The enhancer landscape predetermines the skeletal regeneration capacity of stromal cells

Author:

Hochmann Sarah1ORCID,Ou Kristy2ORCID,Poupardin Rodolphe1ORCID,Mittermeir Michaela1,Textor Martin34,Ali Salaheddine356ORCID,Wolf Martin1ORCID,Ellinghaus Agnes34ORCID,Jacobi Dorit34ORCID,Elmiger Juri A. J.34,Donsante Samantha7ORCID,Riminucci Mara7ORCID,Schäfer Richard89ORCID,Kornak Uwe35610ORCID,Klein Oliver3ORCID,Schallmoser Katharina11ORCID,Schmidt-Bleek Katharina34ORCID,Duda Georg N.3412ORCID,Polansky Julia K.213ORCID,Geissler Sven3414ORCID,Strunk Dirk1ORCID

Affiliation:

1. Cell Therapy Institute, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), 5020 Salzburg, Austria.

2. Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), T Cell Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany.

3. Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany.

4. Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Julius Wolff Institute (JWI), Augustenburger Platz 1, 13353 Berlin, Germany.

5. Institute for Medical Genetics and Human Genetics, Charité – Universitätsmedizin Berlin, 13353 Berlin, Germany.

6. Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.

7. Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy.

8. Institute for Transfusion Medicine and Immunohematology, Goethe University Hospital, German Red Cross Blood Service Baden-Württemberg—Hessen gGmbH, 60323 Frankfurt am Main, Germany.

9. Institute for Transfusion Medicine and Gene Therapy, Medical Center – University of Freiburg, 79106 Freiburg, Germany.

10. Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany.

11. Institute for Transfusion Medicine, PMU, 5020 Salzburg, Austria.

12. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA.

13. German Rheumatism Research Centre (DRFZ), 10117 Berlin, Germany.

14. Berlin Center for Advanced Therapies (BECAT), Charité – Universitätsmedizin Berlin, 13353 Berlin, Germany.

Abstract

Multipotent stromal cells are considered attractive sources for cell therapy and tissue engineering. Despite numerous experimental and clinical studies, broad application of stromal cell therapeutics is not yet emerging. A major challenge is the functional diversity of available cell sources. Here, we investigated the regenerative potential of clinically relevant human stromal cells from bone marrow (BMSCs), white adipose tissue, and umbilical cord compared with mature chondrocytes and skin fibroblasts in vitro and in vivo. Although all stromal cell types could express transcription factors related to endochondral ossification, only BMSCs formed cartilage discs in vitro that fully regenerated critical-size femoral defects after transplantation into mice. We identified cell type–specific epigenetic landscapes as the underlying molecular mechanism controlling transcriptional stromal differentiation networks. Binding sites of commonly expressed transcription factors in the enhancer and promoter regions of ossification-related genes, including Runt and bZIP families, were accessible only in BMSCs but not in extraskeletal stromal cells. This suggests an epigenetically predetermined differentiation potential depending on cell origin that allows common transcription factors to trigger distinct organ-specific transcriptional programs, facilitating forward selection of regeneration-competent cell sources. Last, we demonstrate that viable human BMSCs initiated defect healing through the secretion of osteopontin and contributed to transient mineralized bone hard callus formation after transplantation into immunodeficient mice, which was eventually replaced by murine recipient bone during final tissue remodeling.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

General Medicine

Reference62 articles.

1. C. B. Wigley in Gray’s Anatomy E-Book: The Anatomical Basis of Clinical Practice S. Standring Ed. (Elsevier Limited 2016) pp. 28–41.

2. Bone development

3. Identification of the Human Skeletal Stem Cell

4. Cellular biology of fracture healing

5. Bone defect reconstruction via endochondral ossification: A developmental engineering strategy

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