Identification of mTEC precursor cells

Medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (Aire) are critical for preventing the onset of autoimmunity. However, the differentiation program of Aire-expressing mTECs (Aire+ mTECs) is unclear. Here, we describe novel embryonic precursors of Aire+ mTECs. We found the candidate precursors of Aire+ mTECs (pMECs) by monitoring the expression of receptor activator of nuclear factor-κB (RANK), which is required for Aire+ mTEC differentiation. pMECs unexpectedly expressed cortical TEC molecules in addition to the mTEC markers UEA-1 ligand and RANK and differentiated into mTECs in reaggregation thymic organ culture. Introduction of pMECs in the embryonic thymus permitted long-term maintenance of Aire+ mTECs and efficiently suppressed the onset of autoimmunity induced by Aire+ mTEC deficiency. Mechanistically, pMECs differentiated into Aire+ mTECs by tumor necrosis factor receptor-associated factor 6-dependent RANK signaling. Moreover, nonclassical nuclear factor-κB activation triggered by RANK and lymphotoxin-β receptor signaling promoted pMEC induction from progenitors exhibiting lower RANK expression and higher CD24 expression. Thus, our findings identified two novel stages in the differentiation program of Aire+ mTECs

Unphosphorylated and tyrosine-phosphorylated forms of a focal adhesion protein, paxillin, are substrates for calpain II in vitro: Implications for the possible involvement of calpain II in mitosis-specific degradation of paxillin

AbstractCell-to-substratum adhesion becomes weakened during mitosis of the cell cycle in fibroblasts. The level of one focal adhesion protein, paxillin, is greatly reduced in mitotic-arrested cells. We show here the possible involvement of calpain II, known to be localized in focal adhesion plaques, in the degradation of paxillin. Paxillin is tyrosine-phosphorylated during interphase of the cell cycle by protein tyrosine kinases (PTK) such as c-Src and Csk, and becomes dephosphorylated during mitosis. Our data, however, indicate that tyrosine phosphorylation of paxillin does not affect the rate of paxillin degradation by calpain in vitro

Pro-angiogenic scaffold-free Bio three-dimensional conduit developed from human induced pluripotent stem cell-derived mesenchymal stem cells promotes peripheral nerve regeneration

Although autologous nerve grafting is widely accepted as the gold standard treatment for segmental nerve defects, harvesting autologous nerves is highly invasive and leads to functional loss of the ablated part. In response, artificial nerve conduits made of artificial materials have been reported, but the efficacy of the nerve regeneration still needs improvement. The purpose of this study is to investigate the efficacy and mechanism of the Bio three-dimensional (3D) conduit composed of xeno-free human induced pluripotent stem cell-derived mesenchymal stem cells (iMSCs). The 5-mm nerve gap of the sciatic nerve in immunodeficient rats was bridged with the Bio 3D conduit or silicone tube. Functional and histological recovery were assessed at 8 weeks after surgery. The regenerated nerve in the Bio 3D group was significantly superior to that in the silicone group based on morphology, kinematics, electrophysiology, and wet muscle weight. Gene expression analyses demonstrated neurotrophic and angiogenic factors. Macroscopic observation revealed neovascularization both inside and on the surface of the Bio 3D conduit. Upon their subcutaneous implantation, iMSCs could induce angiogenesis. The Bio 3D conduit fabricated from iMSCs are an effective strategy for nerve regeneration in animal model. This technology will be useful in future clinical situations

Renal replacement therapy as a therapeutic option for right heart failure in severe pulmonary arterial hypertension

Abstract Pulmonary arterial hypertension (PAH) is a progressively life‐threatening disease that causes right heart failure (RHF). Renal dysfunction frequently complicates PAH with RHF and is associated with a worse prognosis. Renal replacement therapy (RRT) may be a therapeutic option, although its efficacy and safety are unclear. We describe a 30‐year‐old male with severe PAH who developed renal insufficiency and diuretic‐refractory volume overload complicated with RHF but was successfully managed with intermittent RRT via a subcutaneously fixed superficial artery for 4 years. RRT led to haemodynamic stability, which enabled us to carefully de‐titrate parenteral PAH drugs without worsening RHF. This case highlights that RRT may be a potential alternative for haemodynamic and volume control of refractory fluid retention complicated with RHF in severe PAH cases. Further studies are warranted to gain more insight into patient selection and the optimal timing of RRT in PAH patients with deteriorating RHF

Cardiac index predicts long-term outcomes in patients with heart failure.

BackgroundThe role of cardiac index (CI) and right atrial pressure (RAP) for predicting long-term outcomes of heart failure has not been well established. The aim of this study was to investigate long-term cardiac outcomes in patients with heart failure having various combinations of CI and RAP.MethodsA total of 787 heart failure patients who underwent right-heart catheterization were retrospectively categorized into the following four groups: Preserved CI (≥2.5 L/min/m2) and Low RAP (ResultsThe RED-CI/L-RAP and RED-CI/H-RAP groups were significantly associated with MACE as compared with the PRE-CI/L-RAP and PRE-CI/H-RAP groups after adjustment for confounding factors (RED-CI/L-RAP vs. PRE-CI/L-RAP: HR 2.11 [95% CI 1.33-3.37], p = 0.002; RED-CI/H-RAP vs. PRE-CI/L-RAP: HR 2.18 [95% CI 1.37-3.49], p = 0.001; RED-CI/L-RAP vs. PRE-CI/H-RAP: HR 1.86 [95% CI 1.16-3.00], p = 0.01; RED-CI/H-RAP vs. PRE-CI/H-RAP: HR 1.92 [95% CI 1.26-2.92], p = 0.002), whereas the difference between the RED-CI/H-RAP and RED-CI/L-RAP groups was not significant (HR 1.03 [95% CI 0.64-1.66], p = 0.89).ConclusionsThe hemodynamic severity categorized by CI and RAP levels provided clear risk stratification in patients with symptomatic heart failure. Low CI was an independent predictor of long-term cardiac outcomes