TY - JOUR
T1 - Nanoparticle-encapsulated siRNAs for gene silencing in the haematopoietic stem-cell niche
AU - Krohn-Grimberghe, Marvin
AU - Mitchell, Michael J.
AU - Schloss, Maximilian J.
AU - Khan, Omar F.
AU - Courties, Gabriel
AU - Guimaraes, Pedro P.G.
AU - Rohde, David
AU - Cremer, Sebastian
AU - Kowalski, Piotr S.
AU - Sun, Yuan
AU - Tan, Mingchee
AU - Webster, Jamie
AU - Wang, Karin
AU - Iwamoto, Yoshiko
AU - Schmidt, Stephen P.
AU - Wojtkiewicz, Gregory R.
AU - Nayar, Ribhu
AU - Frodermann, Vanessa
AU - Hulsmans, Maarten
AU - Chung, Amanda
AU - Hoyer, Friedrich Felix
AU - Swirski, Filip K.
AU - Langer, Robert
AU - Anderson, Daniel G.
AU - Nahrendorf, Matthias
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
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.
UR - https://www.scopus.com/pages/publications/85092088005
U2 - 10.1038/s41551-020-00623-7
DO - 10.1038/s41551-020-00623-7
M3 - Article
C2 - 33020600
AN - SCOPUS:85092088005
SN - 2157-846X
VL - 4
SP - 1076
EP - 1089
JO - Nature Biomedical Engineering
JF - Nature Biomedical Engineering
IS - 11
ER -
