PMID- 33020600 OWN - NLM STAT- MEDLINE DCOM- 20210129 LR - 20210720 IS - 2157-846X (Electronic) IS - 2157-846X (Linking) VI - 4 IP - 11 DP - 2020 Nov TI - Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche. PG - 1076-1089 LID - 10.1038/s41551-020-00623-7 [doi] AB - Bone-marrow endothelial cells in the haematopoietic stem-cell niche form a network of blood vessels that regulates blood-cell traffic as well as the maintenance and function of haematopoietic stem and progenitor cells. Here, we report the design and in vivo performance of systemically injected lipid-polymer nanoparticles encapsulating small interfering RNA (siRNA), for the silencing of genes in bone-marrow endothelial cells. In mice, nanoparticles encapsulating siRNA sequences targeting the proteins stromal-derived factor 1 (Sdf1) or monocyte chemotactic protein 1 (Mcp1) enhanced (when silencing Sdf1) or inhibited (when silencing Mcp1) the release of stem and progenitor cells and of leukocytes from the bone marrow. In a mouse model of myocardial infarction, nanoparticle-mediated inhibition of cell release from the haematopoietic niche via Mcp1 silencing reduced leukocytes in the diseased heart, improved healing after infarction and attenuated heart failure. Nanoparticle-mediated RNA interference in the haematopoietic niche could be used to investigate haematopoietic processes for therapeutic applications in cancer, infection and cardiovascular disease. FAU - Krohn-Grimberghe, Marvin AU - Krohn-Grimberghe M AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. AD - Department of Cardiology and Angiology I, Heart Center Freiburg University, Freiburg, Germany. FAU - Mitchell, Michael J AU - Mitchell MJ AUID- ORCID: 0000-0002-3628-2244 AD - Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA. AD - Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. FAU - Schloss, Maximilian J AU - Schloss MJ AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Khan, Omar F AU - Khan OF AUID- ORCID: 0000-0003-3811-2369 AD - Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA. FAU - Courties, Gabriel AU - Courties G AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Guimaraes, Pedro P G AU - Guimaraes PPG AD - Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA. FAU - Rohde, David AU - Rohde D AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Cremer, Sebastian AU - Cremer S AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Kowalski, Piotr S AU - Kowalski PS AUID- ORCID: 0000-0001-8607-0189 AD - Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA. FAU - Sun, Yuan AU - Sun Y AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Tan, Mingchee AU - Tan M AD - Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA. FAU - Webster, Jamie AU - Webster J AD - Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA. FAU - Wang, Karin AU - Wang K AUID- ORCID: 0000-0001-7812-2583 AD - Molecular and Integrative Physiological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA. FAU - Iwamoto, Yoshiko AU - Iwamoto Y AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Schmidt, Stephen P AU - Schmidt SP AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Wojtkiewicz, Gregory R AU - Wojtkiewicz GR AUID- ORCID: 0000-0002-3148-8411 AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Nayar, Ribhu AU - Nayar R AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Frodermann, Vanessa AU - Frodermann V AUID- ORCID: 0000-0001-5566-6692 AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Hulsmans, Maarten AU - Hulsmans M AUID- ORCID: 0000-0003-1009-658X AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Chung, Amanda AU - Chung A AD - Molecular and Integrative Physiological Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA. FAU - Hoyer, Friedrich Felix AU - Hoyer FF AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Swirski, Filip K AU - Swirski FK AUID- ORCID: 0000-0002-3163-9152 AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. FAU - Langer, Robert AU - Langer R AUID- ORCID: 0000-0003-4255-0492 AD - Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA. FAU - Anderson, Daniel G AU - Anderson DG AUID- ORCID: 0000-0001-5629-4798 AD - Department of Chemical Engineering, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA, USA. dgander@mit.edu. FAU - Nahrendorf, Matthias AU - Nahrendorf M AUID- ORCID: 0000-0002-4021-1887 AD - Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. mnahrendorf@mgh.harvard.edu. AD - Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. mnahrendorf@mgh.harvard.edu. AD - Department of Internal Medicine I, University Hospital Wuerzburg, Wuerzburg, Germany. mnahrendorf@mgh.harvard.edu. LA - eng GR - HHSN268201000045C/HL/NHLBI NIH HHS/United States GR - R01 HL125428/HL/NHLBI NIH HHS/United States GR - P30 CA014051/CA/NCI NIH HHS/United States GR - P01 HL142494/HL/NHLBI NIH HHS/United States GR - F32 CA200351/CA/NCI NIH HHS/United States GR - R01 HL131495/HL/NHLBI NIH HHS/United States GR - R37 EB000244/EB/NIBIB NIH HHS/United States GR - R35 HL139598/HL/NHLBI NIH HHS/United States GR - T32 HL076136/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20201005 PL - England TA - Nat Biomed Eng JT - Nature biomedical engineering JID - 101696896 RN - 0 (RNA, Small Interfering) SB - IM CIN - Nat Biomed Eng. 2020 Nov;4(11):1026-1027. PMID: 33159192 MH - Animals MH - Bone Marrow Cells/drug effects/metabolism MH - Cells, Cultured MH - Disease Models, Animal MH - Drug Delivery Systems/*methods MH - Endothelial Cells/drug effects/metabolism MH - Gene Silencing/*drug effects MH - Hematopoietic Stem Cells/*drug effects/metabolism MH - Mice, Inbred C57BL MH - Myocardial Infarction/prevention & control MH - Nanoparticles/*administration & dosage/*chemistry MH - RNA, Small Interfering/*administration & dosage/*chemistry MH - Stem Cell Niche/*genetics PMC - PMC7655681 MID - NIHMS1626519 COIS- Competing interests The authors declare no competing interests. EDAT- 2020/10/07 06:00 MHDA- 2021/01/30 06:00 PMCR- 2021/04/05 CRDT- 2020/10/06 05:30 PHST- 2018/08/09 00:00 [received] PHST- 2020/09/03 00:00 [accepted] PHST- 2020/10/07 06:00 [pubmed] PHST- 2021/01/30 06:00 [medline] PHST- 2020/10/06 05:30 [entrez] PHST- 2021/04/05 00:00 [pmc-release] AID - 10.1038/s41551-020-00623-7 [pii] AID - 10.1038/s41551-020-00623-7 [doi] PST - ppublish SO - Nat Biomed Eng. 2020 Nov;4(11):1076-1089. doi: 10.1038/s41551-020-00623-7. Epub 2020 Oct 5.