Valerie D Roobrouck1, Esther Wolfs2, Michel Delforge3, Dorien Broekaert1, Soumen Chakraborty4, Kathleen Sels1, Thomas Vanwelden1, Bryan Holvoet5, Larissa Lhoest1, Satish Khurana1, Shubham Pandey1, Chloé Hoornaert6, Peter Ponsaerts7, Tom Struys8, Nancy Boeckx9, Peter Vandenberghe10, Christophe M Deroose5, Catherine M Verfaillie11. 1. Department of Development and Regeneration, Unit Embryology and Stem Cell Biology, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium. 2. Nuclear Medicine & Molecular Imaging and Molecular Small Animal Imaging Center, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium; Morphology Research Group, Biomedical Research Institute, Universiteit Hasselt, Diepenbeek, Belgium. 3. Department of Development and Regeneration, Unit Embryology and Stem Cell Biology, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium; Department of Hematology, University Hospitals Leuven, Belgium. 4. Department of Gene Function and Regulation, Institute of Life Sciences, Bhubaneswar, Odisha, India. 5. Nuclear Medicine & Molecular Imaging and Molecular Small Animal Imaging Center, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium. 6. Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium. 7. Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium. 8. Morphology Research Group, Biomedical Research Institute, Universiteit Hasselt, Diepenbeek, Belgium. 9. Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium. 10. Department of Hematology, University Hospitals Leuven, Belgium; Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium. 11. Department of Development and Regeneration, Unit Embryology and Stem Cell Biology, Stem Cell Institute Leuven, KU Leuven, Leuven, Belgium. Electronic address: catherine.verfaillie@med.kuleuven.be.
Abstract
BACKGROUND AIMS: Myelodysplastic syndromes (MDS) are a group of clonal stem cell disorders affecting the normal hematopoietic differentiation process and leading to abnormal maturation and differentiation of all blood cell lineages. Treatment options are limited, and there is an unmet medical need for effective therapies for patients with severe cytopenias. METHODS: We demonstrate that multipotent adult progenitor cells (MAPC) improve the function of hematopoietic progenitors derived from human MDS bone marrow (BM) by significantly increasing the frequency of primitive progenitors as well as the number of myeloid colonies. RESULTS: This effect was more pronounced in a non-contact culture, indicating the importance of soluble factors produced by the MAPC cells. Moreover, the cells did not stimulate the growth of the abnormal MDS clone, as shown by fluorescent in situ hybridization analysis on BM cells from patients with a known genetic abnormality. We also demonstrate that MAPC cells can provide stromal support for patient-derived hematopoietic cells. When MAPC cells were intravenously injected into a mouse model of MDS, they migrated to the site of injury and increased the hematopoietic function in diseased mice. DISCUSSION: The preclinical studies undertaken here indicate an initial proof of concept for the use of MAPC cell therapy in patients with MDS-related severe and symptomatic cytopenias and should pave the way for further investigation in clinical trials.
BACKGROUND AIMS: Myelodysplastic syndromes (MDS) are a group of clonal stem cell disorders affecting the normal hematopoietic differentiation process and leading to abnormal maturation and differentiation of all blood cell lineages. Treatment options are limited, and there is an unmet medical need for effective therapies for patients with severe cytopenias. METHODS: We demonstrate that multipotent adult progenitor cells (MAPC) improve the function of hematopoietic progenitors derived from human MDS bone marrow (BM) by significantly increasing the frequency of primitive progenitors as well as the number of myeloid colonies. RESULTS: This effect was more pronounced in a non-contact culture, indicating the importance of soluble factors produced by the MAPC cells. Moreover, the cells did not stimulate the growth of the abnormal MDS clone, as shown by fluorescent in situ hybridization analysis on BM cells from patients with a known genetic abnormality. We also demonstrate that MAPC cells can provide stromal support for patient-derived hematopoietic cells. When MAPC cells were intravenously injected into a mouse model of MDS, they migrated to the site of injury and increased the hematopoietic function in diseased mice. DISCUSSION: The preclinical studies undertaken here indicate an initial proof of concept for the use of MAPC cell therapy in patients with MDS-related severe and symptomatic cytopenias and should pave the way for further investigation in clinical trials.
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