Acute kidney injury (AKI) is a major kidney disease characterized by an abrupt loss of renal function. Accumulating evidence indicates that incomplete or maladaptive repair after AKI can result in kidney fibrosis and the development and progression of chronic kidney disease (CKD). Hypoxia, a condition of insufficient supply of oxygen to cells and tissues, occurs in both acute and chronic kidney diseases under a variety of clinical and experimental conditions. Hypoxia-inducible factors (HIFs) are the “master” transcription factors responsible for gene expression in hypoxia. Recent researches demonstrate that HIFs play an important role in kidney injury and repair by regulating HIF target genes, including microRNAs. However, there are controversies regarding the pathological roles of HIFs in kidney injury and repair. In this review, we describe the regulation, expression, and functions of HIFs, and their target genes and related functions. We also discuss the involvement of HIFs in AKI and kidney repair, presenting HIFs as effective therapeutic targets.

Hypoxia and Hypoxia-Inducible Factors in Kidney Injury and Repair

Tissue-engineered skin (TES), as an analogue of native skin, is promising for wound repair and regeneration. However, a major drawback of TES products is a lack of skin appendages and nerves to enhance skin healing, structural integrity and skin vitality. Skin appendages and nerves are important constituents for fully functional skin. To date, many studies have yielded remarkable results in the field of skin appendages reconstruction and nerve regeneration. However, patients often complain about a loss of skin sensation and even cutaneous chronic pain. Restoration of pain, temperature, and touch perceptions should now be a major challenge to solve in order to improve patients’ quality of life. Current strategies to create skin appendages and sensory nerve regeneration are mainly based on different types of seeding cells, scaffold materials, bioactive factors and involved signaling pathways. This article provides a comprehensive overview of different strategies for, and advances in, skin appendages and sensory nerve regeneration, which is an important issue in the field of tissue engineering and regenerative medicine.

/pdf/regeneration-of-skin-appendages-and-nerves-current-status-2g1f5fctd0.pdf

Regeneration of skin appendages and nerves: current status and further challenges.

Pathogenesis of AKI is complex and involves both local events in the kidney as well as systemic effects in the body that are interconnected and interdependent. Despite intensive investigations there is still no pharmacological agent that could provide complete protection against cisplatin nephrotoxicity. In the last decade mesenchymal stem cells (MSCs) have been proposed as a potentially useful therapeutic strategy in various diseases, including acute kidney injury. Although MSCs have potent immunosuppressive properties, animal studies also suggest that transplanted MSCs may elicit immune response. Interestingly, tumorigenicity of transplanted MSCs in animal studies has been rarely studied. Since the risk of tumorigenicity of particular therapy as well as the immune response to solid or cell grafts is a major issue in clinical trials, the aim of the present paper is to critically summarize the results of MSC transplantation on animal models of AKI, particularly cisplatin-induced animal models, and to expose results and main concerns about immunogenicity and tumorigenicity of transplanted MSCs, two important issues that need to be addressed in future studies.

/pdf/mesenchymal-stem-cell-based-therapy-in-cisplatin-induced-1te766fxpp.pdf

(Mesenchymal) Stem Cell-Based Therapy in Cisplatin-Induced Acute Kidney Injury Animal Model: Risk of Immunogenicity and Tumorigenicity.

Brief O2 uploading during continuous hypothermic machine perfusion is simple yet effective oxygenation method to improve initial kidney function in a porcine autotransplant model.

Cisplatin has been hypothesized to induce nephrotoxicity through triggering the apoptosis of tubular cells; however, the drug remains widely administered for the treatment of tumors. Recently, mesenchymal stem cells (MSCs) have been demonstrated to protect the kidney from the adverse effects induced by cisplatin. The aim of the present study was to investigate the mechanisms underlying the protective effects of human adipose-derived MSCs (AD-MSCs) on kidney function and tubular cells. Sprague-Dawley rats were divided into three groups, which included the healthy controls, those subjected to cisplatin-induced acute kidney injury (AKI) for 24 h without subsequent treatment and those subjected to cisplatin-induced AKI for 24 h, followed by AD-MSC engraftment. The rats were sacrificed at day 5 and the effects were analyzed using various methods, including biochemical analysis, structural examination and cell tracking experiments. In addition, an in vitro experiment with NRK-52E cells was performed. The cells were divided into three groups, including the healthy control, cisplatin induction and cisplatin induction with co-culture of AD-MSCs, and were subsequently assessed with a Transwell assay. After culture for four days, the cells were lysed and the total protein extract was subjected to western blot analysis. Cisplatin-induced renal dysfunction and tissue damage was shown to recover following AD-MSC infusion, although there were few AD-MSCs observed around the injured kidney tubules in the kidney. When the cisplatin-treated NRK-52E cells were co-cultured with AD-MSCs, the activation of p38 and BAX were inhibited, while the expression of Bcl-2 was upregulated, as compared with the cisplatin-treated NRK-52E cells that were not co-cultured. Therefore, AD-MSCs were shown to markedly improve cisplatin-induced renal failure and tubular cells necrosis through the secretion of certain factors, which subsequently inhibited the apoptosis pathway in vitro. It was hypothesized that AD-MSC secretion was triggered by the injured tubular cells. Thus, AD-MSCs may be important for the therapy of patients with renal injury due to their antiapoptotic capacity.

