Generation of salivary glands derived from pluripotent stem cells via conditional blastocyst complementation
Junichi Tanaka,
Akihiro Miura,
Yuko Shimamura,
Youngmin Hwang,
Dai Shimizu,
Yuri Kondo,
Anri Sawada,
Hemanta Sarmah,
Zurab Ninish,
Kenji Mishima,
Munemasa Mori
Affiliations
Junichi Tanaka
Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA; Division of Pathology, Department of Oral Diagnostic Sciences, Showa University School of Dentistry, Tokyo 142-8555, Japan; Corresponding author
Akihiro Miura
Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
Yuko Shimamura
Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
Youngmin Hwang
Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
Dai Shimizu
Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
Yuri Kondo
Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
Anri Sawada
Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
Hemanta Sarmah
Columbia Stem Cell Initiative, Stem Cell Core, Columbia University Irving Medical Center, New York, NY 10032, USA
Zurab Ninish
Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
Kenji Mishima
Division of Pathology, Department of Oral Diagnostic Sciences, Showa University School of Dentistry, Tokyo 142-8555, Japan
Munemasa Mori
Columbia Center for Human Development and Division of Pulmonary, Allergy, Critical Care, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA; Corresponding author
Summary: Whole salivary gland generation and transplantation offer potential therapies for salivary gland dysfunction. However, the specific lineage required to engineer complete salivary glands has remained elusive. In this study, we identify the Foxa2 lineage as a critical lineage for salivary gland development through conditional blastocyst complementation (CBC). Foxa2 lineage marking begins at the boundary between the endodermal and ectodermal regions of the oral epithelium before the formation of the primordial salivary gland, thereby labeling the entire gland. Ablation of Fgfr2 within the Foxa2 lineage in mice leads to salivary gland agenesis. We reversed this phenotype by injecting donor pluripotent stem cells into the mouse blastocysts, resulting in mice that survived to adulthood with salivary glands of normal size, comparable to those of their littermate controls. These findings demonstrate that CBC-based salivary gland regeneration serves as a foundational experimental approach for future advanced cell-based therapies.
