Marino Nakajima

Tokyo Metropolitan Institute of Medical Science

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Takahiko Hara

Tokyo Metropolitan Institute of Medical Science

Mai Kanokoda

Tokyo Metropolitan Institute of Medical Science

Kenji Kitajima

Tokyo Metropolitan Institute of Medical Science

Manami Kawaguchi

Tokyo Metropolitan Institute of Medical Science

Hidenori Suzuki

Nippon Medical School

Kohji Kasahara

Tokyo Metropolitan Institute of Medical Science

Kazuya Miyashita

Medical & Biological Laboratories (Japan)

Minako Shingai

Tokyo Metropolitan Institute of Medical Science

Masashi Toyoda

National Center For Child Health and Development

Abhijit Dandapat

Editas Medicine (United States)

Cooperative Institutions

Tokyo Metropolitan Institute of Medical Science

Tokyo Medical and Dental University

Stem Cell Institute

The University of Tokyo

National Institutes of Health

University of Minnesota

University of Minnesota System

Tohoku University

Tokyo Metropolitan University

National Center For Child Health and Development

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In vitro differentiation of mouse T cell-derived hybrid cells obtained through cell fusion with embryonic stem cells

Biochemical and Biophysical Research Communications (2019)

Marino Nakajima Teruhiko Suzuki Takahiko Hara Kenji Kitajima

Reprogramming

Embryoid body

Cell fusion

Cell potency

10.1016/j.bbrc.2019.04.038

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Citations (1)

GSK3β inhibition activates the CDX/HOX pathway and promotes hemogenic endothelial progenitor differentiation from human pluripotent stem cells

Experimental Hematology (2015)

Kenji Kitajima Marino Nakajima Mai Kanokoda Michael Kyba Abhijit Dandapat

Hemangioblast

10.1016/j.exphem.2015.09.007

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Citations (23)

Efficient production of T cells from mouse pluripotent stem cells by controlled expression ofLhx2

Genes to Cells (2015)

Kenji Kitajima Manami Kawaguchi Kazuya Miyashita Marino Nakajima Mai Kanokoda

LIM ‐homeobox transcription factor Lhx2 induces ex vivo amplification of adult hematopoietic stem cells ( HSC s) in mice. We previously showed that engraftable HSC ‐like cells are generated from mouse embryonic stem cells ( ESC s) and induced pluripotent stem cells by enforced expression of Lhx2 . However, when these HSC ‐like cells were transplanted into irradiated congenic mice, donor‐derived T cells were barely detectable, whereas other lineages of hematopoietic cells were continuously produced. Here we investigated T‐cell differentiation potential of the Lhx2 ‐induced HSC ‐like cells using ESC s carrying doxycycline (dox)‐inducible Lhx2 expression cassette. Dox‐mediated over‐expression of Lhx2 conferred a self‐renewing activity to ESC ‐derived c‐Kit + CD 41 + embryonic hematopoietic progenitor cells ( HPC s), thereby converting them to HSC ‐like cells. When these HSC ‐like cells were transplanted into irradiated immunodeficient mice and they were supplied with a dox‐containing water, CD 4/8 double negative T cells were detected in their thymi. Once the Lhx2 expression was terminated, differentiation of CD 4/8 double positive and single positive T cells was initiated in the thymi of transplanted mice and mature T cells were released in the peripheral blood. These results showed that engraftable HSC ‐like cells with full hematopoietic potential can be obtained from ESC s by the conditional expression of Lhx2 .

KOSR

10.1111/gtc.12266

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Modification of Lhx2 activity for ex vivo amplification of human iPSC-derived hematopoietic stem/progenitor cells

Frontiers in Cell and Developmental Biology (2024)

Kenji Kitajima Yuna Takahashi Hikaru Ando Minako Shingai Mako Hamasaki

Hematopoietic stem cells (HSCs) obtained from patient-derived human induced pluripotent stem cells (iPSCs) are a promising tool for curing various hematological disorders. We previously demonstrated that enforced expression of the LIM-homeobox transcription factor Lhx2, which is essential for mouse embryonic hematopoiesis, leads to generation of engraftable and expandable hematopoietic stem cells (HSCs) from mouse iPSCs. However, it remained unknown whether Lhx2 can induce HSCs from human iPSCs. Here, we investigated the effect of Lhx2 overexpression on hematopoietic differentiation of human iPSCs. Unexpectedly, Lhx2 severely inhibited proliferation of human iPSC-derived hematopoietic cells. Thus, Lhx2 exhibited differential effects on mouse and human hematopoietic cells. Further studies implied that the inhibitory effect of Lhx2 on human iPSC-derived hematopoietic cells was due to insufficient transcriptional activation ability. Therefore, we modified Lhx2 to strengthen its activity as a transcriptional activator. This modified Lhx2 could induce ex vivo amplification of human iPSC-derived hematopoietic stem/progenitor cells (HSPCs). We believe that these findings will facilitate the development of a method to efficiently produce HSCs from human iPSCs.

Hematopoietic stem cell

Ex vivo

10.3389/fcell.2024.1482989

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Domain-specific biological functions of the transcription factor Gata2 on hematopoietic differentiation of mouse embryonic stem cells

Genes to Cells (2018)

Kenji Kitajima Mai Kanokoda Marino Nakajima Takahiko Hara

The generation of mouse hematopoietic stem cells from hemogenic endothelial cells (HECs) in the aorta/gonad/mesonephros region of developing embryos requires a zinc finger transcription factor Gata2. In the previous study, an enforced expression of Gata2 in vitro promoted the production of HECs from mesodermal cells differentiated from mouse embryonic stem cells (ESCs). Our research group has previously demonstrated that the enforced expression of Gata2 in ESC-derived HECs enhances erythroid and megakaryocyte differentiation and inhibits macrophage differentiation. However, the manner in which the multiple functions of Gata2 are regulated remains unclear. Mouse ESCs differentiate into various types of hematopoietic cells when cocultured with OP9 stromal cells (OP9 system). Using this system and the inducible gene cassette exchange system, which facilitates the establishment of ESCs carrying inducible transgenes under an identical gene expression regulatory unit, the domain-specific functions of Gata2 were systematically dissected in this study. We determined that the N-terminal (amino acid 1-110) region of Gata2 was an erythroid-inducing region, both the middle (amino acid 111-200) and C-terminal (amino acid 413-480) regions were megakaryocyte-inducing regions. Furthermore, the present data strongly suggest that intramolecular antagonistic interactions between each of these regions fine-tune the biological functions of Gata2.

GATA2

GATA transcription factor

GATA1

10.1111/gtc.12628

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Citations (7)

Efficient production of platelets from mouse embryonic stem cells by enforced expression of Gata2 in late hemogenic endothelial cells

Biochemical and Biophysical Research Communications (2016)

Manami Kawaguchi Kenji Kitajima Mai Kanokoda Hidenori Suzuki Kazuya Miyashita

GATA2

10.1016/j.bbrc.2016.04.140

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