Specification of chondrocytes and cartilage tissues from embryonic stem cells

April M. Craft, Nazish Ahmed, Jason S. Rockel, Gurpreet S. Baht, Benjamin A. Alman, Rita A. Kandel, Agamemnon E. Grigoriadis, Gordon M. Keller*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

90 Citations (Scopus)

Abstract

Osteoarthritis primarily affects the articular cartilage of synovial joints. Cell and/or cartilage replacement is a promising therapy, provided there is access to appropriate tissue and sufficient numbers of articular chondrocytes. Embryonic stem cells (ESCs) represent a potentially unlimited source of chondrocytes and tissues as they can generate a broad spectrum of cell types under appropriate conditions in vitro. Here, we demonstrate that mouse ESC-derived chondrogenic mesoderm arises from a Flk-1(-)/Pdgfr alpha(+) (F-P+) population that emerges in a defined temporal pattern following the development of an early cardiogenic F-P+ population. Specification of the late-arising F-P+ population with BMP4 generated a highly enriched population of chondrocytes expressing genes associated with growth plate hypertrophic chondrocytes. By contrast, specification with Gdf5, together with inhibition of hedgehog and BMP signaling pathways, generated a population of non-hypertrophic chondrocytes that displayed properties of articular chondrocytes. The two chondrocyte populations retained their hypertrophic and non-hypertrophic properties when induced to generate spatially organized proteoglycan-rich cartilage-like tissue in vitro. Transplantation of either type of chondrocyte, or tissue generated from them, into immunodeficient recipients resulted in the development of cartilage tissue and bone within an 8-week period. Significant ossification was not observed when the tissue was transplanted into osteoblast-depleted mice or into diffusion chambers that prevent vascularization. Thus, through stage-specific manipulation of appropriate signaling pathways it is possible to efficiently and reproducibly derive hypertrophic and non-hypertrophic chondrocyte populations from mouse ESCs that are able to generate distinct cartilage-like tissue in vitro and maintain a cartilage tissue phenotype within an avascular and/or osteoblast-free niche in vivo.

Original languageEnglish
Pages (from-to)2597-2610
Number of pages14
JournalDevelopment
Volume140
Issue number12
DOIs
Publication statusPublished - 15 Jun 2013

Keywords

  • Cartilage
  • Chondrocyte
  • Embryonic stem cell
  • Induced pluripotent stem cell
  • Paraxial
  • Somite
  • ARTICULAR-CARTILAGE
  • IN-VITRO
  • MOUSE EMBRYO
  • CHONDROGENIC DIFFERENTIATION
  • SKELETAL DEVELOPMENT
  • PRIMITIVE STREAK
  • PROGENITOR CELLS
  • SOMITE FORMATION
  • SYNOVIAL JOINT
  • EXPRESSION

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