SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys.

The steps governing healing with or without fibrosis within the same microenvironment are unclear. After acute kidney injury (AKI), injured proximal tubular epithelial cells activate SOX9 for self-restoration. Using a multimodal approach for a head-to-head comparison of injury-induced SOX9 lineages, we identified a dynamic SOX9 switch in repairing epithelia. Lineages that regenerated epithelia silenced SOX9 and healed without fibrosis (SOX9on-off). By contrast, lineages with unrestored apicobasal polarity maintained SOX9 activity in sustained efforts to regenerate, which were identified as a SOX9on-on Cadherin6pos cell state. These reprogrammed cells generated substantial single-cell WNT activity to provoke a fibroproliferative response in adjacent fibroblasts, driving AKI to chronic kidney disease. Transplanted human kidneys displayed similar SOX9/CDH6/WNT2B responses. Thus, we have uncovered a sensor of epithelial repair status, the activity of which determines regeneration with or without fibrosis.

Human CD133+ Renal Progenitor Cells Induce Erythropoietin Production and Limit Fibrosis After Acute Tubular Injury.

Persistent alterations of the renal tissue due to maladaptive repair characterize the outcome of acute kidney injury (AKI), despite a clinical recovery. Acute damage may also limit the renal production of erythropoietin, with impairment of the hemopoietic response to ischemia and possible lack of its reno-protective action. We aimed to evaluate the effect of a cell therapy using human CD133+ renal progenitor cells on maladaptive repair and fibrosis following AKI in a model of glycerol-induced rhabdomyolysis. In parallel, we evaluated the effect of CD133+ cells on erythropoietin production. Administration of CD133+ cells promoted the restoration of the renal tissue, limiting the presence of markers of injury and pro-inflammatory molecules. In addition, it promoted angiogenesis and protected against fibrosis up to day 60. No effect of dermal fibroblasts was observed. Treatment with CD133+ cells, but not with PBS or fibroblasts, limited anemia and increased erythropoietin levels both in renal tissue and in circulation. Finally, CD133+ cells contributed to the local production of erythropoietin, as observed by detection of circulating human erythropoietin. CD133+ cells appear therefore an effective source for cell repair, able to restore renal functions, including erythropoietin release, and to limit long term maldifferentiation and fibrosis.

Spiral laminar flow, the earliest predictor for maturation of arteriovenous fistula for hemodialysis access.

INTRODUCTION: Arteriovenous fistula (AVF) is the gold standard vascular access for hemodialysis (HD). A thrill or murmur immediately after creation of AVF is considered a predictive sign of success. However, this does not ensure final maturation for successful HD. Our objective was to determine different clinical and duplex parameters within AVF to predict maturation and subsequent successful HD. MATERIALS AND METHODS: A prospective observational study was conducted on 187 patients who had AVF formation from July 2012 to May 2013. Following surgery, all patients had Doppler ultrasound (DU) on Days 0 and 7. Doppler parameters noted in the outflow vein were: Thrill, broadening of spectral waveform with increased peak systolic velocity (PSV) and spiral laminar flow (SLF). Patients with at least one positive parameter at Day 0 were followed-up serially and underwent repeat Doppler imaging on Day 7. Patients with the absence of all three parameters on Day 0 were excluded from the study. Endpoint was maturation of AVF, i.e. successful HD. Statistical analysis was performed with binary logistic regression, to find out the strongest and earliest predictor for maturation of AVF using SPSS version 20. RESULTS: SLF and broadening of spectral waveform with increased PSV were found to have a significant association with maturation (P = 0.0001). Presence of SLF on Day 0 most strongly predicted maturation. Presence of thrill or murmur could not predict the maturation. CONCLUSIONS: SLF pattern in AVF is the most important and the earliest predictor of maturation.

Concise review: stem/progenitor cells for renal tissue repair: current knowledge and perspectives.

The kidney is a specialized low-regenerative organ with several different types of cellular lineages; however, the identity of renal stem/progenitor cells with nephrogenic potential and their preferred niche(s) are largely unknown and debated. Most of the therapeutic approaches to kidney regeneration are based on administration of cells proven to enhance intrinsic reparative capabilities of the kidney. Endogenous or exogenous cells of different sources were tested in rodent models of ischemia-reperfusion, acute kidney injury, or chronic disease. The translation to clinics is at the moment focused on the role of mesenchymal stem cells. In addition, bioproducts from stem/progenitor cells, such as extracellular vesicles, are likely a new promising approach for reprogramming resident cells. This concise review reports the current knowledge about resident or exogenous stem/progenitor populations and their derived bioproducts demonstrating therapeutic effects in kidney regeneration upon injury. In addition, possible approaches to nephrogenesis and organ generation using organoids, decellularized kidneys, and blastocyst complementation are surveyed.

Role of immune responses in the pathogenesis of low-risk MDS and high-risk MDS: implications for immunotherapy.

The myelodysplastic syndromes (MDS) constitute a group of heterogeneous clonal haemopoietic stem cell disorders, characterized by ineffective and dysplastic haematopoiesis with varying degrees of peripheral cytopenia. Low-risk MDS is characterized by increased apoptosis in the bone marrow (BM) with autoimmune characteristics whereas the advanced or high-risk stages involve immune evasion and secondary DNA damage, giving cells growth potential to progress into acute myeloid leukaemia (AML). Nevertheless, the causes of MDS remain poorly defined and it is not clear how the disease progresses from an early stage to advanced MDS and AML. Although there are clear indications for a role of the immune system, the exact mechanism by which the immune response contributes to the progression is not yet clear. New insights into the pathophysiology of MDS with regard to the immune system will be instrumental for the development of novel patient-oriented therapies. This review is focused on the role of immune responses in MDS and the implications for the development of novel immune therapies.

Selective transduction of dendritic cells in human lymph nodes and superior induction of high-avidity melanoma-reactive cytotoxic T cells by a CD40-targeted adenovirus.

Targeted delivery of tumor antigen genes to dendritic cells (DCs) using adenoviral (Ad) vectors holds great potential for cancer immunotherapy. We previously showed that CD40 targeting of Ad vectors enhanced specific transduction of DC in human skin, while simultaneously ensuring their stable maturation and superior allogeneic T-cell stimulatory capacity. In this study, we evaluated whether CD40-targeted Ad encoding the full-length melanoma antigen recognized by T cells-1 (CD40-Ad-MART-1) could be used to efficiently and selectively transduce conventional and plasmacytoid DC to prime melanoma-specific CD8(+) T-effector cells in human melanoma-draining sentinel lymph nodes (SLNs). CD40 targeting of Ad was achieved using a bispecific fusion protein, binding and neutralizing the Ad fiber knob through soluble coxsackie and adenovirus receptor while retargeting the virus to hCD40 through the tumor necrosis factor-like domain of mCD40L. Selective transduction of conventional and plasmacytoid DC subsets by CD40-Ad was observed in suspensions of human melanoma-draining SLN. Moreover, CD40-Ad-MART-1 enhanced the expansion of functional MART-1-specific CD8(+) T cells from SLN with concomitant decreases in CD4:CD8 T-cell ratios and CD4(+)CD25(hi)FoxP3(+) regulatory T-cell rates. Additional studies revealed that transduction and activation of monocyte-derived DCs with CD40-Ad-MART-1 significantly enhanced their priming efficiency of functional CD8(+) effector T cells with high avidity. These findings provide preclinical evidence of possible efficacy of this approach for cancer immunotherapy.