Mesenchymal Stromal Cells Facilitate Neutrophil-Trained Immunity by Reprogramming Hematopoietic Stem Cells
Novel therapeutics are urgently needed to prevent opportunistic infections in immunocompromised individuals undergoing cancer treatments or other immune-suppressive therapies. Trained immunity is a promising strategy to reduce this burden of disease. We previously demonstrated that mesenchymal strom...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Karger Publishers
2023-10-01
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| Series: | Journal of Innate Immunity |
| Subjects: | |
| Online Access: | https://beta.karger.com/Article/FullText/533732 |
| _version_ | 1797641323751145472 |
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| author | Julie Ng Anna E. Marneth Alec Griffith Daniel Younger Sailaja Ghanta Alan Jiao Gareth Willis Junwen Han Jewel Imani Bailin Niu Joshua W. Keegan Brandon Hancock Fei Guo Yang Shi Mark A. Perrella James A. Lederer |
| author_facet | Julie Ng Anna E. Marneth Alec Griffith Daniel Younger Sailaja Ghanta Alan Jiao Gareth Willis Junwen Han Jewel Imani Bailin Niu Joshua W. Keegan Brandon Hancock Fei Guo Yang Shi Mark A. Perrella James A. Lederer |
| author_sort | Julie Ng |
| collection | DOAJ |
| description | Novel therapeutics are urgently needed to prevent opportunistic infections in immunocompromised individuals undergoing cancer treatments or other immune-suppressive therapies. Trained immunity is a promising strategy to reduce this burden of disease. We previously demonstrated that mesenchymal stromal cells (MSCs) preconditioned with a class A CpG oligodeoxynucleotide (CpG-ODN), a Toll-like receptor 9 (TLR9) agonist, can augment emergency granulopoiesis in a murine model of neutropenic sepsis. Here, we used a chimeric mouse model to demonstrate that MSCs secrete paracrine factors that act on lineage-negative c-kit+ hematopoietic stem cells (HSCs), leaving them “poised” to enhance emergency granulopoiesis months after transplantation. Chimeric mice developed from HSCs exposed to conditioned media from MSCs and CpG-ODN-preconditioned MSCs showed significantly higher bacterial clearance and increased neutrophil granulopoiesis following lung infection than control mice. By Cleavage Under Targets and Release Using Nuclease (CUT&RUN) chromatin sequencing, we identified that MSC-conditioned media leaves H3K4me3 histone marks in HSCs at genes involved in myelopoiesis and in signaling persistence by the mTOR pathway. Both soluble factors and extracellular vesicles from MSCs mediated these effects on HSCs and proteomic analysis by mass spectrometry revealed soluble calreticulin as a potential mediator. In summary, this study demonstrates that trained immunity can be mediated by paracrine factors from MSCs to induce neutrophil-trained immunity by reprogramming HSCs for long-lasting functional changes in neutrophil-mediated antimicrobial immunity. |
| first_indexed | 2024-03-11T13:43:59Z |
| format | Article |
| id | doaj.art-12ec38b6a3d0419793c624e7617e2e10 |
| institution | Directory Open Access Journal |
| issn | 1662-8128 |
| language | English |
| last_indexed | 2024-03-11T13:43:59Z |
| publishDate | 2023-10-01 |
| publisher | Karger Publishers |
| record_format | Article |
| series | Journal of Innate Immunity |
| spelling | doaj.art-12ec38b6a3d0419793c624e7617e2e102023-11-02T10:50:45ZengKarger PublishersJournal of Innate Immunity1662-81282023-10-0115176578110.1159/000533732533732Mesenchymal Stromal Cells Facilitate Neutrophil-Trained Immunity by Reprogramming Hematopoietic Stem CellsJulie Ng0Anna E. Marneth1Alec Griffith2Daniel Younger3Sailaja Ghanta4Alan Jiao5Gareth Willis6Junwen Han7Jewel Imani8Bailin Niu9Joshua W. Keegan10Brandon Hancock11Fei Guo12Yang Shi13Mark A. Perrella14James A. Lederer15Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USADivision of Hematology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USADepartment of Surgery, Brigham and Women’s Hospital, Boston, MA, USADepartment of Surgery, Brigham and Women’s Hospital, Boston, MA, USADepartment