In vitro bone-like nodules generated from patient-derived iPSCs recapitulate pathological bone phenotypes

• Published in: Nature biomedical engineering Vol. 3; no. 7; pp. 558 - 570
• Main Authors: Kawai, Shunsuke, Yoshitomi, Hiroyuki, Sunaga, Junko, Alev, Cantas, Nagata, Sanae, Nishio, Megumi, Hada, Masataka, Koyama, Yuko, Uemura, Maya, Sekiguchi, Kazuya, Maekawa, Hirotsugu, Ikeya, Makoto, Tamaki, Sakura, Jin, Yonghui, Harada, Yuki, Fukiage, Kenichi, Adachi, Taiji, Matsuda, Shuichi, Toguchida, Junya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2019; Nature Publishing Group
• Subjects: 13/100; 13/107; 13/21; 14/19; 38/61; 38/89; 42/41; 631/154; 631/1647; 631/80; 692/699; Animals; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedical materials; Biomedicine; Bone and Bones - drug effects; Bone and Bones - pathology; Bone and Bones - physiology; Bone growth; Bone Morphogenetic Proteins; Cell Differentiation; Cells, Cultured; Differentiation (biology); Gene Expression Regulation; Humans; In Vitro Techniques; Induced Pluripotent Stem Cells - drug effects; Induced Pluripotent Stem Cells - pathology; Induced Pluripotent Stem Cells - physiology; Inhibitory postsynaptic potentials; Male; Mice; Mice, Nude; Mice, SCID; Mutation; Nodules; Osteoblastogenesis; Osteogenesis; Osteogenesis - drug effects; Osteogenesis - genetics; Osteogenesis - physiology; Phenotype; Phenotypes; Pluripotency; Rapamycin; Receptors, Retinoic Acid - drug effects; Retinoic acid; Retinoic acid receptors; Signal transduction; Signaling; Stem cell transplantation; Stem cells; TOR protein; TOR Serine-Threonine Kinases - drug effects; Transplantation; Tretinoin - pharmacology; Wnt protein; Wnt Signaling Pathway
• ISSN: 2157-846X
• DOI: 10.1038/s41551-019-0410-7

The recapitulation of bone formation via the in vitro generation of bone-like nodules is frequently used to understand bone development. However, current bone-induction techniques are slow and difficult to reproduce. Here, we report the formation of bone-like nodules within ten days, via the use of retinoic acid (RA) to induce the osteogenic differentiation of human induced pluripotent stem cells (hiPSCs) into osteoblast-like and osteocyte-like cells that create human bone tissue when implanted in calvarial defects in mice. We also show that the induction of bone formation depends on cell signalling through the RA receptors RARα and RARβ, which simultaneously activate the BMP (bone morphogenetic protein) and Wnt signalling pathways. Moreover, by using patient-derived hiPSCs, the bone-like nodules recapitulated the osteogenesis-imperfecta phenotype, which was rescued via the correction of disease-causing mutations and partially by an mTOR (mechanistic target of rapamycin) inhibitor. The method of inducing bone nodules may serve as a fast and reproducible model for the study of the formation of both healthy and pathological bone. A fast in vitro model of the formation of bone-like nodules, enabled by the retinoic-acid-mediated induction of the osteogenic differentiation of patient-derived induced pluripotent stem cells, recapitulates the osteogenesis-imperfecta phenotype.