Regulation of cellular lineages by PAX2 during kidney development

• Project/Area Number: 20H03699
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Kumamoto University
• Principal Investigator: Kobayashi Akio 熊本大学, 発生医学研究所, 准教授 (90840223)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2022: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2021: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2020: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
• Keywords: 腎臓発生 / 前駆細胞 / 細胞系譜境界 / ネフロン / PAX2 / 腎臓 / 間質 / 細胞系譜解析

Outline of Research at the Start

哺乳類の腎臓において、機能単位であるネフロンは胎児期にのみ作られ、生後新しいネフロンは生成されない。よって成体内でネフロンは増えることなく、徐々に失われていくことで腎臓病となる。本研究では、ネフロンと間質間の細胞系譜境界制御機構について、PAX2遺伝子を手がかりにすることで解明することにより、腎臓内でのネフロン再生の可能性について研究を行う。将来的に、ヒトPAX2変異であるRenal coloboma syndrome (RCS)を含む腎臓病において、ネフロン再生による腎機能回復の新しい治療法を開発することで、透析や腎移植の負担をなくすことを目指すものである。

Outline of Final Research Achievements

It is currently unclear how cellular linages are formed during kidney development in mammals. We previously discovered that the cellular lineage boundary between the nephron and renal interstitium is established by PAX2 function in nephron progenitor cells repressing renal interstitial cell fates in the mouse. Here, we showed that this PAX2 function regulating the nephron-interstitium lineage boundary is restricted to nephron progenitor cells and is lost upon initiation of nephron differentiation. We further found that the requirement of PAX2 function can be recapitulated in nephron organoids generated from induced pluripotent stem (iPS) cells.

Academic Significance and Societal Importance of the Research Achievements

哺乳類の腎臓発生における細胞系譜境界形成の機構は不明であるが、本研究成果であるPAX2機能を手がかりに、細胞系譜境界の形成メカニズムを解き明かせる可能性が開けた。またヒト腎臓オルガノイドを用いてヒトPAX2変異であるRenal coloboma syndrome (RCS)の疾患モデルを確立することで、より良い再生医療ための知識の基礎を築き、将来的に透析・腎移植の必要性を無くし、RCSを含む腎臓病患者やその家族の負担を軽減することに繋がると期待される。

Research Products

• [Journal Article] Mice Lacking Wnt9a or Wnt4 Are Prone to Develop Spontaneous Osteoarthritis With Age and Display Alteration in Either the Trabecular or Cortical Bone Compartment (2022)
  • Author(s): Teufel Stefan、Wolff Lena、Konig Ulrich、Kobayashi Akio、Behringer Richard、Hartmann Christine
  • Journal Title: Journal of Bone and Mineral Research Volume: 37 Issue: 7 Pages: 1335-1351
  • DOI: 10.1002/jbmr.4569
  • Peer Reviewed
• [Journal Article] Generation of the organotypic kidney structure by integrating pluripotent stem cell-derived renal (2022)
  • Author(s): 2.Tanigawa S, Tanaka E, Miike K, Ohmori T, Inoue D, Cai C-L, Taguchi A, Kobayashi A, Nishinakamura R
  • Journal Title: Nature Communications Volume: 13 Issue: 1 Pages: 611-611
  • DOI: 10.1038/s41467-022-28226-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Building kidney organoids from pluripotent stem cells (2022)
  • Author(s): Kobayashi Akio、Nishinakamura Ryuichi
  • Journal Title: Current Opinion in Nephrology and Hypertension Volume: 31 Issue: 4 Pages: 367-373
  • DOI: 10.1097/mnh.0000000000000807
  • Peer Reviewed
• [Journal Article] Molecular detection of maturation stages in the developing kidney (2021)
  • Author(s): Naganuma H, Miike K, Ohmori T, Tanigawa S, Ichikawa T, Yamane M, Eto M, Niwa H, Kobayashi A, Nishinakamura R
  • Journal Title: Dev Biol Volume: 470 Pages: 62-73
  • DOI: 10.1016/j.ydbio.2020.11.002
  • Peer Reviewed
• [Journal Article] PKD1-dependent renal cytogenesis in human induced pluripotent stem cell-derived ureteric bud/collecting duct organoids (2020)
  • Author(s): Kuraoka S, Tanigawa S, Taguchi A, Hotta A, Nakazato H, Osafune K, Kobayashi A, Nishinakamura R.
  • Journal Title: J Am Soc Nephrol Volume: 31 Issue: 10 Pages: 2355-2371
  • DOI: 10.1681/asn.2020030378
  • Peer Reviewed
• [Presentation] Genetic regulation of cellular lineages in the kidney (2021)
  • Author(s): Akio Kobayashi
  • Organizer: The 4th KAIST-KU Workshop and Joint Symposium
  • Int'l Joint Research / Invited
• [Presentation] Genetic regulation of cellular lineages during kidney development" (2020)
  • Author(s): Akio Kobayashi
  • Organizer: The 15th International Symposium of The Institute Network for Biomedical Sciences
  • Invited
• [Remarks] PKD1変異を有するヒトiPS細胞由来尿管芽/集合管オルガノイドにおける腎嚢胞再現
  • URL: http://www.imeg.kumamoto-u.ac.jp/np107/
• [Remarks] 発生期腎臓の成熟段階を反映する遺伝子群の同定
  • URL: http://www.imeg.kumamoto-u.ac.jp/np115/