Splenic macrophage phagocytosis of intravenously infused mesenchymal stromal cells attenuates tumor localization |
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| Authors: | Suheyla Hasgur Laura Desbourdes Theresa Relation Kathleen M. Overholt Joseph R. Stanek Adam J. Guess Minjun Yu Pratik Patel Linda Roback Massimo Dominici Satoru Otsuru Edwin M. Horwitz |
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| Affiliation: | 1. Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children''s Hospital, Columbus, Ohio, USA;2. Aflac Cancer & Blood Disorders Center, Children''s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA;3. Department of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, Modena, Italy;1. Seattle Children''s Research Institute, Seattle, Washington, USA;2. University of California San Francisco, San Francisco, California, USA;3. Children''s Hospital Los Angeles, Los Angeles, California, USA;4. Center for Cancer and Immunology Research, Center for Cancer and Blood Disorders, Children''s National Hospital, Washington, DC, USA;5. The George Washington University, Washington, DC, USA;1. Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea;2. Department of Biomedical Science, Chonnam National University Graduate School, Gwangju, Republic of Korea;3. Department of Pathology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Republic of Korea;4. Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea;5. Department of Nuclear Medicine, Chonnam National University Hwasun Hospital, Gwangju, Republic of Korea;6. Department of Companion and Laboratory Animal Science, Kongju National University, Yesan, Republic of Korea;1. Elite Regenerative Stem Cell Specialists, LLC, Johnstown, Colorado, USA;2. R&D Regenerative Laboratory Resources, LLC, Johnstown, Colorado, USA;3. Colorado Spine Institute, PLLC, Johnstown, Colorado, USA;1. Center for Autoimmune Genomics and Etiology, Cincinnati Children''s Hospital Medical Center, Cincinnati, Ohio, USA;2. Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA;3. Immunology Graduate Training Program, Cincinnati, Ohio, USA;4. Molecular and Developmental Biology Graduate Program, Cincinnati, Ohio, USA;5. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA;6. Division of Rheumatology, Cincinnati Children''s Hospital Medical Center, Cincinnati, Ohio, USA;1. Biomedical Ethics Research Program, Mayo Clinic, Rochester, Minnesota, USA;2. University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA;3. Department of Biological Sciences, College of Science, University of Notre Dame, Notre Dame, Indiana, USA;4. Department of Anatomy and Neuroscience, Centre for Stem Cell Systems, University of Melbourne, Parkville, Australia;5. Division of Pulmonary and Critical Care Medicine and Biomedical Ethics Research Program, Mayo Clinic, Rochester, Minnesota, USA;6. Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA;7. Department of Orthopedic Surgery and Center for Regenerative Medicine, Mayo Clinic College of Medicine, Jacksonville, Florida, USA;8. Biomedical Ethics Research Program and Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA;1. McGovern Medical School, The University of Texas Health Science Center, Houston, Texas, USA;2. Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA;3. Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA;4. College of Arts and Sciences, Ohio State University, Columbus, Ohio, USA;5. Cellf Bio LLC, Winston-Salem, North Carolina, USA;6. Department of Medicine, Gastroenterology Unit, Giambattista Rossi University Hospital, University Hospital Integrated Trust of Verona, University of Verona, Verona, Italy |
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| Abstract: | Mesenchymal stromal cells (MSCs) possess remarkable tumor tropism, making them ideal vehicles to deliver tumor-targeted therapeutic agents; however, their value in clinical medicine has yet to be realized. A barrier to clinical utilization is that only a small fraction of infused MSCs ultimately localize to the tumor. In an effort to overcome this obstacle, we sought to enhance MSC trafficking by focusing on the factors that govern MSC arrival within the tumor microenvironment. Our findings show that MSC chemoattraction is only present in select tumors, including osteosarcoma, and that the chemotactic potency among similar tumors varies substantially. Using an osteosarcoma xenograft model, we show that human MSCs traffic to the tumor within several hours of infusion. After arrival, MSCs are observed to localize in clusters near blood vessels and MSC-associated bioluminescence signal intensity is increased, suggesting that the seeded cells expand after engraftment. However, our studies reveal that a significant portion of MSCs are eliminated en route by splenic macrophage phagocytosis, effectively limiting the number of cells available for tumor engraftment. To increase MSC survival, we transiently depleted macrophages with liposomal clodronate, which resulted in increased tumor localization without substantial reduction in tumor-associated macrophages. Our data suggest that transient macrophage depletion will significantly increase the number of MSCs in the spleen and thus improve MSC localization within a tumor, theoretically increasing the effective dose of an anti-cancer agent. This strategy may subsequently improve the clinical efficacy of MSCs as vehicles for the tumor-directed delivery of therapeutic agents. |
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