Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland.
Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
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.
间质基质细胞（MSC）疗法与肾脏脉冲聚焦超声（pFUS）预处理相结合，可提高 MSC 归巢率，改善顺铂诱导的急性肾损伤（AKI），优于单独使用 MSC。然而，改善结果的机制尚不清楚。我们假设 pFUS 上调肾脏干扰素-γ（IFNγ），并刺激 MSC 在迁移到肾脏后产生白细胞介素-10（IL-10）。最初证明，MSC 与 IFNγ 共培养可上调 IL-10。当输注 IFNγ 刺激的 MSC 时，在肾脏中检测到更多的 MSC 衍生的 IL-10，并且它们比未刺激的 MSC 改善 AKI 更好。接下来，用 AKI 治疗 IFNγ 敲除小鼠接受 pFUS+MSC，但 MSC 衍生的 IL-10 表达和 AKI 与单独使用 MSC 相似。与单独给予 IL-10 缺陷 MSC 相比，接受 pFUS 和 IL-10 缺陷 MSC 的野生型小鼠的 AKI 也没有改善。IDO（吲哚胺 2,3-双加氧酶）是一种由 IFNγ 在 MSC 中上调的抗炎酶，在 AKI 期间上调，但在 pFUS 处理的肾脏来源的 MSC 中没有进一步升高，这表明 IDO 不参与 pFUS+MSC 改善 AKI 愈合。这些数据表明，pFUS 上调 IFNγ，并且在静脉内输注的 MSC 归巢到 pFUS 处理的肾脏后，IFNγ 刺激 MSC 产生更多的 IL-10 以改善 AKI。类似的超声处理组织微环境刺激治疗性 MSC 的机制可能存在于其他病理情况下，辅助超声技术是成功的。
