Abstract
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.
Highlights
Bone marrow mesenchymal stromal cells (MSCs), known as mesenchymal stem cells, have improved outcomes in numerous disease models.[1]
C3H mice with acute kidney injury (AKI) were given i v infusions of 106 IL‐10‐silenced human MSC (MSCsi-IL10) with or without pulsed focused ultrasound (pFUS) (n = 6 mice for all experimental groups). (A) pFUS significantly increased MSCsi-IL10 homing to AKI kidneys (P < 0.05)
Fluorescence IHC for human mitochondria is shown to the right. (B) Renal function (BUN and Serum creatinine (SCr) clearance) in C3H mice was significantly improved by MSC si-IL10 alone (P < 0.05 compared to untreated controls), but additional significant reductions were not observed when mice were treated with pFUS+MSC si-IL10 (P > 0.05 compared to MSC alone). (C) Renal KIM‐1 expression, D) TUNEL+ cells during AKI in C3H mice are significantly improved by infusion of MSCsi-IL10 alone (P < 0.05 compared to untreated controls), but not further reduced (P > 0.05 compared to MSC alone) with pFUS+MSCsi-IL10
Summary
Bone marrow mesenchymal stromal cells (MSCs), known as mesenchymal stem cells, have improved outcomes in numerous disease models.[1] Transplanted MSCs typically do not engraft in host tissue; rather, the cells persist in situ only temporarily (usually 3‐ 7 days)[2,3,4] where they function as local “factories” to secrete paracrine factors into the microenvironment that modulate the immune. We employed combinations of transgenic IFNγ‐ deficient mice and IL‐10‐deficient MSCs to selectively probe the molecular mechanisms behind pFUS improving MSC therapy for AKI in vivo
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