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

Nat Biomed Eng. 2019 Jul;3(7):558-570. doi: 10.1038/s41551-019-0410-7. Epub 2019 Jun 10.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins
  • Bone and Bones / drug effects
  • Bone and Bones / pathology*
  • Bone and Bones / physiology*
  • Cell Differentiation
  • Cells, Cultured
  • Gene Expression Regulation
  • Humans
  • In Vitro Techniques
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / pathology*
  • Induced Pluripotent Stem Cells / physiology*
  • Male
  • Mice
  • Mice, Nude
  • Mice, SCID
  • Mutation
  • Osteogenesis / drug effects
  • Osteogenesis / genetics
  • Osteogenesis / physiology*
  • Phenotype
  • Receptors, Retinoic Acid / drug effects
  • TOR Serine-Threonine Kinases / drug effects
  • Transplantation
  • Tretinoin / pharmacology
  • Wnt Signaling Pathway

Substances

  • Bone Morphogenetic Proteins
  • Receptors, Retinoic Acid
  • Tretinoin
  • TOR Serine-Threonine Kinases