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

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.

Focused ultrasound activates voltage-gated calcium channels through depolarizing TRPC1 sodium currents in kidney and skeletal muscle

“…We previously demonstrated increased homing of intravenously-infused mesenchymal stromal cells (MSC) to sonicated tissues following pFUS to kidneys 11-14 or skeletal muscle 15-17. Using pFUS as a neoadjuvant prior to MSC infusions led to improved outcomes in diseased muscle and kidneys compared to MSC infusions alone 12, 17.…”

Mesenchymal Stromal Cell Homing: Mechanisms and Strategies for Improvement

“…In a mouse model of cisplatin-induced AKI, pFUS + MSCs significantly enhanced kidney homing and clinical outcomes compared with MSCs alone (Burks et al., 2015). In the AKI model, pFUS was found to upregulate IFN-γ in the kidney, which signals MSCs to produce the anti-inflammatory IL-10 (Burks et al., 2018). Jang et al.…”

Stem cells: a potential treatment option for kidney diseases

“…Due to their vitality in enhancing the kidney-directional migration of transplanted MSCs for increasing the efficiency of tissue repair, some novel preconditioning strategies were explored, including incubation with cytokines or chemical compounds [112][113][114], co-injection [115,116], hypoxia stimulation [117], and genetic modifications [118,119]. Also, pulse-focused ultrasound (pFUS) has elicited local molecular responses through mechanotransduction, thus enhancing the renal homing of circulating MSCs [120][121][122].…”