TY - JOUR
T1 - Mesenchymal stem cells exert renoprotection via extracellular vesicle-mediated modulation of M2 macrophages and spleen-kidney network
AU - Shimamura, Yuko
AU - Furuhashi, Kazuhiro
AU - Tanaka, Akihito
AU - Karasawa, Munetoshi
AU - Nozaki, Tomoya
AU - Komatsu, Shintaro
AU - Watanabe, Kenshi
AU - Shimizu, Asuka
AU - Minatoguchi, Shun
AU - Matsuyama, Makoto
AU - Sawa, Yuriko
AU - Tsuboi, Naotake
AU - Ishimoto, Takuji
AU - Suzuki, Hiroshi I.
AU - Maruyama, Shoichi
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Adipose-derived mesenchymal stem cells (ASCs) have shown therapeutic potentials against refractory diseases. However, the detailed therapeutic mechanisms remain unclear. Here, we report the therapeutic actions of human ASCs in nephritis, focusing on cellular dynamics and multi-organ networks. Intravenously-administered ASCs accumulated in spleen but not kidneys. Nevertheless, ASCs increased M2 macrophages and Tregs in kidneys and drove strong renoprotection. Splenectomy abolished these therapeutic effects. ASC-derived extracellular vesicles (EVs) were transferred to M2 macrophages, which entered the bloodstream from spleen. EVs induced the transcriptomic signatures of hyperpolarization and PGE2 stimulation in M2 macrophages and ameliorated glomerulonephritis. ASCs, ASC-derived EVs, and EV-transferred M2 macrophages enhanced Treg induction. These findings suggest that EV transfer from spleen-accumulated ASCs to M2 macrophages and subsequent modulation of renal immune-environment underlie the renoprotective effects of ASCs. Our results provide insights into the therapeutic actions of ASCs, focusing on EV-mediated modulation of macrophages and the spleen-kidney immune network.
AB - Adipose-derived mesenchymal stem cells (ASCs) have shown therapeutic potentials against refractory diseases. However, the detailed therapeutic mechanisms remain unclear. Here, we report the therapeutic actions of human ASCs in nephritis, focusing on cellular dynamics and multi-organ networks. Intravenously-administered ASCs accumulated in spleen but not kidneys. Nevertheless, ASCs increased M2 macrophages and Tregs in kidneys and drove strong renoprotection. Splenectomy abolished these therapeutic effects. ASC-derived extracellular vesicles (EVs) were transferred to M2 macrophages, which entered the bloodstream from spleen. EVs induced the transcriptomic signatures of hyperpolarization and PGE2 stimulation in M2 macrophages and ameliorated glomerulonephritis. ASCs, ASC-derived EVs, and EV-transferred M2 macrophages enhanced Treg induction. These findings suggest that EV transfer from spleen-accumulated ASCs to M2 macrophages and subsequent modulation of renal immune-environment underlie the renoprotective effects of ASCs. Our results provide insights into the therapeutic actions of ASCs, focusing on EV-mediated modulation of macrophages and the spleen-kidney immune network.
UR - http://www.scopus.com/inward/record.url?scp=85135189009&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85135189009&partnerID=8YFLogxK
U2 - 10.1038/s42003-022-03712-2
DO - 10.1038/s42003-022-03712-2
M3 - Article
C2 - 35902687
AN - SCOPUS:85135189009
SN - 2399-3642
VL - 5
JO - Communications biology
JF - Communications biology
IS - 1
M1 - 753
ER -
