■ Organogenesis and Regeneration
During fertilization and the early stages of embryonic development, positional information is provided by the body plan, determining which part of the body each region will become. Organ formation appropriate to this positional information is then induced during the fetal period. Organs are formed from organ germs—primordial seeds of organs and tissues—that are induced through epithelial–mesenchymal interactions in the fetus. From these two types of stem cells, multiple cell types contributing to organ function are generated, enabling the organ to develop into a three-dimensional structure and to express its physiological functions after birth.
In principle, this organ formation is limited to the fetal stage, as the stem cells responsible for organogenesis exist only during fetal development. After birth, they transition into somatic stem cells that maintain the organ. Consequently, because stem cells capable of forming entire organs cannot be obtained from the body after birth, transplantation of organs or tissues remains the only available medical intervention when organ failure occurs.
■ Strategies for Organ Regeneration Based on Development and Regeneration
The development of regenerative medicine technologies has progressed from first-generation stem cell transplantation therapies to second-generation tissue regeneration, some of which are already entering clinical application. Three-dimensional organ regeneration is positioned as the third generation. Although tissue engineering has been studied for more than 50 years from the perspectives of scaffolds, cells, and bioactive substances, no practical applications have been realized to date. The main challenge lies in the fact that organs are complex, high-density three-dimensional structures composed of multiple cell types.
With the arrival of the 21st century, stem cell biology has made significant advances in the fields of development and regeneration. We sought to apply these principles of development and regeneration, together with the body’s intrinsic healing power, to approach the challenge of organ regeneration.
Our initial focus was on developing cell manipulation techniques to control two types of stem cells, each possessing the inductive capacity for organ formation during the fetal stage, in an ex vivo environment. Once removed from the body, cells disperse, and determining how to spatially organize these two types of cells posed a major challenge. Although developmental biology had been exploring this issue for over 30 years, the technology remained incomplete.
Through years of trial and error, we succeeded in 2007 in inventing the ‘Organ Germ Method,’ a technique that enables epithelial and mesenchymal stem cells to self-organize into distinct, high-density compartments resembling their in vivo interactions. This innovation became the foundation for all subsequent progress in organ regeneration.
