Open AccessMesenchymal stromal cell potency to treat acute kidney injury increased by ultrasound‐activated interferon‐γ/interleukin‐10 axis
Author(s) -
Burks Scott R.,
Nagle Matthew E.,
Bresler Michele N.,
Kim Saejeong J.,
Star Robert A.,
Frank Joseph A.
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13874
Subject(s) - medicine , mesenchymal stem cell , kidney , acute kidney injury , stromal cell , cancer research , pathology , interferon gamma , cytokine , immunology
Mesenchymal stromal cell ( MSC ) therapies combined with renal pulsed focused ultrasound ( pFUS ) pretreatment increase MSC homing and improve cisplatin‐induced acute kidney injury ( AKI ) better than MSC alone. However, mechanisms underlying improved outcomes remain unknown. We hypothesize pFUS up‐regulates renal interferon‐γ ( IFN γ) and stimulates MSC to produce interleukin‐10 ( IL ‐10) after migrating to kidneys. To demonstrate initially, MSC cultured with IFN γ up‐regulated IL ‐10. More MSC ‐derived IL ‐10 was detected in kidneys when IFN γ‐stimulated MSC were infused and they improved AKI better than unstimulated MSC . Next, IFN γ‐knockout mice with AKI received pFUS + MSC , but MSC ‐derived IL ‐10 expression and AKI were similar to using MSC alone. AKI in wild‐type mice receiving pFUS and IL ‐10‐deficient MSC was also unimproved compared to administering IL ‐10‐deficient MSC alone. Indoleamine 2,3‐dioxygenase ( IDO ), an anti‐inflammatory enzyme up‐regulated in MSC by IFN γ, was up‐regulated during AKI , but was not further elevated in MSC from pFUS ‐treated kidneys, suggesting that IDO is not involved in improved AKI healing by pFUS + MSC . These data suggest IFN γ is up‐regulated by pFUS and after i.v.‐infused MSC home to pFUS ‐treated kidneys, IFN γ stimulates additional IL ‐10 production by MSC to improve AKI . Analogous mechanisms of ultrasound‐treated tissue microenvironments stimulating therapeutic MSC may exist in other pathologies where adjuvant ultrasound techniques are successful.