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.

Considering the unique therapeutic potential of mesenchymal stem cells (MSCs), including their immunosuppressive and immunomodulatory properties as well as their ability to improve tissue regeneration, these cells have attracted the attention of scientists and clinicians for the treatment of different inflammatory and immune system mediated disorders. However, various clinical trials using MSCs for the therapeutic purpose are conflicting and differ from the results of promising preclinical studies. This inconsistency is caused by several factors such as poor migration and homing capacities, low survival rate, low level of proliferation and differentiation, and donor-dependent variation of the cells. Enhancement and retention of persistent therapeutic effects of the cells remain a challenge to overcome in MSC-based therapy. In this review, we summarized various approaches to enhance the clinical outcomes of MSC-based therapy as well as revised current and future perspectives for the creation of cellular products with improved potential for diverse clinical applications.

Recent advances to enhance the immunomodulatory potential of mesenchymal stem cells

Ischemia-reperfusion injury (IRI) plays a significant role in the pathogenesis of acute kidney injury (AKI). The complicated interaction between injured tubular cells, activated endothelial cells, and the immune system leads to oxidative stress and systemic inflammation, thereby exacerbating the apoptosis of renal tubular cells and impeding the process of tissue repair. Stem cell therapy is an innovative approach to ameliorate IRI due to its antioxidative, immunomodulatory, and anti-apoptotic properties. Therefore, it is crucial to understand the biological effects and mechanisms of action of stem cell therapy in the context of acute ischemic AKI to improve its therapeutic benefits. The recent finding that treatment with conditioned medium (CM) derived from stem cells is likely an effective alternative to conventional stem cell transplantation increases the potential for future therapeutic uses of stem cell therapy. In this review, we discuss the recent findings regarding stem cell-mediated cytoprotection, with a focus on the anti-inflammatory effects via suppression of oxidative stress and uncompromised immune responses following AKI. Stem cell-derived CM represents a favorable approach to stem cell-based therapy and may serve as a potential therapeutic strategy against acute ischemic AKI.

The Anti-Inflammatory, Anti-Oxidative, and Anti-Apoptotic Benefits of Stem Cells in Acute Ischemic Kidney Injury.

Acute kidney injury (AKI) is a common, severe emergency case in clinics, with high incidence, significant mortality and increased costs. Despite development in the understanding of its pathophysiology, the therapeutic choices are still confined to dialysis and renal transplantation. Considering their antiapoptotic, immunomodulatory, antioxidative and pro-angiogenic effects, mesenchymal stem cells (MSCs) may be a promising candidate for AKI management. Based on these findings, some clinical trials have been performed, but the results are contradictory (NCT00733876, NCT01602328). The low engraftment, poor survival rate, impaired paracrine ability and delayed administration of MSCs are the four main reasons for the limited clinical efficacy. Investigators have developed a series of preconditioning strategies to improve MSC survival rates and paracrine ability. In this review, by summarizing these encouraging studies, we intend to provide a comprehensive understanding of various preconditioning strategies on AKI therapy and improve the prognosis of AKI patients by regenerative medicine.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcmm.14035

Preconditioning strategies for improving the survival rate and paracrine ability of mesenchymal stem cells in acute kidney injury.

MicroRNA-218 promotes high glucose-induced apoptosis in podocytes by targeting heme oxygenase-1.

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

OBJECTIVE To explore the effects of erythropoietin (EPO) on the differentiation and secretion of cultured bone marrow-derived mesenchymal stem cells (BM-MSC) in the microenvironment of acute kidney injury (AKI). METHODS C57BL/6 murine BM-MSC (mBM-MSC) were successfully isolated by the methods of Percoll density gradient centrifugation and adherence cultivation. The AKI murine model was induced by ischemia/reperfusion (I/R). The homogenate supernatants were prepared for normal and I/R murine kidney. P3-mBM-MSC were treated differently: Group A: low glucose DMEM medium with 10% fetal bovine serum, Group B: normal murine kidney homogenate supernatant intervention, Group C: I/R kidney homogenate supernatant intervention, Group D: I/R kidney homogenate supernatant plus different concentrations of EPO (1, 5, 10, 50 U/ml). Each group was incubated for 1, 3, 5 and 7 days. Inverted microscope was used to observe the morphological changes of these cells and their ultrastructural changes were observed by transmission electron microscope. Cytokeratin-18 was detected by flow cytometry. The levels of bone morphogenetic protein-7 (BMP-7), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) were detected by ELISA in culture medium. RESULTS The cells yielded a high expression of CD29 and CD44 and a low expression of CD34 and CD45. Compared with Groups A and B, the cells of Group C presented oval and short fusiform shapes. After the intervention of EPO, Group D showed a cobble appearance. More organelles were also found. A trace expression of CK18 was found in Groups A and B. A positive expression of CK18 was significantly higher in Groups C and D than Groups A and B (P < 0.01). The expression of EPO 50 U/ml at Day 5 and 7 was higher than Group C of the same time (5 d: 35.22 ± 4.04 vs 8.72 ± 0.38, 7 d: 42.00 ± 5.39 vs 13.20 ± 1.14, both P < 0.01). The results of ELISA showed that the levels of BMP-7, HGF and VEGF in Group C decreased significantly (P < 0.01 or P < 0.05). CONCLUSION The intervention of EPO may boost the differentiation of mBM-MSC but reverse its low secretion.

