Scripts used for: THE ENHANCER LANDSCAPE PREDETERMINES THE SKELETAL REGENERATION CAPACITY OF STROMAL CELLS
Authors/Creators
- Hochmann Sarah1
- Ou Kristy2
- Poupardin Rodophe1
- Mittermeir Michaela1
- Textor Martin3
- Salaheddine Ali4
- Wolf Martin1
- Ellinghaus Agnes3
- Jacobi Dorit5
- Elmiger Juri A.J.5
- Donsante Samantha6
- Riminucci Mara6
- Schäfer Richard7
- Kornak Uwe8
- Klein Oliver5
- Schallmoser Katharina9
- Schmidt-Bleek Katharina10
- Duda Georg N.11
- Polansky Julia K.12
- Geissler Sven13
- Strunk Dirk1
- 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; Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Julius Wolff Institute (JWI), Augustenburger Platz 1, 13353 Berlin, Germany
- 4. Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany; 5Institute for Medical Genetics and Human Genetics, Charité – Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany
- 5. Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany
- 6. Department of Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy
- 7. Institute for Transfusion Medicine and Immunohematology, Goethe University Hospital, German Red Cross Blood Service Baden-Württemberg—Hessen gGmbH, 60323 Frankfurt am Main, Germany; Institute for Transfusion Medicine and Gene Therapy, Medical Center – University of Freiburg, 79106 Freiburg, Germany
- 8. Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany ; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, GermanyInstitute for Medical Genetics and Human Genetics, Charité – Universitätsmedizin Berlin, 13353 Berlin, Germany
- 9. Transfusion Medicine Institute, PMU, 5020 Salzburg, Austria
- 10. Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany;Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Julius Wolff Institute (JWI), Augustenburger Platz 1, 13353 Berlin, Germany
- 11. Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany; Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Julius Wolff Institute (JWI), Augustenburger Platz 1, 13353 Berlin, Germany; Wyss Institute for Biologically Inspired Engineering, Harvard, Boston, MA 02115, USA
- 12. Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), T Cell Epigenetics, Augustenburger Platz 1, 13353 Berlin, Germany; German Rheumatism Research Centre (DRFZ), 10117 Berlin, Germany
- 13. Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany ; Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Julius Wolff Institute (JWI), Augustenburger Platz 1, 13353 Berlin, Germany; erlin Center for Advanced Therapies (BECAT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany
Description
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 to mature chondrocytes and skin fibroblasts in-vitro and in vivo. Although all stromal cell types can express transcription factors related to endochondral ossification, only BMSCs formed cartilage discs in vitro that fully regenerated critical-sized 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 extra-skeletal 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.