Tadashi Kato

Long-term peritoneal injury results in loss of mesothelial integrity and impaired ultrafiltration, limiting the durability of peritoneal dialysis. Because primary human peritoneal mesothelial cells (PMCs) are difficult to obtain and expand, regenerative strategies for restoring peritoneal function have remained limited. We developed a protocol to differentiate human induced pluripotent stem cells (iPSCs) into functional peritoneal mesothelial-like cells (iPMCs). The molecular and functional characteristics of iPMCs were evaluated using gene expression analyses and functional assays, including comparison with a mesothelial cell model. The therapeutic effect of iPMCs was evaluated in a methylglyoxal-induced experimental peritoneal injury mouse model. iPMCs exhibited typical cobblestone morphology and expressed key mesothelial markers including CK18, WT1 and MSLN. Transcriptomic analysis demonstrated strong similarity between iPMCs and primary PMCs. In vivo, intraperitoneal administration of iPMCs partially improved peritoneal transport parameters in a mouse model of peritoneal injury. We successfully generated functional mesothelial cells from human iPSCs that reproduce mesothelial-like functional properties and suggest potential for restoring peritoneal integrity. This study demonstrates the feasibility of iPSC-derived mesothelial cells as a regenerative cell source for peritoneal repair and provides a foundation for future peritoneal regeneration therapy.

Background: Central venous catheters are primarily used for emergency hemodialysis in patients with end-stage renal failure. Catheter-related internal jugular vein thrombosis occurs frequently; however, the risk of its occurrence and options for treatment have not been adequately investigated. Methods: A single-center retrospective study was conducted to examine the risk factors for internal jugular vein thrombosis in 72 patients undergoing hemodialysis using central venous catheters. Results: Ultrasound examination confirmed intravenous thrombus in 21 patients (29.2%). Patients taking anticoagulants at the start of dialysis and those with high intact parathyroid levels had significantly higher rates of central venous thrombosis. The most common reason for anticoagulant use was atrial fibrillation (50.0%), but the presence or absence of atrial fibrillation was not significantly associated with central venous thrombus formation. Conclusions: These results suggest that thrombotic predisposition and calcium metabolism abnormalities at the start of hemodialysis are associated with central venous thrombus formation during vascular access catheter insertion.

Background Elevated parathyroid hormone (PTH) levels are associated with cardiovascular events, bone disease, and mortality in patients undergoing maintenance hemodialysis. Although PTH levels vary widely in patients undergoing hemodialysis, whether this affects mortality is unclear. Methods A total of 315 maintenance hemodialysis patients who underwent PTH measurements at least twice a year were enrolled. The association between all-cause mortality, cardiovascular events, and fractures was evaluated in patients with PTH concentrations of 60–240 pg/mL (time-in-target range (TTR) 100%) and those with TTR values of 75% ≤ TTR < 100%, 50% ≤ TTR < 75%, and TTR < 50%. Results There were 122 patients with TTR 100%, 81 patients with 75% ≤ TTR < 100%, 52 patients with 50% ≤ TTR < 75%, and 74 patients with TTR < 50%. Over the 4-year observation period, patients with TTR of 100% had significantly lower all-cause mortality than those with TTR < 50%. (HR 2.26, 95% CI 1.33–3.86) Subgroup analysis by presence or absence of pharmacological intervention showed no statistically significant difference in all-cause mortality in the treatment group (HR 2.08, 95% CI 1.16–3.72), but showed significant differences in the no-treatment group (HR 1.58, 95% CI 0.92–2.70). Conclusion A prolonged period of deviation from the optimal PTH range was associated with increased all-cause mortality, particularly among patients not receiving SHPT medication. However, this effect was not observed in patients who received pharmacological interventions. These results suggest that early intervention is desirable when PTH levels vary from the optimal range in patients with secondary hyperparathyroidism.

The parathyroid gland plays an essential role in mineral and bone metabolism. A cultivation for physiological human parathyroid cells has yet to be established and the method by which parathyroid cells differentiate from pluripotent stem cells remains uncertain. Therefore, it has been hard to clarify the mechanisms underlying the onset of parathyroid disorders, such as hyperparathyroidism. Here, we developed a new method of parathyroid cell differentiation from human induced pluripotent stem (iPS) cells. The parathyroid cell differentiation occurred in accordance with embryologic development. The differentiated cells, which expressed parathyroid hormone, adopted a unique cell aggregation similar to the parathyroid gland. In addition, these differentiated cells were identified as calcium-sensing receptor (CaSR)/epithelial cell adhesion molecule (EpCAM) double-positive cells. Interestingly, stimulation with transforming growth factor-α (TGF-α), which is considered a causative molecule of parathyroid hyperplasia, increased the CaSR/EpCAM double-positive cells, but this effect was suppressed by erlotinib, which is an epidermal growth factor receptor (EGFR) inhibitor. These results suggest that TGF-α/EGFR signaling promotes parathyroid cell differentiation from iPS cells in a similar manner to parathyroid hyperplasia.

The peritoneum, which provides a slippery, nonadhesive, and protective surface for body cavities and internal organs, comprises peritoneal mesothelial cells (PMCs). Peritoneum is semipermeable, which makes it useful for performing peritoneal dialysis, but prolonged exposure to dialysate causes peritoneal adhesions. PMC replenishment could help treat adhesions in patients undergoing peritoneal dialysis; however, it is difficult to obtain a sufficient yields of PMCs to achieve this. Here, we developed a method for differentiating PMCs from human induced pluripotent stem cells (hiPSCs). The hiPSCs were initially differentiated to the intermediate lateral plate mesoderm (LPM) stage in the presence of FGF2 and BMP4. The LPM-stage cells were then differentiated into PMCs by activation of Wnt and retinoic acid signaling pathways and BMP inhibition. Expression of PMC markers verified correct cellular differentiation. Passaging of the induced PMCs (iPMCs) resulted in a uniform population of mature cells that were permeable to small molecules but only exhibited low permeability for large molecules. In addition, the iPMCs appeared to have regenerative and restorative properties. These findings suggest that iPMCs could help study human peritoneal function and be used for cell therapy in patients undergoing peritoneal dialysis.