Stem cell therapy is a promising future enterprise for renal replacement in patients with acute and chronic kidney disease, conditions which affect millions worldwide and currently require patients to undergo lifelong...Stem cell therapy is a promising future enterprise for renal replacement in patients with acute and chronic kidney disease, conditions which affect millions worldwide and currently require patients to undergo lifelong medical treatments through dialysis and/or organ transplant. Reprogramming differentiated renal cells harvested from the patient back into a pluripotent state would decrease the risk of tissue rejection and provide a virtually unlimited supply of cells for regenerative medicine treatments, making it an exciting area of current research in nephrology. Among the major hurdles that need to be overcome before stem cell therapy for the kidney can be applied in a clinical setting are ensuring the fidelity and relative safety of the reprogrammed cells, as well as achieving feasible efficiency in the reprogramming processes that are utilized. Further, improved knowledge about the genetic control of renal lineage development is vital to identifying predictable and efficient reprogramming approaches, such as the expression of key modulators or the regulation of geneactivity through small molecule mimetics. Here, we discuss several recent advances in induced pluripotent stem cell technologies. We also explore strategies that have been successful in renal progenitor generation, and explore what these methods might mean for the development of cell-based regenerative therapies for kidney disease.展开更多
End-stage renal disease （ESRD） patients have a defec-tive T-cell-mediated immune system which is related to excessive premature ageing of the T-cell compartment. This is likely to be caused by the uremia-associated ...End-stage renal disease （ESRD） patients have a defec-tive T-cell-mediated immune system which is related to excessive premature ageing of the T-cell compartment. This is likely to be caused by the uremia-associated pro-infammatory milieu, created by loss of renal func-tion. Therefore, ESRD patients are highly susceptible for infections, have an increased risk for virus-associated cancers, respond poorly to vaccination and have an increased risk for atherosclerotic diseases. Three ageing parameters can be used to assess an immu-nological T-cell age. First, thymic output can be deter-mined by assessing the T-cell receptor excision circles-content together with CD31 expression within the na？ve T cells. Second, the telomere length of T cells and third the T-cell differentiation status are also indicators of T-cell ageing. Analyses based on these parameters in ESRD patients revealed that the immunological T-cell age is increased by on average 20 years compared to the chronological age. After kidney transplantation （KTx） the aged T-cell phenotype persists although the pro-inflammatory milieu is diminished. This might be explained by epigenetic modifcations at hematopoietic stem cells level. Assessment of an immunological T-cell age could be an important tool to identify KTx recipi-ents who are at risk for allograft rejection or to prevent over-immunosuppression.展开更多
基金Supported by National Institutes of Health,No.DP2 OD008470,R01 DK100237Start-up funds from the University of Notre Dame and College of Sciencea generous donation for stem cell research to the University of Notre Dame by Elizabeth and Michael Gallagher on behalf of the Gallagher family
文摘Stem cell therapy is a promising future enterprise for renal replacement in patients with acute and chronic kidney disease, conditions which affect millions worldwide and currently require patients to undergo lifelong medical treatments through dialysis and/or organ transplant. Reprogramming differentiated renal cells harvested from the patient back into a pluripotent state would decrease the risk of tissue rejection and provide a virtually unlimited supply of cells for regenerative medicine treatments, making it an exciting area of current research in nephrology. Among the major hurdles that need to be overcome before stem cell therapy for the kidney can be applied in a clinical setting are ensuring the fidelity and relative safety of the reprogrammed cells, as well as achieving feasible efficiency in the reprogramming processes that are utilized. Further, improved knowledge about the genetic control of renal lineage development is vital to identifying predictable and efficient reprogramming approaches, such as the expression of key modulators or the regulation of geneactivity through small molecule mimetics. Here, we discuss several recent advances in induced pluripotent stem cell technologies. We also explore strategies that have been successful in renal progenitor generation, and explore what these methods might mean for the development of cell-based regenerative therapies for kidney disease.
文摘End-stage renal disease （ESRD） patients have a defec-tive T-cell-mediated immune system which is related to excessive premature ageing of the T-cell compartment. This is likely to be caused by the uremia-associated pro-infammatory milieu, created by loss of renal func-tion. Therefore, ESRD patients are highly susceptible for infections, have an increased risk for virus-associated cancers, respond poorly to vaccination and have an increased risk for atherosclerotic diseases. Three ageing parameters can be used to assess an immu-nological T-cell age. First, thymic output can be deter-mined by assessing the T-cell receptor excision circles-content together with CD31 expression within the na？ve T cells. Second, the telomere length of T cells and third the T-cell differentiation status are also indicators of T-cell ageing. Analyses based on these parameters in ESRD patients revealed that the immunological T-cell age is increased by on average 20 years compared to the chronological age. After kidney transplantation （KTx） the aged T-cell phenotype persists although the pro-inflammatory milieu is diminished. This might be explained by epigenetic modifcations at hematopoietic stem cells level. Assessment of an immunological T-cell age could be an important tool to identify KTx recipi-ents who are at risk for allograft rejection or to prevent over-immunosuppression.
文摘目的探讨核心蛋白聚糖对转化生长因子β_1(TGF-β_1)诱导的人肾小管上皮细胞(HK-2)转分化的影响。方法将体外培养的 HK-2细胞分为6组:阴性对照组(A 组);10 ng/mlTGF-β_1组(B 组);10 ng/ml 核心蛋白聚糖组(C 组);100 ng/ml 核心蛋白聚糖组(D 组);10 ng/mlTGF-β_1+10 ng/ml 核心蛋白聚糖组(E 组);10 ng/ml TGF-β_1+100 ng/ml 核心蛋白聚糖组(F 组)。倒置显微镜下观察加入刺激因子48 h 后,各组细胞形态学变化;应用逆转录-聚合酶链反应(RT-PCR)检测核心蛋白聚糖对 TGF-β_1诱导的 HK-2细胞内α平滑肌肌动蛋白(α-SMA)、波形蛋白、角蛋白mRNA 表达的影响。结果 B 组与 A 组相比较,细胞形态发生明显变化,大部分细胞拉长呈梭形,似成纤维细胞;E 组和 F 组比 B 组梭形样细胞明显减少,尤其是 F 组梭形样细胞减少更明显;C 组和 D组与 A 组细胞形态无明显区别,为椭圆形;B 组与 A 组比较,波形蛋白、α-SMA mRNA 表达明显提高,角蛋白 mRNA 表达减少。B 组平均值分别为(0.828±0.297)、(0.332±0.025)、(0.075±0.040),A组平均值分别为(0.033±0.060)、(0.003±0.000)、(0.348±0.012),差异有统计学意义(P<0.05);E 组和 F 组与 B 组相比,波形蛋白、α-SMA 的表达有所下降,角蛋白的表达呈上升趋势(P<0.05),平均值分别为 E 组(0.234±0.313)、(0.214±0.196)、(0.098±0.056),F 组(0.155±0.053)、(0.122±0.130)、(0.215±0.122)。C 组和 D 组与 A 组比较差异无统计学意义(P>0.05)。结论 TGF-β_1能诱导正常人肾小管上皮细胞发生转分化;核心蛋白聚糖对 TGF-β_1诱导的 HK-2细胞转分化具有抑制作用,且呈剂量依赖性。
