An Organoid for Woven Bone

Anat Akiva (Corresponding author), Johanna Melke, Sana Ansari, Nalan Liv, Robin van der Meijden, Merijn van Erp, Feihu Zhao, Merula Stout, Wouter H. Nijhuis, Cilia de Heus, Claudia Muñiz Ortera, Job Fermie, Judith Klumperman, Keita Ito, Nico Sommerdijk, Sandra Hofmann

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Bone formation (osteogenesis) is a complex process in which cellular differentiation and the generation of a mineralized organic matrix are synchronized to produce a hybrid hierarchical architecture. To study the mechanisms of osteogenesis in health and disease, there is a great need for functional model systems that capture in parallel, both cellular and matrix formation processes. Stem cell-based organoids are promising as functional, self-organizing 3D in vitro models for studying the physiology and pathology of various tissues. However, for human bone, no such functional model system is yet available. This study reports the in vitro differentiation of human bone marrow stromal cells into a functional 3D self-organizing co-culture of osteoblasts and osteocytes, creating an organoid for early stage bone (woven bone) formation. It demonstrates the formation of an organoid where osteocytes are embedded within the collagen matrix that is produced by the osteoblasts and mineralized under biological control. Alike in in vivo osteocytes, the embedded osteocytes show network formation and communication via expression of sclerostin. The current system forms the most complete 3D living in vitro model system to investigate osteogenesis, both in physiological and pathological situations, as well as under the influence of external triggers (mechanical stimulation, drug administration).

Original languageEnglish
Article number2010524
Number of pages9
JournalAdvanced Functional Materials
Volume31
Issue number17
Early online date9 Mar 2021
DOIs
Publication statusPublished - 22 Apr 2021

Bibliographical note

Funding Information:
A.A. and J.M. contributed equally to this work. The authors would like to thank Lia Addadi and Steve Weiner for providing the zebrafish and embryonic chicken data, the ICMS animation studio (Koen Pieterse) for the graphics of the cells, and Carlijn Bouten for providing CNA35 collagen probe. The authors also thank Deniz Daviran for her help in preparing the figures. A.A. was supported by the Marie Curie Individual Fellowship (H2020‐MSCA‐IF‐2017‐794296‐SUPERMIN), by the Netherlands Organization for Scientific Research (NWO) through an ECHO grant to NS, and by the National Postdoctoral Award Program for Advancing Women in Science – the Weizmann Institute of Science, Israel. N.S., R.v.d.M. and M.v.E. were supported by the European Research Council (ERC) Advanced Investigator grant (H2020‐ERC‐2017‐ADV‐788982‐COLMIN) to N.S. S.A. was supported by the Ministry of Education, Culture and Science (Gravitation Program 024.003.013). N.L. was supported by the Netherlands Organization for Scientific Research (NWO) through a ZonMW‐TOP grant to JK. J.M., F.Z., and S.H. were supported by the ERC Starting grant (FP7‐ERC‐2013‐StG‐336043‐REMOTE) to SH.

Publisher Copyright:
© 2021 The Authors. Advanced Functional Materials published by Wiley-VCH GmbH.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

  • 3D cell culture
  • 3D electron microscopy
  • biomineralization
  • bone model
  • organoid

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