Cóndor José M, Rodrigues Camila E, Sousa Moreira Roberto de, Canale Daniele, Volpini Rildo A, Shimizu Maria H M, Camara Niels O S, Noronha Irene de L, Andrade Lúcia
Division of Nephrology, University of São Paulo, São Paulo, Brazil School of Medical Technology, National University of San Marcos, Lima, Peru.
Division of Nephrology, University of São Paulo, São Paulo, Brazil.
Stem Cells Transl Med. 2016 Aug;5(8):1048-57. doi: 10.5966/sctm.2015-0138. Epub 2016 Jun 8.
: The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks. Downregulation of endothelial nitric oxide synthase contributes to sepsis-induced endothelial dysfunction. Human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) are known to reduce expression of proinflammatory cytokines and markers of apoptosis. We hypothesized that treatment with WJ-MSCs would protect renal, hepatic, and endothelial function in a cecal ligation and puncture (CLP) model of sepsis in rats. Rats were randomly divided into three groups: sham-operated rats; rats submitted to CLP and left untreated; and rats submitted to CLP and intraperitoneally injected, 6 hours later, with 1 × 10(6) WJ-MSCs. The glomerular filtration rate (GFR) was measured at 6 and 24 hours after CLP or sham surgery. All other studies were conducted at 24 hours after CLP or sham surgery. By 6 hours, GFR had decreased in the CLP rats. At 24 hours, Klotho renal expression significantly decreased. Treatment with WJ-MSCs improved the GFR; improved tubular function; decreased the CD68-positive cell count; decreased the fractional interstitial area; decreased expression of nuclear factor κB and of cytokines; increased expression of eNOS, vascular endothelial growth factor, and Klotho; attenuated renal apoptosis; ameliorated hepatic function; increased glycogen deposition in the liver; and improved survival. Sepsis-induced acute kidney injury is a state of Klotho deficiency, which WJ-MSCs can attenuate. Klotho protein expression was higher in WJ-MSCs than in human adipose-derived MSCs. Because WJ-MSCs preserve renal and hepatic function, they might play a protective role in sepsis.
Sepsis is the leading cause of death in intensive care units. Although many different treatments for sepsis have been tested, sepsis-related mortality rates remain high. It was hypothesized in this study that treatment with human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) would protect renal, hepatic, and endothelial function in a model of sepsis in rats. Treatment with WJ-MSCs improved the glomerular filtration rate, improved tubular function, decreased expression of nuclear factor κB and of cytokines, increased expression of eNOS and of Klotho, attenuated renal apoptosis, and improved survival. Sepsis-induced acute kidney injury is a state of Klotho deficiency, which WJ-MSCs can attenuate.
脓毒症的病理生理学涉及复杂的细胞因子和炎症介质网络。内皮型一氧化氮合酶的下调促成了脓毒症诱导的内皮功能障碍。已知人脐带华通氏胶间充质干细胞（WJ-MSCs）可降低促炎细胞因子的表达和凋亡标志物。我们假设，在大鼠盲肠结扎和穿刺（CLP）脓毒症模型中，用WJ-MSCs进行治疗可保护肾脏、肝脏和内皮功能。大鼠被随机分为三组：假手术大鼠；接受CLP且未治疗的大鼠；接受CLP且6小时后腹腔注射1×10⁶个WJ-MSCs的大鼠。在CLP或假手术后6小时和24小时测量肾小球滤过率（GFR）。所有其他研究均在CLP或假手术后24小时进行。到6小时时，CLP大鼠的GFR下降。在24小时时，肾脏中klotho的表达显著降低。用WJ-MSCs进行治疗可改善GFR；改善肾小管功能；减少CD68阳性细胞计数；减少间质面积分数；降低核因子κB和细胞因子的表达；增加内皮型一氧化氮合酶、血管内皮生长因子和klotho的表达；减轻肾脏凋亡；改善肝功能；增加肝脏中的糖原沉积；并提高生存率。脓毒症诱导的急性肾损伤是一种klotho缺乏状态，WJ-MSCs可减轻这种状态。WJ-MSCs中klotho蛋白的表达高于人脂肪来源的间充质干细胞。由于WJ-MSCs可保护肾脏和肝脏功能，它们可能在脓毒症中发挥保护作用。
脓毒症是重症监护病房死亡的主要原因。尽管已经测试了许多不同的脓毒症治疗方法，但脓毒症相关的死亡率仍然很高。本研究假设，用人脐带华通氏胶间充质干细胞（WJ-MSCs）进行治疗可在大鼠脓毒症模型中保护肾脏、肝脏和内皮功能。用WJ-MSCs进行治疗可改善肾小球滤过率，改善肾小管功能，降低核因子κB和细胞因子的表达，增加内皮型一氧化氮合酶和klotho的表达，减轻肾脏凋亡，并提高生存率。脓毒症诱导的急性肾损伤是一种klotho缺乏状态,WJ-MSCs可减轻这种状态。
