Reversing Acute Kidney Injury Using Pulsed Focused Ultrasound and MSC Therapy: A Role for HSP-Mediated PI3K/AKT Signaling.,Molecular Therapy - Methods & Clinical Development

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Reversing Acute Kidney Injury Using Pulsed Focused Ultrasound and MSC Therapy: A Role for HSP-Mediated PI3K/AKT Signaling.
Molecular Therapy - Methods & Clinical Development ( IF 4.6 ) Pub Date : 2020-03-30 , DOI: 10.1016/j.omtm.2020.03.023
Mujib Ullah ₁ , Daniel D Liu ₁ , Sravanthi Rai ₁ , Arya Dadhania ₁ , Sriya Jonnakuti ₁ , Waldo Concepcion ₁ , Avnesh S Thakor ₁

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Acute kidney injury (AKI) is characterized by a sudden failure of renal function, but despite increasing worldwide prevalence, current treatments are largely supportive, with no curative therapies. Mesenchymal stromal cell (MSC) therapy has been shown to have a promising regenerative effect in AKI but is limited by the ability of cells to home to damaged tissue. Pulsed focused ultrasound (pFUS), wherein target tissues are sonicated by short bursts of sound waves, has been reported to enhance MSC homing by upregulating local homing signals. However, the exact mechanism by which pFUS enhances MSC therapy remains insufficiently explored. In this study, we studied the effect of bone marrow-derived MSCs (BM-MSCs), in conjunction with pFUS, in a mouse model of cisplatin-induced AKI. Here, BM-MSCs improved kidney function, reduced histological markers of kidney injury, decreased inflammation and apoptosis, and promoted cellular proliferation. Surprisingly, whereas pFUS did not upregulate local cytokine expression or improve BM-MSC homing, it did potentiate the effect of MSC treatment in AKI. Further analysis linked this effect to the upregulation of heat shock protein (HSP)20/HSP40 and subsequent phosphatidylinositol 3-kinase (PI3K)/Akt signaling. In summary, our results suggest that pFUS and BM-MSCs have independent as well as synergistic therapeutic effects in the context of AKI.

中文翻译：

使用脉冲聚焦超声和MSC治疗逆转急性肾脏损伤：HSP介导的PI3K / AKT信号传导的作用。

急性肾损伤（AKI）的特征是肾功能突然衰竭，但尽管全世界范围内患病率正在增加，但目前的治疗方法在很大程度上支持治疗，没有治愈性疗法。间充质基质细胞（MSC）治疗已被证明在AKI中具有有希望的再生作用，但受细胞适应受损组织的能力的限制。据报道，脉冲聚焦超声（pFUS）可通过上调局部归巢信号来增强MSC归巢，其中目标组织通过短时的声波声波进行超声处理。然而，pFUS增强MSC治疗的确切机制仍未得到充分的探索。在这项研究中，我们在顺铂诱导的AKI小鼠模型中研究了骨髓衍生MSC（BM-MSC）与pFUS的结合作用。在这里，BM-MSC可改善肾脏功能，减少肾脏损伤的组织学标记，减少炎症和细胞凋亡，并促进细胞增殖。令人惊讶地，尽管pFUS没有上调局部细胞因子表达或改善BM-MSC归巢，但确实增强了AKI中MSC治疗的效果。进一步的分析将此作用与热休克蛋白（HSP）20 / HSP40的上调以及随后的磷脂酰肌醇3-激酶（PI3K）/ Akt信号转导联系起来。总之，我们的结果表明，pFUS和BM-MSC在AKI的背景下具有独立的和协同的治疗作用。进一步的分析将此作用与热休克蛋白（HSP）20 / HSP40的上调以及随后的磷脂酰肌醇3-激酶（PI3K）/ Akt信号转导联系起来。总之，我们的结果表明，pFUS和BM-MSC在AKI的背景下具有独立的和协同的治疗作用。进一步的分析将此作用与热休克蛋白（HSP）20 / HSP40的上调以及随后的磷脂酰肌醇3-激酶（PI3K）/ Akt信号转导联系起来。总之，我们的结果表明，pFUS和BM-MSC在AKI的背景下具有独立的和协同的治疗作用。

更新日期：2020-03-30

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