腎臓発生・再生グループ

　私たちのグループの使命は、発生過程において腎臓の構造と機能がどのように構築されるのか、腎臓の成り立ちを明らかにすることで、現代医学では未だ根治が困難である慢性腎臓病に対する新たな治療法を確立することです。

　「発生学」にはあまり馴染みが無い方も居るかもしれませんが、臓器の発生機構を理解することは、その臓器の器官としての「設計図」を解読する作業であり、それを明らかにして初めて、疾患によって変容した臓器の組織や機能の修復法、すなわち「臓器再生」が可能になると考えます。それは例えば事故で取れてしまった車の部品をとりあえずガムテープで貼り付けて修復するのか、作られた際の設計図に沿って、元通り組み立て直すのかの違いです。

　私たちはこれまでに、発生初期における腎臓の起源が従来の教科書的理解とは異なることを明らかにしました。この発見は、それまで不可能であった、腎臓のネフロンオルガノイド、集合管オルガノイドの創出を可能にしました。さらに間質前駆細胞と合わせた３種類の前駆細胞を組み合わせて胎児腎臓の高次構造を再現し、かつては夢物語と考えられていた腎臓組織の「形」を試験管内で再現する技術を革新してきました。しかし、その先にある「機能の再現」は、いまだ十分とは言えません。

　腎臓はどのような分子・細胞メカニズムによって高度な代謝機能を獲得するのか。私たちは発生後期の成熟化過程に着目し、それを生体外で再現する研究に取り組んでいます。この仕組みを解明することができれば、機能低下状態にある慢性腎臓病に対して、その機能を回復させる新たな再生医療の創出へとつながると期待されます。

　私たちは、マウスを用いた生体内解析に加え、初代培養や独自のマウス・ヒトの各腎臓オルガノイド技術を駆使し、生体に出来るだけ近いコンテクストを生体外へと持ち出し、操作・解析することを強みとしています。さらに、ゲノム編集、フローサイトメトリー、単一細胞トランスクリプトミクス、CRISPRスクリーニング、バイオインフォマティクスなどの最先端手法を統合することで、分子レベルにおける遺伝子発現制御ネットワークの解明と、その制御基盤の確立を目指しています。

Our mission is to understand how the structure and function of the kidney are established during development and, through this understanding, to develop new therapeutic strategies for chronic kidney disease (CKD), which remains difficult to cure with current medical treatments.

Developmental biology may not be a familiar field to everyone. Yet understanding how an organ develops is, in essence, like deciphering the “blueprint” from which the organ is built. We believe that only by understanding this blueprint can we learn how to restore tissues and functions that have been altered by disease—in other words, how to achieve true “organ regeneration.” To use a simple analogy, imagine repairing a car after a part has been torn off in an accident. One option is to simply tape the broken part back into place. The other is to rebuild it properly according to the original design. We believe that regenerative medicine should aim for the latter.

Our previous research revealed that the developmental origin of the kidney during early embryogenesis differs from the conventional textbook model. This discovery enabled the generation of nephron and collecting duct organoids, which had previously been difficult to achieve. By further combining three distinct progenitor populations—including stromal progenitors—we have reconstructed higher-order structures of the fetal kidney in vitro. Through these studies, we have helped advance technologies that reproduce the “form” of kidney tissue in a dish—something that was once considered almost impossible. However, recapitulating kidney “function” remains a major challenge.

How does the kidney acquire its highly specialized metabolic functions at the molecular and cellular levels? To address this question, we focus on the late stages of kidney development, particularly the process of functional maturation, and seek to recapitulate this process in vitro. By uncovering the mechanisms that drive kidney maturation, we hope to establish a new paradigm for regenerative medicine: rather than simply replacing damaged tissue, we aim to restore lost organ function in chronic kidney disease.

Our strength lies in our ability to bring physiologically relevant developmental contexts from the body into experimentally accessible in vitro systems. In addition to in vivo studies using mouse models, we employ primary cell cultures and our unique mouse and human kidney organoid technologies to reconstruct, manipulate, and analyze kidney development under controlled conditions.

We further integrate state-of-the-art approaches—including genome editing, flow cytometry, single-cell transcriptomics, CRISPR screening, and bioinformatics—to decipher the gene regulatory networks that govern kidney development and maturation at the molecular level. Ultimately, we aim not only to understand these regulatory mechanisms, but also to establish strategies for manipulating them to restore kidney function in disease.