Recapitulation of endochondral bone formation using human adult mesenchymal stem cells as a paradigm for developmental engineering

Celeste Scotti, Beatrice Tonnarelli, Adam Papadimitropoulos, Arnaud Scherberich, Stefan Schaeren, Alexandra Schauerte, Javier Lopez-Rios, Rolf Zeller, Andrea Barbero, Ivan Martin

Research output: Contribution to journalArticlepeer-review

Abstract

Mesenchymal stem/stromal cells (MSC) are typically used to generate bone tissue by a process resembling intramembranous ossification, i.e., by direct osteoblastic differentiation. However, most bones develop by endochondral ossification, i.e., via remodeling of hypertrophic cartilaginous templates. To date, endochondral bone formation has not been reproduced using human, clinically compliant cell sources. Here, we aimed at engineering tissues from bone marrow-derived, adult human MSC with an intrinsic capacity to undergo endochondral ossification. By analogy to embryonic limb development, we hypothesized that successful execution of the endochondral program depends on the initial formation of hypertrophic cartilaginous templates. Human MSC, subcutaneously implanted into nude mice at various stages of chondrogenic differentiation, formed bone trabeculae only when they had developed in vitro hypertrophic tissue structures. Advanced maturation in vitro resulted in accelerated formation of larger bony tissues. The underlying morphogenetic process was structurally and molecularly similar to the temporal and spatial progression of limb bone development in embryos. In particular, Indian hedgehog signaling was activated at early stages and required for the in vitro formation of hypertrophic cartilage. Subsequent development of a bony collar in vivo was followed by vascularization, osteoclastic resorption of the cartilage template, and appearance of hematopoietic foci. This study reveals the capacity of human MSC to generate bone tissue via an endochondral program and provides a valid model to study mechanisms governing bone development. Most importantly, this process could generate advanced grafts for bone regeneration by invoking a "developmental engineering" paradigm.

Original languageEnglish
Pages (from-to)7251-7256
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number16
DOIs
Publication statusPublished - Apr 20 2010

Keywords

  • Bone repair
  • Endochondral ossification
  • Hypertrophic chondrocytes
  • Regenerative medicine
  • Tissue engineering

ASJC Scopus subject areas

  • General

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