that expression of Prep1 in the hematopoietic cell compartment is not essential for either embryonic or adult hematopoiesis, although its absence causes significant hematopoietic abnormalities in the adult bone marrow. Loss of Prep1 promotes cell cycling of hematopoietic stem/progenitor cells (HSPC), leading to the expansion of the HSPC pool. Prep1 deficiency also results in the accumulation of lineage-committed progenitors, increased monocyte/macrophage differentiation and arrested erythroid maturation. Maturation of T cells and B cells is also perturbed in Prep-deficient mice. These findings provide novel insight into the pleiotropic roles of Prep1 in adult hematopoiesis that were unrecognized in previous studies using germline Prep1 hypomorphic mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136107PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540428PMC
May 2016

Generation of a Tlx1(CreER-Venus) knock-in mouse strain for the study of spleen development.

Genesis 2014 Nov 18;52(11):916-23. Epub 2014 Oct 18.

Division of Development and Aging, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan.

The spleen is a lymphoid organ that serves as a unique niche for immune reactions, extramedullary hematopoiesis, and the removal of aged erythrocytes from the circulation. While much is known about the immunological functions of the spleen, the mechanisms governing the development and organization of its stromal microenvironment remain poorly understood. Here we report the generation and analysis of a Tlx1(Cre) (ER) (-Venus) knock-in mouse strain engineered to simultaneously express tamoxifen-inducible CreER(T2) and Venus fluorescent protein under the control of regulatory elements of the Tlx1 gene, which encodes a transcription factor essential for spleen development. We demonstrated that Venus as well as CreER expression recapitulates endogenous Tlx1 transcription within the spleen microenvironment. When Tlx1(Cre) (ER) (-Venus) mice were crossed with the Cre-inducible reporter strain, Tlx1-expressing cells as well as their descendants were specifically labeled following tamoxifen administration. We also showed by cell lineage tracing that asplenia caused by Tlx1 deficiency is attributable to altered contribution of mesenchymal cells in the spleen anlage to the pancreatic mesenchyme. Thus, Tlx1(Cre) (ER) (-Venus) mice represent a new tool for lineage tracing and conditional gene manipulation of spleen mesenchymal cells, essential approaches for understanding the molecular mechanisms of spleen development.
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http://dx.doi.org/10.1002/dvg.22829DOI Listing
November 2014

BLNK binds active H-Ras to promote B cell receptor-mediated capping and ERK activation.

J Biol Chem 2009 Apr 13;284(15):9804-13. Epub 2009 Feb 13.

Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, 2669 Yamazaki, Noda, Chiba 278-0022, Japan.

Cross-linked B cell receptor (BCR) aggregates on the cell surface, then assembles into the "cap" where Ras is co-localized, and transduces various intracellular signals including Ras-ERK activation. BCR signals induce proliferation, differentiation, or apoptosis of B cells depending on their maturational stage. The adaptor protein BLNK binds various signaling proteins and Igalpha, a signaling subunit of the BCR complex, and plays an important role in the BCR signal transduction. BLNK was shown to be required for activation of ERK, but not of Ras, after BCR cross-linking, raising a question how BLNK facilitates ERK activation. Here we demonstrate that BLNK binds the active form of H-Ras, and their binding is facilitated by BCR cross-linking. We have identified a 10-amino acid Ras-binding domain within BLNK that is necessary for restoration of BCR-mediated ERK activation in BLNK-deficient B cells and for anti-apoptotic signaling. The Ras-binding domain fused with a CD8alpha-Igalpha chimeric receptor could induce prolonged ERK phosphorylation, transcriptional activation of Elk1, as well as the capping of the receptor in BLNK-deficient B cells. These results indicate that BLNK recruits active H-Ras to the BCR complex, which is essential for sustained surface expression of BCR in the form of the cap and for the signal leading to functional ERK activation.
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http://dx.doi.org/10.1074/jbc.M809051200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2665102PMC
April 2009

PKC eta directs induction of IRF-4 expression and Ig kappa gene rearrangement in pre-BCR signaling pathway.

Int Immunol 2008 Nov 9;20(11):1417-26. Epub 2008 Sep 9.

Division of Molecular Biology, Tokyo University of Science, Noda, Chiba 278-0022, Japan.

Pre-B cell receptor (pre-BCR) signals promote pre-B cell differentiation, in which the adaptor protein B-cell linker (BLNK) plays a crucial role. However, the molecular pathways downstream of BLNK are currently unclear. Utilizing pre-B leukemia cell lines (BKO84 and others) derived from BLNK-deficient mice as in vitro models of the pre-B cell differentiation, we have demonstrated that reconstitution of BLNK as well as an active form of protein kinase C (PKC)eta induces the differentiation events, such as pre-BCR down-regulation and kappa gene rearrangement. Here we show that the same events are induced by cross-linking of pre-BCR with anti-mu antibody in these pre-B cell lines, as well as in ex vivo pre-B cells from BLNK-deficient mice, suggesting a function of BLNK as an internal cross-linker of pre-BCR. Anti-mu treatment of BKO84 cells up-regulated membrane recruitment of PKC eta and the expression of IRF-4, a transcription factor known to promote light chain gene rearrangements. Anti-mu induction of surface kappa chain on BKO84 cells was blocked by reagents that inhibit phospholipase C or PKC. Enforced expression of the active PKC eta in BKO84 cells resulted in up-regulation of IRF-4 expression. Conversely, siRNA-mediated silencing of PKC eta expression strikingly attenuated the anti-mu-induced IRF-4 expression and kappa gene rearrangement, which were restored by PKC eta reconstitution. Finally, enforced expression of IRF-4, but not of BLNK, in the PKC eta-silenced BKO84 cells resulted in kappa gene rearrangement. These results indicate that PKC eta directs the induction of IRF-4 expression downstream of BLNK in the pre-BCR signaling pathway promoting kappa gene rearrangement.
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http://dx.doi.org/10.1093/intimm/dxn101DOI Listing
November 2008