of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, MA, USALudwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UKDepartment of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, MA, USADivision of Pulmonary and Critical Care, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USADivision of Pulmonary and Critical Care, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USADepartment of Surgery, Brigham and Women’s Hospital, Boston, MA, USADepartment of Surgery, Brigham and Women’s Hospital, Boston, MA, USADepartment of Surgery, Brigham and Women’s Hospital, Boston, MA, USADepartment of Surgery, Brigham and Women’s Hospital, Boston, MA, USALudwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UKDivision of Pulmonary and Critical Care, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USADepartment of Surgery, Brigham and Women’s Hospital, Boston, MA, USANovel therapeutics are urgently needed to prevent opportunistic infections in immunocompromised individuals undergoing cancer treatments or other immune-suppressive therapies. Trained immunity is a promising strategy to reduce this burden of disease. We previously demonstrated that mesenchymal stromal cells (MSCs) preconditioned with a class A CpG oligodeoxynucleotide (CpG-ODN), a Toll-like receptor 9 (TLR9) agonist, can augment emergency granulopoiesis in a murine model of neutropenic sepsis. Here, we used a chimeric mouse model to demonstrate that MSCs secrete paracrine factors that act on lineage-negative c-kit+ hematopoietic stem cells (HSCs), leaving them “poised” to enhance emergency granulopoiesis months after transplantation. Chimeric mice developed from HSCs exposed to conditioned media from MSCs and CpG-ODN-preconditioned MSCs showed significantly higher bacterial clearance and increased neutrophil granulopoiesis following lung infection than control mice. By Cleavage Under Targets and Release Using Nuclease (CUT&RUN) chromatin sequencing, we identified that MSC-conditioned media leaves H3K4me3 histone marks in HSCs at genes involved in myelopoiesis and in signaling persistence by the mTOR pathway. Both soluble factors and extracellular vesicles from MSCs mediated these effects on HSCs and proteomic analysis by mass spectrometry revealed soluble calreticulin as a potential mediator. In summary, this study demonstrates that trained immunity can be mediated by paracrine factors from MSCs to induce neutrophil-trained immunity by reprogramming HSCs for long-lasting functional changes in neutrophil-mediated antimicrobial immunity.https://beta.karger.com/Article/FullText/533732trained immunityepigeneticshematopoietic stem cellsneutrophilstoll-like receptor 9 |
| spellingShingle | Julie Ng Anna E. Marneth Alec Griffith Daniel Younger Sailaja Ghanta Alan Jiao Gareth Willis Junwen Han Jewel Imani Bailin Niu Joshua W. Keegan Brandon Hancock Fei Guo Yang Shi Mark A. Perrella James A. Lederer Mesenchymal Stromal Cells Facilitate Neutrophil-Trained Immunity by Reprogramming Hematopoietic Stem Cells Journal of Innate Immunity trained immunity epigenetics hematopoietic stem cells neutrophils toll-like receptor 9 |
| title | Mesenchymal Stromal Cells Facilitate Neutrophil-Trained Immunity by Reprogramming Hematopoietic Stem Cells |
| title_full | Mesenchymal Stromal Cells Facilitate Neutrophil-Trained Immunity by Reprogramming Hematopoietic Stem Cells |
| title_fullStr | Mesenchymal Stromal Cells Facilitate Neutrophil-Trained Immunity by Reprogramming Hematopoietic Stem Cells |
| title_full_unstemmed | Mesenchymal Stromal Cells Facilitate Neutrophil-Trained Immunity by Reprogramming Hematopoietic Stem Cells |
| title_short | Mesenchymal Stromal Cells Facilitate Neutrophil-Trained Immunity by Reprogramming Hematopoietic Stem Cells |
| title_sort | mesenchymal stromal cells facilitate neutrophil trained immunity by reprogramming hematopoietic stem cells |
| topic | trained immunity epigenetics hematopoietic stem cells neutrophils toll-like receptor 9 |
| url | https://beta.karger.com/Article/FullText/533732 |
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