| 1. |
Fumio Arai, Patrick S Stumpf, Yoshiko M Ikushima, Kentaro Hosokawa, Aline Roch, Matthias P Lutolf, Toshio Suda, Ben D MacArthur, Machine Learning of Hematopoietic Stem Cell Divisions from Paired Daughter Cell Expression Profiles Reveals Effects of Aging on Self-Renewal, CELL SYSTEMS, 10.1016/j.cels.2020.11.004, 11, 6, 640-+, 2020.12, Changes in stem cell activity may underpin aging. However, these changes are not completely understood. Here, we combined single-cell profiling with machine learning and in vivo functional studies to explore how hematopoietic stem cell (HSC) divisions patterns evolve with age. We first trained an artificial neural network (ANN) to accurately identify cell types in the hematopoietic hierarchy and predict their age from single-cell gene-expression patterns. We then used this ANN to compare identities of daughter cells immediately after HSC divisions and found that the self-renewal ability of individual HSCs declines with age. Furthermore, while HSC cell divisions are deterministic and intrinsically regulated in young and old age, they are variable and niche sensitive in mid-life. These results indicate that the balance between intrinsic and extrinsic regulation of stem cell activity alters substantially with age and help explain why stem cell numbers increase through life, yet regenerative potency declines.. |
| 2. |
Kazuhito Gotoh, Yuya Kunisaki, Soichi Mizuguchi, Daiki Setoyama, Kentaro Hosokawa, Hisayuki Yao, Yuya Nakashima, Mikako Yagi, Takeshi Uchiumi, Yuichiro Semba, Jumpei Nogami, Koichi Akashi, Fumio Arai, Dongchon Kang, Mitochondrial Protein Synthesis Is Essential for Terminal Differentiation of CD45(-) TER119(-) Erythroid and Lymphoid Progenitors, ISCIENCE, 10.1016/j.isci.2020.101654, 23, 11, 2020.11, p32/C1qbp regulates mitochondrial protein synthesis and is essential for oxidative phosphorylation in mitochondria. Although dysfunction of p32/C1qbp impairs fetal development and immune responses, its role in hematopoietic differentiation remains unclear. Here, we found that mitochondrial dysfunction affected terminal differentiation of newly identified erythroid/B-lymphoid progenitors among CD45- Ter119- CD31- triple-negative cells (TNCs) in bone marrow. Hematopoietic cell-specific genetic deletion of p32/C1qbp (p32cKO) in mice caused anemia and B-lymphopenia without reduction of hematopoietic stem/progenitor cells. In addition, p32cKO mice were susceptible to hematopoietic stress with delayed recovery from anemia. p32/C1qbp-deficient CD51- TNCs exhibited impaired mitochondrial oxidation that consequently led to inactivation of mTORC1 signaling, which is essential for erythropoiesis. These findings uncover the importance of mitochondria, especially at the stage of TNCs during erythropoiesis, suggesting that dysregulation of mitochondrial protein synthesis is a cause of anemia and B-lymphopenia with an unknown pathology.. |
| 3. |
Hosokawa Kentaro, MacArthur BD, Ikushima YM, Toyama H, Masuhiro Y, Hanazawa S, Suda T, Fumio Arai, The telomere binding protein Pot1 maintains haematopoietic stem cell activity with age., Nature Communications, 10.1038/s41467-017-00935-4, 8, 1, 2017.10. |
| 4. |
Sakamoto H, Takeda N, Fumio Arai, Hosokawa Kentaro, Garcia P, Suda T, Frampton J, Ogawa M, Determining c-Myb protein levels can isolate functional hematopoietic stem cell subtypes, Stem Cells, 10.1002/stem.1855, 2015.02. |
| 5. |
Horio E, Kadomatsu T, Miyata K, Arai Y, Hosokawa Kentaro, Doi Y, Ninomiya T, Horiguchi H, Endo M, Tabata M, Tazume H, Tian Z, Takahashi O, Terada K, Takeya M, Hao H, Hirose N, Minami T, Suda T, Oike Y, Role of endothelial cell-derived angptl2 in vascular inflammation leading to endothelial dysfunction and atherosclerosis progression., Arterioscler Thromb Vasc Biol., 2014.04. |
| 6. |
Yamashita M, Nitta E, Nagamatsu Go, Ikushima YM, Hosokawa Kentaro, Fumio Arai, Suda T, Nucleostemin is indispensable for the maintenance and genetic stability of hematopoietic stem cells., Biochem Biophys Res Commun., 2013.11. |
| 7. |
Ikushima YM, Hosokawa Kentaro, Fumio Arai, Toyama H, Takubo K, Furuyashiki T, Narumiya S, Suda T, Prostaglandin E(2) regulates murine hematopoietic stem/progenitor cells directly via EP4 receptor and indirectly through mesenchymal progenitor cells., Blood., 2013.03. |
