Mesenchymal stromal cell potency to treat acute kidney injury increased by ultrasound-activated interferon-γ/interleukin-10 axis

J Cell Mol Med. 2018 Dec;22(12):6015-6025. doi: 10.1111/jcmm.13874. Epub 2018 Sep 14.


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 (IFNγ) and stimulates MSC to produce interleukin-10 (IL-10) after migrating to kidneys. To demonstrate initially, MSC cultured with IFNγ up-regulated IL-10. More MSC-derived IL-10 was detected in kidneys when IFNγ-stimulated MSC were infused and they improved AKI better than unstimulated MSC. Next, IFNγ-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 IFNγ, 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 IFNγ is up-regulated by pFUS and after i.v.-infused MSC home to pFUS-treated kidneys, IFNγ 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.

Keywords: acute kidney injury; cell therapy; cisplatin; focused ultrasound; high intensity focused ultrasound; interferon-γ; interleukin 10; mesenchymal stem cell; mesenchymal stromal cell; therapeutic ultrasound; ultrasound.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / therapy*
  • Animals
  • Cisplatin / adverse effects
  • Disease Models, Animal
  • Gene Expression Regulation, Developmental / radiation effects
  • Humans
  • Interferon-gamma / genetics*
  • Interleukin-10 / genetics*
  • Kidney / injuries
  • Kidney / metabolism
  • Kidney / pathology
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells
  • Mice
  • Mice, Knockout
  • Ultrasonic Waves


  • Interleukin-10
  • Interferon-gamma
  • Cisplatin