/pdf/human-adipose-derived-mesenchymal-stem-cells-repair-59k4j1efa8.pdf

Human adipose-derived mesenchymal stem cells repair cisplatin-induced acute kidney injury through antiapoptotic pathways

Current therapeutic options for acute kidney injury (AKI) are limited to the use of supportive measures and dialysis. A recent approach that has sparked great interest and gained enormous popularity is the implantation of stem cells to repair acutely damaged kidney organ. Hypoxia inducible factor-1α (HIF-1α) is effective in protecting the kidney from ischemia and nephrotoxicity. In this study, we investigated whether HIF-1α-modified adipose-derived stem cells (ASCs) had an enhanced protective effect on cisplatin-induced kidney injury in vivo. Cisplatin-induced AKI was established in nude mice. Our study demonstrated that HIF-1α-modified ASCs obviously promoted the recovery of renal function, ameliorated the extent of histologic injury and reduced renal apoptosis and inflammation, but HIF-1α-modified ASCs homed to kidney tissues at very low levels after transplantation. In addition, we also found that HIF-1α-modified ASCs significantly increased HO-1 expression in cisplatin-induced AKI in vivo. Thus, our study indicated HIF-1α-modified ASCs implantation could provide advanced benefits in the protection again AKI, which will contribute to developing a new therapeutic strategy for the treatment of AKI.

/pdf/enhanced-renoprotective-effect-of-hif-1a-modified-human-12f0ymo2w4.pdf

Enhanced renoprotective effect of HIF-1α modified human adipose-derived stem cells on cisplatin-induced acute kidney injury in vivo

Reprogramming of mouse renal tubular epithelial cells to induced pluripotent stem cells.

Insight into Novel Fe3c/Mo2c@Carbonized Polyaniline Activated Pms for Parachlorophenol Degradation: Key Roles of Mo2+, C=O Bonds and N-Doping

Human adipose-derived stem cells (hASCs) improve renal function in acute kidney injury. Hypoxia-inducible factor-1α (HIF-1α) was transfected into hASCs. hASCs modified by lentivirus-mediated empty-vector and HIF-1α maintained their stem cell characteristics. The expression of the renal-protective gene, heme oxygenase-1 and vascular endothelial growth factor were significantly increased in hASCs modified by HIF-1α, compared to hASCs modified by empty-vector. Cellular ultra-structure and TUNEL staining revealed that hASCs modified by HIF-1α promoted the recovery of apoptotic morphology in cisplatin-treated human kidney-2 cells (HK-2 cells) when compared to hASCs modified by empty-vector. Additionally, hASCs modified by empty-vector inhibited caspase-3 expression and up-regulated Bcl-2 expression in cisplatin-treated HK-2 cells, an effect even more pronounced with hASCs modified by HIF-1α. Thus, HIF-1α gene-modified ASCs could be an effective way to enhance the renal-protective effect.

Human adipose-derived stem cells modified by HIF-1α accelerate the recovery of cisplatin-induced acute renal injury in vitro.

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Enhanced renoprotective effect of HIF-1α modified human adipose-derived stem cells on cisplatin-induced acute kidney injury in vivo

Reprogramming of mouse renal tubular epithelial cells to induced pluripotent stem cells.

Insight into Novel Fe3c/Mo2c@Carbonized Polyaniline Activated Pms for Parachlorophenol Degradation: Key Roles of Mo2+, C=O Bonds and N-Doping

Human adipose-derived stem cells modified by HIF-1α accelerate the recovery of cisplatin-induced acute renal injury in vitro.