| 8. |
Ikushima YM, Fumio Arai, Nakamura Y, Hosokawa Kentaro, Kubota Y, Hirashima M, Toyama H, Suda T, Enhanced Angpt1/Tie2 signaling affects the differentiation and long-term repopulation ability of hematopoietic stem cells., Biochem Biophys Res Commun., 2013.01. |
| 9. |
Toyama H, Fumio Arai, Hosokawa Kentaro, Ikushima YM, Suda T, N-cadherin+ HSCs in fetal liver exhibit higher long-term bone marrow reconstitution activity than N-cadherin- HSCs., Biochem Biophys Res Commun., 2012.11. |
| 10. |
Zou P, Yoshihara H, Hosokawa Kentaro, Tai I, Shinmyozu K, Tsukahara F, Maru Y, Nakayama K, Keiichi Nakayama, Suda T, p57(Kip2) and p27(Kip1) cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc70., Cell Stem Cell., 2011.09. |
| 11. |
Nitta E, Yamashita M, Hosokawa Kentaro, Xian M, Takubo K, Fumio Arai, Nakada S, Suda T, Telomerase reverse transcriptase protects ATM-deficient hematopoietic stem cells from ROS-induced apoptosis through a telomere-independent mechanism., Blood., 2011.04. |
| 12. |
Nakamura Y, Fumio Arai, Iwasaki H, Hosokawa Kentaro, Kobayashi I, Gomei Y, Matsumoto Y, Yoshihara H, Suda T, Isolation and characterization of endosteal niche cell populations that regulate hematopoietic stem cells., Blood., 2010.08. |
| 13. |
Hosokawa Kentaro, Fumio Arai, Yoshihara H, Iwasaki H, Nakamura Y, Gomei Y, Suda T, Knockdown of N-cadherin suppresses the long-term engraftment of hematopoietic stem cells., Blood., 2010.07. |
| 14. |
Hosokawa Kentaro, Fumio Arai, Yoshihara H, Iwasaki H, Hembree M, Yin T, Nakamura Y, Gomei Y, Takubo K, Shiama H, Matsuoka S, Li L, Suda T, Cadherin-based adhesion is a potential target for niche manipulation to protect hematopoietic stem cells in adult bone marrow., Cell Stem Cell., 2010.03. |
| 15. |
Gomei Y, Nakamura Y, Yoshihara H, Hosokawa Kentaro, Iwasaki H, Suda T, Fumio Arai, Functional differences between two Tie2 ligands, angiopoietin-1 and -2, in regulation of adult bone marrow hematopoietic stem cells., Exp Hematol., 2010.02. |
| 16. |
Shima H, Takubo K, Iwasaki H, Yoshihara H, Gomei Y, Hosokawa Kentaro, Fumio Arai, Takahashi T, Suda T, Reconstitution activity of hypoxic cultured human cord blood CD34-positive cells in NOG mice., Biochem Biophys Res Commun., 2009.01. |
| 17. |
Matsuoka S, Oike Y, Onoyama I, Iwama A, Fumio Arai, Takubo K, Mashimo Y, Oguro H, Nitta E, Ito K, Miyamoto K, Yoshiwara H, Hosokawa Kentaro, Nakamura Y, Gomei Y, Iwasaki H, Hayashi Y, Matsuzaki Y, Keiichi Nakayama, Suda T, Fbxw7 acts as a critical fail-safe against premature loss of hematopoietic stem cells and development of T-ALL., Genes Dev., 2008.04. |
| 18. |
Yoshihara H, Fumio Arai, Hosokawa Kentaro, Hagiwara T, Takubo K, Nakamura Y, Gomei Y, Iwasaki H, Matsuoka S, Miyamoto K, Miyazaki H, Takahashi T, Suda T, Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche., Cell Stem Cell., 2007.12. |
| 19. |
Hosokawa Kentaro, Fumio Arai, Yoshihara H, Nakamura Y, Gomei Y, Iwasaki H, Miyamoto K, Shima H, Ito K, Suda T, Function of oxidative stress in the regulation of hematopoietic stem cell-niche interaction., Biochem Biophys Res Commun., 2007.11. |
| 20. |
Miyamoto K, Araki KY, Naka K, Fumio Arai, Takubo K, Yamazaki S, Matsuoka S, Miyamoto T, Ito K, Ohmura M, Chen C, Hosokawa Kentaro, Nakauchi H, Nakayama K, Keiichi Nakayama, Harada M, Motoyama N, Suda T, Hirao A, Foxo3a is essential for maintenance of the hematopoietic stem cell pool., Cell Stem Cell., 2007.06. |
| 21. |
Ito K, Takubo K, Fumio Arai, Satoh H, Matsuoka S, Ohmura M, Naka K, Azuma M, Miyamoto K, Hosokawa Kentaro, Ikeda Y, Mak TW, Suda T, Hirao A, Regulation of reactive oxygen species by Atm is essential for proper response to DNA double-strand breaks in lymphocytes., J Immunol., 2007.01. |
| 22. |
Ito K, Hirao A, Fumio Arai, Takubo K, Matsuoka S, Miyamoto K, Ohmura M, Naka K, Hosokawa Kentaro, Ikeda Y, Suda T, Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells., Nat Med., 2006.04. |
| 23. |
Ito K, Hirao A, Fumio Arai, Matsuoka S, Takubo K, Hamaguchi I, Nomiyama K, Hosokawa Kentaro, Sakurada K, Nakagata N, Ikeda Y, Mak TW, Suda T, Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells., Nature., 2004.10. |