[Effects of erythropoietin on mesenchymal stem cells' function of differentiation and secretion cultured under acute kidney injury microenvironment].

Bone-marrow mesenchymal stem cells (BMSCs) transplantation is effective for acute kidney injury (AKI) repair but with limited efficiency. In the present study, BMSCs marked by bromodeoxyuridine (Br...

Erythropoietin promotes the repair effect of acute kidney injury by bone-marrow mesenchymal stem cells transplantation.

The aim of the present study was to investigate the effect of heme oxygenase-1 (HO-1) overexpression on the survival and differentiation ability of bone marrow‑derived mesenchymal stem cells (BMSCs) in the acute kidney injury (AKI) microenvironment. HO-1-BMSCs and enhanced green fluorescent protein (eGFP)-BMSCs were constructed. Rat ischemia/reperfusion (I/R)‑AKI-kidney homogenate supernatant was prep-ared to treat the BMSCs, eGFP-BMSCs and HO-1-BMSCs in vitro. In the AKI microenvironment, the HO-1-BMSCs exhibited a smaller proportion of cells at the G0/G1 phase, and a larger proportion of cells expressing proliferating cell nuclear antigen (PCNA) and cytokeratin 18 (CK18). Phosphorylated protein kinase B (Akt) and extracellular signal‑regulated kinase (ERK) protein levels were observed to be increased in the HO-1-BMSCs compared with the BMSCs. LY294002 and PD98059 each inhibited the above effects. BMSCs, eGFP-BMSCs and HO-1-BMSCs were implanted into an I/R-AKI rat model. The proportions of PCNA+ BMSCs and CK18+ BMSCs were higher in the HO-1-BMSCs group compared with the BMSCs group, which resulted in a decreased acute tubular necrosis score and improved renal function for the AKI rats. In conclusion, the enhanced proliferation and differentiation of HO-1-BMSCs suggest the beneficial effects of such cells in the BMSC-based therapy of AKI. The mechanism underlying these effects may involve the stimulation of Akt and ERK signaling.

/pdf/enhanced-proliferation-and-differentiation-of-ho-1-gene-3kdxrbcxqs.pdf

Enhanced proliferation and differentiation of HO-1 gene-modified bone marrow-derived mesenchymal stem cells in the acute injured kidney.

BACKGROUND Residual renal function (RRF) is a crucial factor that plays an important role in peritoneal dialysis (PD) patients, but whether RRF influences the quality of life (QOL) of PD patients is still controversial. The aims of this study were to explore the effects of RRF on QOL in patients with continuous ambulatory peritoneal dialysis (CAPD) and analyze the related factors that might affect patients' QOL. MATERIALS AND METHODS All 120 adult patients in this study received regular CAPD treatment for at least 3 months. Patients were divided into two groups: an RRF group (residual glomerular filtration (rGFR) ≥ 1 mL×min-1×(1.73m2)-1) and a non-RRF group (rGFR ≥ 1 mL×min-1×(1.73m2)-1). The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) was used as a reference to calculate the scores of CAPD patients for assessing their QOL. Multiple- and single-linear regression analysis was performed to analyze correlation degree of several SF-36-related indexes. RESULTS The indexes of age, gender, cause of disease, complication, body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP), hemoglobin (HB), cholesterol, triglycerides, high- and low-density lipoprotein, normalized protein catabolic rate (nPCR), and cardiothoracic ratio (CTR) showed no difference between the two groups (RRF and non-RRF). Comparing with RRF group, the patients without RRF showed a significant difference on indexes of PD duration, urine volume, ultrafiltration volume, dialysis dose, serum albumin, potassium, Kt/V (urea reduction ratio), creatinine, calcium, phosphate, C-reactive protein (CRP), and parathyroid hormone (PTH). Single-linear regression analysis that achieved total score of SF-36 showed no correlation with rGFR, but there was a correlation of SF-36 score with CRP, creatinine, CTR, albumin, and ultrafiltration volume. CONCLUSION These results suggested that there was no correlation between RRF and QOL in CAPD patients, but chronic inflammation, fluid overload, and malnutrition were considered as the main factors that affect patients' QOL. .

The impact of residual renal function on quality of life in patients with peritoneal dialysis .

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